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Sample records for single-blind placebo-controlled dose-escalation

  1. Use of ChAd3-EBO-Z Ebola virus vaccine in Malian and US adults, and boosting of Malian adults with MVA-BN-Filo: a phase 1, single-blind, randomised trial, a phase 1b, open-label and double-blind, dose-escalation trial, and a nested, randomised, double-blind, placebo-controlled trial.

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    Tapia, Milagritos D; Sow, Samba O; Lyke, Kirsten E; Haidara, Fadima Cheick; Diallo, Fatoumata; Doumbia, Moussa; Traore, Awa; Coulibaly, Flanon; Kodio, Mamoudou; Onwuchekwa, Uma; Sztein, Marcelo B; Wahid, Rezwanul; Campbell, James D; Kieny, Marie-Paule; Moorthy, Vasee; Imoukhuede, Egeruan B; Rampling, Tommy; Roman, Francois; De Ryck, Iris; Bellamy, Abbie R; Dally, Len; Mbaya, Olivier Tshiani; Ploquin, Aurélie; Zhou, Yan; Stanley, Daphne A; Bailer, Robert; Koup, Richard A; Roederer, Mario; Ledgerwood, Julie; Hill, Adrian V S; Ballou, W Ripley; Sullivan, Nancy; Graham, Barney; Levine, Myron M

    2016-01-01

    The 2014 west African Zaire Ebola virus epidemic prompted worldwide partners to accelerate clinical development of replication-defective chimpanzee adenovirus 3 vector vaccine expressing Zaire Ebola virus glycoprotein (ChAd3-EBO-Z). We aimed to investigate the safety, tolerability, and immunogenicity of ChAd3-EBO-Z in Malian and US adults, and assess the effect of boosting of Malians with modified vaccinia Ankara expressing Zaire Ebola virus glycoprotein and other filovirus antigens (MVA-BN-Filo). In the phase 1, single-blind, randomised trial of ChAd3-EBO-Z in the USA, we recruited adults aged 18-65 years from the University of Maryland medical community and the Baltimore community. In the phase 1b, open-label and double-blind, dose-escalation trial of ChAd3-EBO-Z in Mali, we recruited adults 18-50 years of age from six hospitals and health centres in Bamako (Mali), some of whom were also eligible for a nested, randomised, double-blind, placebo-controlled trial of MVA-BN-Filo. For randomised segments of the Malian trial and for the US trial, we randomly allocated participants (1:1; block size of six [Malian] or four [US]; ARB produced computer-generated randomisation lists; clinical staff did randomisation) to different single doses of intramuscular immunisation with ChAd3-EBO-Z: Malians received 1 × 10(10) viral particle units (pu), 2·5 × 10(10) pu, 5 × 10(10) pu, or 1 × 10(11) pu; US participants received 1 × 10(10) pu or 1 × 10(11) pu. We randomly allocated Malians in the nested trial (1:1) to receive a single dose of 2 × 10(8) plaque-forming units of MVA-BN-Filo or saline placebo. In the double-blind segments of the Malian trial, investigators, clinical staff, participants, and immunology laboratory staff were masked, but the study pharmacist (MK), vaccine administrator, and study statistician (ARB) were unmasked. In the US trial, investigators were not masked, but participants were. Analyses were per protocol. The primary outcome was safety, measured

  2. Evaluation of homoeopathic treatment in polycystic ovary syndrome: A single-blind, randomised, placebo-controlled pilot study

    OpenAIRE

    Chetna Deep Lamba; Praveen Oberai; Raj K Manchanda; Padmalaya Rath; P Hima Bindu; Maya Padmanabhan

    2018-01-01

    Background and Objectives: This study was conducted with the primary objective of evaluating efficacy of Homoeopathy in establishing the menstrual regularity with improvement in either ultrasonological findings or hirsutism/acne. The quality of life was also assessed using polycystic ovary syndrome questionnaire (PCOSQ). Materials and Methods: A single-blind, randomised, placebo-controlled pilot study was conducted from February 2014 to May 2015 at two research centres. The cases fulfilling t...

  3. Treatment of Common Cold Patients with the Shi-Cha Capsule: A Multicenter, Double-Blind, Randomized, Placebo-Controlled, Dose-Escalation Trial

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    Chang, Jing; Dong, Shou-Jin; She, Bin; Zhang, Rui-Ming; Meng, Mao-Bin; Xu, Yan-Ling; Wan, Li-Ling; Shi, Ke-Hua; Pan, Jun-Hun; Mao, Bing

    2012-01-01

    This study was designed to determine the therapeutic efficacy and safety of the Shi-cha capsule, a Chinese herbal formula, in the treatment of patients with wind-cold type common cold. In our multi-center, prospective, double-blind, randomized, placebo-controlled, dose-escalation trial, patients with wind-cold type common cold received 0.6 g of Shi-cha capsule plus 0.6 g placebo (group A), 1.2 g of Shi-cha capsule (group B), or 1.2 g placebo (group C), three times daily for 3 days and followed up to 10 days. The primary end point was all symptom duration. The secondary end points were main symptom duration, minor symptom duration, the changes in cumulative symptom score, main symptom score, and minor symptom score 4 days after the treatment, as well as adverse events. A total of 377 patients were recruited and 360 met the inclusive criteria; 120 patients constituted each treatment group. Compared with patients in group C, patients in groups A and B had significant improvement in the all symptom duration, main symptom duration, minor symptom duration, as well as change from baseline of cumulative symptom score, main symptom score, and minor symptom score at day 4. The symptom durations and scores showed slight superiority of group B over group A, although these differences were not statistically significant. There were no differences in adverse events. The Shi-cha capsule is efficacious and safe for the treatment of patients with wind-cold type common cold. Larger trials are required to fully assess the benefits and safety of this treatment for common cold. PMID:23346193

  4. Effect of Auricular Acupress Therapy on Insomnia of Cancer Patients : Randomized, Single Blinded, Placebo Controlled Trial

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    In-Sook Jung

    2010-06-01

    Full Text Available Background: Auricular acupressure is one of the traditional health care treatments in oriental medicine. Approximately, 30~40% of the cancer patients have said to be suffering from insomnia and half of them having chronic and severe insomnia at the same time. Insomnia caused cancer patients feel more pain, fatigue, depression and anxiety and it sometimes let the power to have the best of cancer pull down. Objective: To investigate how effective the auricular acupressure treatment to cancer patients suffering from insomnia. Methods: We recruited participants from East-West Cancer Center of Daejeon University. Finally, of the people whose age range from 20 to 75, 12 patients who got less than 40 points from the score of Oh's sleeping score (OSS were recruited. Single-blind, randomized pilot study was performed. The treatment group received auricular acupressure treatment (AAT on active points and the control group had received sham acupressure treatment (SAT for five times. Sleep parameters were checked by using OSS and numeric rating scale (NRS. We checked the scale everytime, both before and after treatment. We analyzed the data statistically by using independent T-test, paired T-test and analysis of variance (ANOVA test. (p<0.05 Results: Twelve cancer patients participated in this pilot study and there was no significant difference between control and treatment group. Only 7 of them had completed the whole treatment process, 4 patients of AAT group and 3 participants of SAT. The OSS of AAT group had increased from 34.0± 4.3 to 39.5±3.1 and that of SAT group had increased from 38.3±3.5 to 40.0±0.0. There was no significant difference between them. The NRS of AAT group had increased from 6.3±2.9 to 4.8±2.1 and that of SAT group had increased from 7.0±1.0 to 5.0±2.6. No significant difference was observed between them. Conclusion: Although both groups did not show significant differences, most of the experimental participants showed

  5. Varenicline for opioid withdrawal in patients with chronic pain: a randomized, single-blinded, placebo controlled pilot trial.

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    Hooten, W Michael; Warner, David O

    2015-03-01

    The objectives of this randomized, single-blinded, placebo-controlled pilot trial were to investigate the effects of varenicline on opioid withdrawal among chronic pain patients undergoing opioid detoxification in an interdisciplinary pain program and the feasibility of varenicline use in this population. Twenty-one patients were recruited (varenicline=10, placebo=11), and 7 patients in the varenicline and 11 in the placebo group completed the study. Opioid withdrawal was quantified using the Clinical Opiate Withdrawal Scale, and varenicline-related adverse effects were assessed. Opioid withdrawal scores tended to decrease over the course of opioid tapering in those receiving varenicline and increase in those receiving placebo. Varenicline was well-tolerated in this population, with no adverse drug effects (including nausea) observed and no effect on improvements in pain severity and depression. This randomized pilot study provides preliminary data for future trials of varenicline in opioid-dependent adults with chronic pain undergoing medically directed opioid detoxification. Copyright © 2014 Elsevier Ltd. All rights reserved.

  6. Evaluation of homoeopathic treatment in polycystic ovary syndrome: A single-blind, randomised, placebo-controlled pilot study

    Directory of Open Access Journals (Sweden)

    Chetna Deep Lamba

    2018-01-01

    Full Text Available Background and Objectives: This study was conducted with the primary objective of evaluating efficacy of Homoeopathy in establishing the menstrual regularity with improvement in either ultrasonological findings or hirsutism/acne. The quality of life was also assessed using polycystic ovary syndrome questionnaire (PCOSQ. Materials and Methods: A single-blind, randomised, placebo-controlled pilot study was conducted from February 2014 to May 2015 at two research centres. The cases fulfilling the eligibility criteria were enrolled (n = 60 and randomised to either the homoeopathic intervention (HI (n = 30 or identical placebo (P (n = 30 with uniform lifestyle modification (LSM for 6 months. Results: The menstrual regularity with improvement in other signs/symptoms was observed in 60% of the cases (n = 18 in HI + LSM group and none (n = 0 in control group (P = 0.001. Statistically significant difference (P = 0.016 was observed in reduction of intermenstrual duration (from 76.1 ± 37.7 to 46.6 ± 38.7 days in HI + LSM in comparison to placebo + LSM group (from 93.0 ± 65.2 to 93.9 ± 96.2 days. In PCOSQ, also, significant improvement was observed in HI group in domains of weight, fertility, emotions and menstrual problems (P < 0.05 with no difference in body hair (P = 0.708. No change was observed in respect of improvement in the ultrasound findings. Pulsatilla was the most frequently indicated medicine (n = 12, 40%. Conclusion: HI along with LSM has shown promising outcome; further comparative study with standard conventional treatment on adequate sample size is desirable.

  7. Efficacy of the Power Balance Silicone Wristband: a single-blind, randomized, triple placebo-controlled study.

    Science.gov (United States)

    Pothier, David D; Thiel, Gundula; Khoo, S G; Dillon, Wanda A; Sulway, Shaleen; Rutka, John A

    2012-06-01

    The Power Balance Silicone Wristband (Power Balance LLC, Laguna Niguel, CA) (power balance band; PBB) consists of a silicone wristband, incorporating two holograms, which is meant to confer improvements in balance on the wearer. Despite its popularity, the PBB has become somewhat controversial, with a number of articles being published in the news media regarding its efficacy. The PBB has not been formally evaluated but remains popular, largely based on anecdotal evidence. This study subjectively and objectively measured the effects of the PBB on balance in normal participants. A prospective, single-blind, randomized, triple placebo-controlled crossover study was undertaken. Twenty participants underwent measurement using the modified Test of Sensory Interaction on Balance (mCTSIB) and gave subjective feedback (visual analogue scale [VAS]) for each of four band conditions: no band, a silicone band, a deactivated PBB, and the PBB. Participants acted as their own controls. The mean of the four mCTSIB conditions (eyes open and closed on both firm and compliant surfaces) was calculated. This mean value and condition 4 of the mCTSIB were compared between band conditions using path length (PL) and root mean square (RMS) as outcome measures. No significant differences were found between band conditions for PL (p  =  .91 and p  =  .94, respectively) and RMS (p  =  .85 and p  =  .96, respectively). VASs also showed no difference between bands (p  =  .25). The PBB appears to have no effect on mCTSIB or VAS measurements of balance.

  8. Immediate effects of kinesiotaping on quadriceps muscle strength: a single-blind, placebo-controlled crossover trial.

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    Vercelli, Stefano; Sartorio, Francesco; Foti, Calogero; Colletto, Lorenzo; Virton, Domenico; Ronconi, Gianpaolo; Ferriero, Giorgio

    2012-07-01

    To investigate the immediate effects on maximal muscle strength of kinesiotaping (KT) applied to the dominant quadriceps of healthy subjects. Single-blind, placebo-controlled crossover trial. "Salvatore Maugeri" Foundation. With ethical approval and informed consent, a convenience sample of 36 healthy volunteers were recruited. Two subjects did not complete the sessions and were excluded from the analysis. Subjects were tested across 3 different sessions, randomly receiving 2 experimental KT conditions applied with the aim of enhancing and inhibiting muscle strength and a sham KT application. Quadriceps muscle strength was measured by means of an isokinetic maximal test performed at 60 and 180 degrees per second. Two secondary outcome measures were performed: the single-leg triple hop for distance to measure limb performance and the Global Rating of Change Scale (GRCS) to calculate agreement between KT application and subjective perception of strength. Compared with baseline, none of the 3 taping conditions showed a significant change in muscle strength and performance (all P > 0.05). Effect size was very low under all conditions (≤0.08). Very few subjects showed an individual change greater than the minimal detectable change. Global Rating of Change Scale scores demonstrated low to moderate agreement with the type of KT applied, but some placebo effects were reported independently of condition. Our findings indicated no significant effect in the maximal quadriceps strength immediately after the application of inhibition, facilitation, or sham KT. These results do not support the use of KT applied in this way to change maximal muscle strength in healthy people.

  9. First-In-Human, Double-Blind, Placebo-Controlled, Randomized, Dose-Escalation Study of BG00010, a Glial Cell Line-Derived Neurotrophic Factor Family Member, in Subjects with Unilateral Sciatica.

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    Rolan, Paul E; O'Neill, Gilmore; Versage, Eve; Rana, Jitesh; Tang, Yongqiang; Galluppi, Gerald; Aycardi, Ernesto

    2015-01-01

    To evaluate the safety, tolerability, and pharmacokinetics of single doses of BG00010 (neublastin, artemin, enovin) in subjects with unilateral sciatica. This was a single-center, blinded, placebo-controlled, randomized Phase 1 sequential-cohort, dose-escalation study (ClinicalTrials.gov identifier NCT00961766; funded by Biogen Idec). Adults with unilateral sciatica were enrolled at The Royal Adelaide Hospital, Australia. Four subjects were assigned to each of eleven cohorts (intravenous BG00010 0.3, 1, 3, 10, 25, 50, 100, 200, 400, or 800 μg/kg, or subcutaneous BG00010 50 μg/kg) and were randomized 3:1 to receive a single dose of BG00010 or placebo. The primary safety and tolerability assessments were: adverse events; clinical laboratory parameters and vital signs; pain as measured by a Likert rating scale; intra-epidermal nerve fiber density; and longitudinal assessment of quantitative sensory test parameters. Blood, serum, and plasma samples were collected for pharmacokinetic and pharmacodynamic assessments. Subjects were blinded to treatment assignment throughout the study. The investigator was blinded to treatment assignment until the Data Safety Review Committee review of unblinded data, which occurred after day 28. Beyond the planned enrollment of 44 subjects, four additional subjects were enrolled into to the intravenous BG00010 200 μg/kg cohort after one original subject experienced mild generalized pruritus. Therefore, a total of 48 subjects were enrolled between August 2009 and December 2011; all were included in the safety analyses. BG00010 was generally well tolerated: in primary analyses, the most common treatment-emergent adverse events were changes in temperature perception, pruritus, rash, or headache; no trends were observed in clinical laboratory parameters, vital signs, intra-epidermal nerve fiber density, or quantitative sensory testing. BG00010 was not associated with any clear, dose-dependent trends in Likert pain scores. BG00010 was

  10. Impact of selected magnetic fields on the therapeutic effect in patients with lumbar discopathy: A prospective, randomized, single-blinded, and placebo-controlled clinical trial.

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    Taradaj, Jakub; Ozon, Marcin; Dymarek, Robert; Bolach, Bartosz; Walewicz, Karolina; Rosińczuk, Joanna

    2018-03-23

    Interdisciplinary physical therapy together with pharmacological treatment constitute conservative treatment strategies related to low back pain (LBP). There is still a lack of high quality studies aimed at an objective evaluation of physiotherapeutic procedures according to their effectiveness in LBP. The aim of this study is to carry out a prospective, randomized, single-blinded, and placebocontrolled clinical trial to evaluate the effectiveness of magnetic fields in discopathy-related LBP. A group of 177 patients was assessed for eligibility based on inclusion and exclusion criteria. In the end, 106 patients were randomly assigned into 5 comparative groups: A (n = 23; magnetic therapy: 10 mT, 50 Hz); B (n = 23; magnetic therapy: 5 mT, 50 Hz); C (n = 20; placebo magnetic therapy); D (n = 20; magnetic stimulation: 49.2 μT, 195 Hz); and E (n = 20; placebo magnetic stimulation). All patients were assessed using tests for pain intensity, degree of disability and range of motion. Also, postural stability was assessed using a stabilographic platform. In this study, positive changes in all clinical outcomes were demonstrated in group A (p 0.05). It was determined that the application of magnetic therapy (10 mT, 50 Hz, 20 min) significantly reduces pain symptoms and leads to an improvement of functional ability in patients with LBP.

  11. Effect of Aromatherapy with Peppermint Oil on the Severity of Nausea and Vomiting in Pregnancy: A Single-blind, Randomized, Placebo-controlled trial.

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    Joulaeerad, Narges; Ozgoli, Giti; Hajimehdipoor, Homa; Ghasemi, Erfan; Salehimoghaddam, Fatemeh

    2018-01-01

    Nausea and vomiting are common complaints in the first half of pregnancy. These symptoms can significantly affect a person's personal and professional life. Aromatherapy is one of the types of complementary medicine that is used in the treatment of nausea and vomiting. The objective of this study was to determine the effect of aromatherapy with peppermint oil on the severity of nausea and vomiting of pregnancy (NVP). This was a single-blind clinical trial that was conducted on 56 pregnant women with mild to moderate severity of NVP and 6 to 20 weeks of gestational age. After the determination of gestational age and base severity of NVP in each woman, they were randomly assigned to one of the two groups: peppermint oil (n=28) or placebo (n=28). Inhalation aromatherapy was done for four days and at the end of each day, they responded to the Pregnancy Unique Quantification of Emesis/Nausea questionnaire (PUQE). The data obtained were analyzed with Mann-Whitney test and ANOVA with repeated measures using SPSS software version 22. Also, the level of significance was paromatherapy with peppermint oil and placebo were the same in this study. This similarity can be due to psychological impacts of intervention on pregnant women.

  12. Effects of fixed orthodontic treatment and two new mouth rinses on gingival health: A prospective cohort followed by a single-blind placebo-controlled randomized clinical trial.

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    Sobouti, Farhad; Rakhshan, Vahid; Heydari, Mohaddeseh; Keikavusi, Shohreh; Dadgar, Sepideh; Shariati, Mahsa

    2018-03-01

    Routine brushing protocols might not suffice to reduce the increased plaque accumulation in orthodontic patients. Antimicrobial mouth rinses are favorable in this regard. This two-phase study evaluated the effects of orthodontic treatment and the application of two mouthwashes not studied before on oral health indices. In this two-phase study (a prospective cohort followed by a parallel randomized controlled trial), plaque index (PI), gingival index (GI), gingival bleeding index (GBI), and pocket probing depth (PPD) were measured in 54 orthodontic patients before orthodontic treatment and 4 months later. Then patients were randomized into three groups of mouthrinses: Persica (herbal), Ortho-Kin (containing diluted chlorhexidine), and Placebo (n=18×3). The effects of orthodontic treatment and mouthrinses were analyzed statistically (α=0.05). All the 4 indices increased between the baseline and 4th month of treatment (P values<0.01, paired t-test). They decreased back to baseline levels or below them, after one month of mouthwash application (P values<0.002). Both mouthwashes showed therapeutic effects compared to placebo in terms of PI and GBI. In the case of GI, only Persica showed significantly better results compared to placebo. Regarding PPD, only Ortho-Kin acted better than placebo (P values≤0.05, Tukey). Lack of positive control (regular chlorhexidine mouth rinse) and negative control (a group with no mouthwashes, even without the placebo). Lack of sample size predetermination based on a priori power calculations. The difference between the regime of Persica with that of Ortho-Kin and placebo (which had similar application protocols) disallowed perfectly effective blinding of the patients (hence, single-blind). Fixed orthodontic treatment might disrupt gingival health. Antimicrobial mouthwashes might reverse this. Both evaluated mouthwashes might have therapeutic effects. Copyright © 2018 CEO. Published by Elsevier Masson SAS. All rights reserved.

  13. MOR103, a human monoclonal antibody to granulocyte–macrophage colony-stimulating factor, in the treatment of patients with moderate rheumatoid arthritis: results of a phase Ib/IIa randomised, double-blind, placebo-controlled, dose-escalation trial

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    Behrens, Frank; Tak, Paul P; Østergaard, Mikkel; Stoilov, Rumen; Wiland, Piotr; Huizinga, Thomas W; Berenfus, Vadym Y; Vladeva, Stoyanka; Rech, Juergen; Rubbert-Roth, Andrea; Korkosz, Mariusz; Rekalov, Dmitriy; Zupanets, Igor A; Ejbjerg, Bo J; Geiseler, Jens; Fresenius, Julia; Korolkiewicz, Roman P; Schottelius, Arndt J; Burkhardt, Harald

    2015-01-01

    Objectives To determine the safety, tolerability and signs of efficacy of MOR103, a human monoclonal antibody to granulocyte–macrophage colony-stimulating factor (GM-CSF), in patients with rheumatoid arthritis (RA). Methods Patients with active, moderate RA were enrolled in a randomised, multicentre, double-blind, placebo-controlled, dose-escalation trial of intravenous MOR103 (0.3, 1.0 or 1.5 mg/kg) once a week for 4 weeks, with follow-up to 16 weeks. The primary outcome was safety. Results Of the 96 randomised and treated subjects, 85 completed the trial (n=27, 24, 22 and 23 for pooled placebo and MOR103 0.3, 1.0 and 1.5 mg/kg, respectively). Treatment emergent adverse events (AEs) in the MOR103 groups were mild or moderate in intensity and generally reported at frequencies similar to those in the placebo group. The most common AE was nasopharyngitis. In two cases, AEs were classified as serious because of hospitalisation: paronychia in a placebo subject and pleurisy in a MOR103 0.3 mg/kg subject. Both patients recovered fully. In exploratory efficacy analyses, subjects in the MOR103 1.0 and 1.5 mg/kg groups showed significant improvements in Disease Activity Score-28 scores and joint counts and significantly higher European League Against Rheumatism response rates than subjects receiving placebo. MOR103 1.0 mg/kg was associated with the largest reductions in disease activity parameters. Conclusions MOR103 was well tolerated and showed preliminary evidence of efficacy in patients with active RA. The data support further investigation of this monoclonal antibody to GM-CSF in RA patients and potentially in those with other immune-mediated inflammatory diseases. Trial registration number NCT01023256 PMID:24534756

  14. Safety, immunogenicity, and tolerability of meningococcal serogroup B bivalent recombinant lipoprotein 2086 vaccine in healthy adolescents: a randomised, single-blind, placebo-controlled, phase 2 trial.

    Science.gov (United States)

    Richmond, Peter C; Marshall, Helen S; Nissen, Michael D; Jiang, Qin; Jansen, Kathrin U; Garcés-Sánchez, Maria; Martinón-Torres, Federico; Beeslaar, Johannes; Szenborn, Leszek; Wysocki, Jacek; Eiden, Joseph; Harris, Shannon L; Jones, Thomas R; Perez, John L

    2012-08-01

    Neisseria meningitidis serogroup B is a major cause of invasive meningococcal disease, but a broadly protective vaccine is not currently licensed. A bivalent recombinant factor H-binding protein vaccine (recombinant lipoprotein 2086) has been developed to provide broad coverage against diverse invasive meningococcus serogroup B strains. Our aim was to test the immune response of this vaccine. This randomised, placebo-controlled trial enrolled healthy adolescents from 25 sites in Australia, Poland, and Spain. Exclusion criteria were previous invasive meningococcal disease or serogroup B vaccination, previous adverse reaction or known hypersensitivity to the vaccine, any significant comorbidities, and immunosuppressive therapy or receipt of blood products in the past 6 months. Participants were randomly assigned with a computerised block randomisation scheme to receive ascending doses of vaccine (60, 120, or 200 μg) or placebo at 0, 2, and 6 months. Principal investigators, participants and their guardians, and laboratory personnel were masked to the allocation; dispensing staff were not. Immunogenicity was measured by serum bactericidal assays using human complement (hSBA) against eight diverse meningococcus serogroup B strains. The co-primary endpoints were seroconversion for the two indicator strains (PMB1745 and PMB17) analysed by the Clopper-Pearson method. Local and systemic reactions and adverse events were recorded. The study is registered at ClinicalTrials.gov, number NCT00808028. 539 participants were enrolled and 511 received all three study vaccinations--116 in the placebo group, 21 in the 60 μg group, 191 in the 120 μg group, and 183 in the 200 μg group. The proportion of participants responding with an hSBA titre equal to or greater than the lower limit of quantitation of the hSBA assays (reciprcocal titres of 7 to 18, depending on test strain) was similar for the two largest doses and ranged from 75·6 to 100·0% for the 120 μg dose and 67·9 to

  15. MOR103, a human monoclonal antibody to granulocyte-macrophage colony-stimulating factor, in the treatment of patients with moderate rheumatoid arthritis: results of a phase Ib/IIa randomised, double-blind, placebo-controlled, dose-escalation trial.

    Science.gov (United States)

    Behrens, Frank; Tak, Paul P; Østergaard, Mikkel; Stoilov, Rumen; Wiland, Piotr; Huizinga, Thomas W; Berenfus, Vadym Y; Vladeva, Stoyanka; Rech, Juergen; Rubbert-Roth, Andrea; Korkosz, Mariusz; Rekalov, Dmitriy; Zupanets, Igor A; Ejbjerg, Bo J; Geiseler, Jens; Fresenius, Julia; Korolkiewicz, Roman P; Schottelius, Arndt J; Burkhardt, Harald

    2015-06-01

    To determine the safety, tolerability and signs of efficacy of MOR103, a human monoclonal antibody to granulocyte-macrophage colony-stimulating factor (GM-CSF), in patients with rheumatoid arthritis (RA). Patients with active, moderate RA were enrolled in a randomised, multicentre, double-blind, placebo-controlled, dose-escalation trial of intravenous MOR103 (0.3, 1.0 or 1.5 mg/kg) once a week for 4 weeks, with follow-up to 16 weeks. The primary outcome was safety. Of the 96 randomised and treated subjects, 85 completed the trial (n=27, 24, 22 and 23 for pooled placebo and MOR103 0.3, 1.0 and 1.5 mg/kg, respectively). Treatment emergent adverse events (AEs) in the MOR103 groups were mild or moderate in intensity and generally reported at frequencies similar to those in the placebo group. The most common AE was nasopharyngitis. In two cases, AEs were classified as serious because of hospitalisation: paronychia in a placebo subject and pleurisy in a MOR103 0.3 mg/kg subject. Both patients recovered fully. In exploratory efficacy analyses, subjects in the MOR103 1.0 and 1.5 mg/kg groups showed significant improvements in Disease Activity Score-28 scores and joint counts and significantly higher European League Against Rheumatism response rates than subjects receiving placebo. MOR103 1.0 mg/kg was associated with the largest reductions in disease activity parameters. MOR103 was well tolerated and showed preliminary evidence of efficacy in patients with active RA. The data support further investigation of this monoclonal antibody to GM-CSF in RA patients and potentially in those with other immune-mediated inflammatory diseases. NCT01023256. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  16. Alga Ecklonia bicyclis, Tribulus terrestris, and Glucosamine Oligosaccharide Improve Erectile Function, Sexual Quality of Life, and Ejaculation Function in Patients with Moderate Mild-Moderate Erectile Dysfunction: A Prospective, Randomized, Placebo-Controlled, Single-Blinded Study

    Science.gov (United States)

    Sansalone, Salvatore; Leonardi, Rosario; Antonini, Gabriele; Vitarelli, Antonio; Vespasiani, Giuseppe

    2014-01-01

    We aimed to evaluate the efficacy of oral therapy with alga Ecklonia bicyclis, Tribulus terrestris, and glucosamine oligosaccharide (Tradamix TX1000) in patients with erectile dysfunction (ED) at 3 months of follow-up. From January 2013 to September 2013, 177 patients diagnosed with mild-moderate ED (IIEF-EF < 26) were enrolled in this multicenter, single-blinded, placebo-controlled study and randomized in Group A (Tradamix, n = 87) and Group B (placebo, n = 90). Penile color Doppler ultrasound measures, IIEF-15 questionnaire, male sexual health questionnaire-ejaculation disorder (MSHQ-EjD), and sexual quality of life (SQoL-M) were collected. We observed significant changes of the IIEF-15 in Group A (mean difference: 11.54; P < 0.05) at 3 months versus Group B (P < 0.05). PSV (P < 0.05), IIEF-intercourse satisfaction (P < 0.05), IIEF-orgasmic function (mean P < 0.05), IIEF-sexual desire (P < 0.05), IIEF-overall satisfaction (P < 0.05), MSHQ-EjD (mean difference: 1.21; P < 0.05), and SQoL-M (mean difference: 10.2; P < 0.05) were significantly changed in Group A versus baseline and Group B. Patients with moderate arterial dysfunction showed significant increase of PSV (P < 0.05), IIEF-EF (P < 0.05), MSHQ-EjD (P < 0.05), and SQoL-M (P < 0.05) in Group A. Therapy with Tradamix improves erectile and ejaculation function and sexual quality of life in patients with mild-moderate ED and in particular for those with moderate arterial dysfunction. PMID:25136552

  17. Alga Ecklonia bicyclis, Tribulus terrestris, and Glucosamine Oligosaccharide Improve Erectile Function, Sexual Quality of Life, and Ejaculation Function in Patients with Moderate Mild-Moderate Erectile Dysfunction: A Prospective, Randomized, Placebo-Controlled, Single-Blinded Study

    Directory of Open Access Journals (Sweden)

    Salvatore Sansalone

    2014-01-01

    Full Text Available We aimed to evaluate the efficacy of oral therapy with alga Ecklonia bicyclis, Tribulus terrestris, and glucosamine oligosaccharide (Tradamix TX1000 in patients with erectile dysfunction (ED at 3 months of follow-up. From January 2013 to September 2013, 177 patients diagnosed with mild-moderate ED (IIEF-EF < 26 were enrolled in this multicenter, single-blinded, placebo-controlled study and randomized in Group A (Tradamix, n=87 and Group B (placebo, n=90. Penile color Doppler ultrasound measures, IIEF-15 questionnaire, male sexual health questionnaire-ejaculation disorder (MSHQ-EjD, and sexual quality of life (SQoL-M were collected. We observed significant changes of the IIEF-15 in Group A (mean difference: 11.54; P<0.05 at 3 months versus Group B (P<0.05. PSV (P<0.05, IIEF-intercourse satisfaction (P<0.05, IIEF-orgasmic function (mean P<0.05, IIEF-sexual desire (P<0.05, IIEF-overall satisfaction (P<0.05, MSHQ-EjD (mean difference: 1.21; P<0.05, and SQoL-M (mean difference: 10.2; P<0.05 were significantly changed in Group A versus baseline and Group B. Patients with moderate arterial dysfunction showed significant increase of PSV (P<0.05, IIEF-EF (P<0.05, MSHQ-EjD (P<0.05, and SQoL-M (P<0.05 in Group A. Therapy with Tradamix improves erectile and ejaculation function and sexual quality of life in patients with mild-moderate ED and in particular for those with moderate arterial dysfunction.

  18. Alga Ecklonia bicyclis, Tribulus terrestris, and glucosamine oligosaccharide improve erectile function, sexual quality of life, and ejaculation function in patients with moderate mild-moderate erectile dysfunction: a prospective, randomized, placebo-controlled, single-blinded study.

    Science.gov (United States)

    Sansalone, Salvatore; Leonardi, Rosario; Antonini, Gabriele; Vitarelli, Antonio; Vespasiani, Giuseppe; Basic, Dragoslav; Morgia, Giuseppe; Cimino, Sebastiano; Russo, Giorgio Ivan

    2014-01-01

    We aimed to evaluate the efficacy of oral therapy with alga Ecklonia bicyclis, Tribulus terrestris, and glucosamine oligosaccharide (Tradamix TX1000) in patients with erectile dysfunction (ED) at 3 months of follow-up. From January 2013 to September 2013, 177 patients diagnosed with mild-moderate ED (IIEF-EF < 26) were enrolled in this multicenter, single-blinded, placebo-controlled study and randomized in Group A (Tradamix, n = 87) and Group B (placebo, n = 90). Penile color Doppler ultrasound measures, IIEF-15 questionnaire, male sexual health questionnaire-ejaculation disorder (MSHQ-EjD), and sexual quality of life (SQoL-M) were collected. We observed significant changes of the IIEF-15 in Group A (mean difference: 11.54; P < 0.05) at 3 months versus Group B (P < 0.05). PSV (P < 0.05), IIEF-intercourse satisfaction (P < 0.05), IIEF-orgasmic function (mean P < 0.05), IIEF-sexual desire (P < 0.05), IIEF-overall satisfaction (P < 0.05), MSHQ-EjD (mean difference: 1.21; P < 0.05), and SQoL-M (mean difference: 10.2; P < 0.05) were significantly changed in Group A versus baseline and Group B. Patients with moderate arterial dysfunction showed significant increase of PSV (P < 0.05), IIEF-EF (P < 0.05), MSHQ-EjD (P < 0.05), and SQoL-M (P < 0.05) in Group A. Therapy with Tradamix improves erectile and ejaculation function and sexual quality of life in patients with mild-moderate ED and in particular for those with moderate arterial dysfunction.

  19. Effect of single-dose low-level helium-neon laser irradiation on orthodontic pain: a split-mouth single-blind placebo-controlled randomized clinical trial.

    Science.gov (United States)

    Sobouti, Farhad; Khatami, Maziar; Chiniforush, Nasim; Rakhshan, Vahid; Shariati, Mahsa

    2015-01-01

    Pain is the most common complication of orthodontic treatment. Low-level laser therapy (LLLT) has been suggested as a new analgesic treatment free of the adverse effects of analgesic medications. However, it is not studied thoroughly, and the available studies are quite controversial. Moreover, helium neon (He-Ne) laser has not been assessed before. This split-mouth placebo-controlled randomized clinical trial was performed on 16 male and 14 female orthodontic patients requiring bilateral upper canine retraction. The study was performed at a private clinic in Sari, Iran, in 2014. It was single blind: patients, orthodontist, and personnel were blinded of the allocations, but the laser operator (periodontist) was not blinded. Once canine retractor was activated, a randomly selected maxillary quarter received a single dose of He-Ne laser irradiation (632.8 nm, 10 mw, 6 j/cm(2) density). The other quarter served as the placebo side, treated by the same device but powered off. In the first, second, fourth, and seventh days, blinded patients rated their pain sensed on each side at home using visual analog scale (VAS) questionnaires. There was no harm identified during or after the study. Pain changes were analyzed using two- and one-way repeated-measures ANOVA, Bonferroni, and t-test (α = 0.01, β > 0.99). This trial was not registered. It was self-funded by the authors. Sixteen males and 11 females remained in the study (aged 12-21). Average pain scores sensed in all 4 intervals on control and laser sides were 4.06 ± 2.85 and 2.35 ± 1.77, respectively (t-test P < 0.0001). One-way ANOVA showed significant pain declines over time, in each group (P < 0.0001). Two-way ANOVA showed significant effects for LLLT (P < 0.0001) and time (P = <0.0001). Single-dose He-Ne laser therapy might reduce orthodontic pain caused by retracting maxillary canines.

  20. A randomized, placebo-controlled, single-blinded, split-faced clinical trial evaluating the efficacy and safety of KLOX-001 gel formulation with KLOX light-emitting diode light on facial rejuvenation

    Directory of Open Access Journals (Sweden)

    Nikolis A

    2016-05-01

    Full Text Available Andreas Nikolis,1 Steven Bernstein,2 Brian Kinney,3 Nicolo Scuderi,4 Shipra Rastogi,5 John S Sampalis6 1Victoria Park, Plastic Surgery Section, Westmount, QC, Canada; 2Dermatology Department, University of Montreal Health Centre, Montreal, QC, Canada; 3Department of Plastic Surgery, USC School of Medicine, Beverley Hills, CA, USA; 4Department of Plastic and Reconstructive Surgery, La Sapienza, Rome, Italy; 5KLOX Technologies, Laval, 6JSS Medical Research, Montreal, QC, Canada Purpose: Many treatment modalities exist to counteract the effects of cutaneous aging. Ablative methods have been the mainstay for nonsurgical facial rejuvenation. In recent years, nonablative techniques have been developed with the aim of achieving facial rejuvenation without epidermal damage. Light-emitting diode (LED photorejuvenation is a novel nonablative technique that induces collagen synthesis through biophotomodulatory pathways. Materials and methods: A single-center, randomized, single-blinded, placebo-controlled, split-faced clinical trial was designed. Thirty-two patients were enrolled for a 12-week study. Patients were randomized into one of four groups: Group A, treatment with KLOX-001 gel formulation and white LED (placebo light; Group B, treatment with a placebo/base gel (no active chromophore formulation and KLOX LED light; Group C, treatment with KLOX-001 gel formulation and KLOX LED light; and Group D, treatment with the standard skin rejuvenating treatment (0.1% retinol-based cream. Patients received treatment at weeks 0, 1, 2, and 3, and returned to the clinic at weeks 4, 8, and 12 for clinical assessments performed by an independent, blinded committee of physicians using subjective clinician assessment scales. Tolerability, adverse outcomes, and patient satisfaction were also assessed. Results: Analysis demonstrated that the KLOX LED light with KLOX placebo/base gel and the KLOX LED light + KLOX-001 gel formulation groups were superior to standard of

  1. Meningococcal serogroup B-specific responses after vaccination with bivalent rLP2086: 4 year follow-up of a randomised, single-blind, placebo-controlled, phase 2 trial.

    Science.gov (United States)

    Marshall, Helen S; Richmond, Peter C; Beeslaar, Johannes; Jiang, Qin; Jansen, Kathrin U; Garcés-Sánchez, Maria; Martinón-Torres, Federico; Szenborn, Leszek; Wysocki, Jacek; Eiden, Joseph; Harris, Shannon L; Jones, Thomas R; Lee, Su-San; Perez, John L

    2017-01-01

    Bivalent rLP2086 is a recombinant factor H binding protein-based vaccine approved in the USA for prevention of meningococcal serogroup B disease in 10-25-year-olds. We aimed to assess the persistence of bactericidal antibodies up to 4 years after a three-dose schedule of bivalent rLP2086. We did this randomised, single-blind, placebo-controlled, phase 2 trial at 25 sites in Australia, Poland, and Spain. In stage 1 of the study (February, 2009-May, 2010), healthy adolescents (aged 11-18 years) were randomly assigned, via an interactive voice and web-response system with computer-generated sequential random numbers, to receive either ascending doses of vaccine (60 μg, 120 μg, and 200 μg) or placebo at months 0, 2, and 6. Dispensing staff were not masked to group allocation, but allocation was concealed from principal investigators, participants and their guardians, and laboratory personnel. In stage 2 of the study (reported here), we enrolled healthy adolescents who had received three doses of 120 μg bivalent rLP2086 (the optimum dose level identified in stage 1) or saline. Immunogenicity was determined in serum bactericidal antibody assay using human complement (hSBA) by use of four meningococcal serogroup B test strains expressing vaccine-heterologous factor H binding protein variants: PMB80 (A22), PMB2001 (A56), PMB2948 (B24), and PMB2707 (B44). Immunogenicity in stage 2 was assessed at months 6, 12, 24, and 48 post-vaccination. We did analysis by intention to treat. This trial is registered as ClinicalTrials.gov number NCT00808028. Between March 17, 2010, and Feb 8, 2011, 170 participants who received 120 μg of bivalent rLP2086 and 80 participants who received placebo in stage 1 of the study were entered into stage 2; 210 participants completed stage 2 up to 48 months. 1 month after the third vaccination, 93% (n=139/149) to 100% (n=48/48) of vaccine recipients achieved protective hSBA titres equal to or greater than the lower limit of quantification to each

  2. Dose escalation of a curcuminoid formulation

    Directory of Open Access Journals (Sweden)

    Crowell James

    2006-03-01

    Full Text Available Abstract Background Curcumin is the major yellow pigment extracted from turmeric, a commonly-used spice in India and Southeast Asia that has broad anticarcinogenic and cancer chemopreventive potential. However, few systematic studies of curcumin's pharmacology and toxicology in humans have been performed. Methods A dose escalation study was conducted to determine the maximum tolerated dose and safety of a single dose of standardized powder extract, uniformly milled curcumin (C3 Complex™, Sabinsa Corporation. Healthy volunteers were administered escalating doses from 500 to 12,000 mg. Results Seven of twenty-four subjects (30% experienced only minimal toxicity that did not appear to be dose-related. No curcumin was detected in the serum of subjects administered 500, 1,000, 2,000, 4,000, 6,000 or 8,000 mg. Low levels of curcumin were detected in two subjects administered 10,000 or 12,000 mg. Conclusion The tolerance of curcumin in high single oral doses appears to be excellent. Given that achieving systemic bioavailability of curcumin or its metabolites may not be essential for colorectal cancer chemoprevention, these findings warrant further investigation for its utility as a long-term chemopreventive agent.

  3. Strategies for Biologic Image-Guided Dose Escalation: A Review

    International Nuclear Information System (INIS)

    Sovik, Aste; Malinen, Eirik; Olsen, Dag Rune

    2009-01-01

    There is increasing interest in how to incorporate functional and molecular information obtained by noninvasive, three-dimensional tumor imaging into radiotherapy. The key issues are to identify radioresistant regions that can be targeted for dose escalation, and to develop radiation dose prescription and delivery strategies providing optimal treatment for the individual patient. In the present work, we review the proposed strategies for biologic image-guided dose escalation with intensity-modulated radiation therapy. Biologic imaging modalities and the derived images are discussed, as are methods for target volume delineation. Different dose escalation strategies and techniques for treatment delivery and treatment plan evaluation are also addressed. Furthermore, we consider the need for response monitoring during treatment. We conclude with a summary of the current status of biologic image-based dose escalation and of areas where further work is needed for this strategy to become incorporated into clinical practice

  4. Dose Escalation Methods in Phase I Cancer Clinical Trials

    OpenAIRE

    Le Tourneau, Christophe; Lee, J. Jack; Siu, Lillian L.

    2009-01-01

    Phase I clinical trials are an essential step in the development of anticancer drugs. The main goal of these studies is to establish the recommended dose and/or schedule of new drugs or drug combinations for phase II trials. The guiding principle for dose escalation in phase I trials is to avoid exposing too many patients to subtherapeutic doses while preserving safety and maintaining rapid accrual. Here we review dose escalation methods for phase I trials, including the rule-based and model-...

  5. Dose escalation methods in phase I cancer clinical trials.

    Science.gov (United States)

    Le Tourneau, Christophe; Lee, J Jack; Siu, Lillian L

    2009-05-20

    Phase I clinical trials are an essential step in the development of anticancer drugs. The main goal of these studies is to establish the recommended dose and/or schedule of new drugs or drug combinations for phase II trials. The guiding principle for dose escalation in phase I trials is to avoid exposing too many patients to subtherapeutic doses while preserving safety and maintaining rapid accrual. Here we review dose escalation methods for phase I trials, including the rule-based and model-based dose escalation methods that have been developed to evaluate new anticancer agents. Toxicity has traditionally been the primary endpoint for phase I trials involving cytotoxic agents. However, with the emergence of molecularly targeted anticancer agents, potential alternative endpoints to delineate optimal biological activity, such as plasma drug concentration and target inhibition in tumor or surrogate tissues, have been proposed along with new trial designs. We also describe specific methods for drug combinations as well as methods that use a time-to-event endpoint or both toxicity and efficacy as endpoints. Finally, we present the advantages and drawbacks of the various dose escalation methods and discuss specific applications of the methods in developmental oncotherapeutics.

  6. Increasing Use of Dose-Escalated External Beam Radiation Therapy for Men With Nonmetastatic Prostate Cancer

    International Nuclear Information System (INIS)

    Swisher-McClure, Samuel; Mitra, Nandita; Woo, Kaitlin; Smaldone, Marc; Uzzo, Robert; Bekelman, Justin E.

    2014-01-01

    Purpose: To examine recent practice patterns, using a large national cancer registry, to understand the extent to which dose-escalated external beam radiation therapy (EBRT) has been incorporated into routine clinical practice for men with prostate cancer. Methods and Materials: We conducted a retrospective observational cohort study using the National Cancer Data Base, a nationwide oncology outcomes database in the United States. We identified 98,755 men diagnosed with nonmetastatic prostate cancer between 2006 and 2011 who received definitive EBRT and classified patients into National Comprehensive Cancer Network (NCCN) risk groups. We defined dose-escalated EBRT as total prescribed dose of ≥75.6 Gy. Using multivariable logistic regression, we examined the association of patient, clinical, and demographic characteristics with the use of dose-escalated EBRT. Results: Overall, 81.6% of men received dose-escalated EBRT during the study period. The use of dose-escalated EBRT did not vary substantially by NCCN risk group. Use of dose-escalated EBRT increased from 70.7% of patients receiving treatment in 2006 to 89.8% of patients receiving treatment in 2011. On multivariable analysis, year of diagnosis and use of intensity modulated radiation therapy were significantly associated with receipt of dose-escalated EBRT. Conclusions: Our study results indicate that dose-escalated EBRT has been widely adopted by radiation oncologists treating prostate cancer in the United States. The proportion of patients receiving dose-escalated EBRT increased nearly 20% between 2006 and 2011. We observed high utilization rates of dose-escalated EBRT within all disease risk groups. Adoption of intensity modulated radiation therapy was strongly associated with use of dose-escalated treatment

  7. Early termination of prostate cancer hyperfractionated dose escalation study

    International Nuclear Information System (INIS)

    Forman, Jeffrey D; Porter, Arthur T; Kocheril, Paul; Grignon, David; Orton, Colin

    1996-01-01

    Purpose: This study was initiated to determine the maximum tolerable dose of hyperfractionated radiation in patients with locally advanced prostate cancer. Materials and Methods: Forty-nine patients with locally advanced prostate cancer (T3-T4 Nx, 0, 1 M0 and/or Gleason Score ≥ 8) were treated on the first two steps of a prospective dose-escalation study using hyperfractionated conformal radiotherapy. The first 25 patients received a minimum dose of 78Gy to the clinical tumor volume (CTV) including the prostate, seminal vesicle and a 5mm margin at 1.3Gy b.i.d. The second group (24 patients) received a minimum dose to the CTV of 82.8Gy at 1.15Gy b.i.d. Twenty eight patients received neo-adjuvant hormonal therapy in conjunction with their radiation (8 of 25 patients at 78Gy and 20 of 24 patients at 82.8Gy). Toxicity was scored according to the RTOG grading scale. Efficacy was evaluated by PSA levels and ultrasound guided biopsies. Median follow up was 36 and 18 months for the 78Gy and 82.8Gy dose levels, respectively. Results: No grade 3 or 4 gastrointestinal (GI) or genitourinary (GU) toxicity was noted. At 36 months, the actuarial probability of Grade 2 GI and GU toxicity were 16 and 20%, respectively. Twelve to 18 months following radiation, 41 patients (86%) underwent ultrasound guided biopsy. At 78Gy, 60% of 20 patients had a biopsy which was negative or showed a marked therapeutic effect. At 82.8Gy, these combined rates were 95% in the 21 patients who had biopsies. Nine patients (50%) who did not receive neo-adjuvant hormones had positive biopsies. No patient who received neo-adjuvant hormones plus 78Gy (5 patients) or 82.8Gy (18 patients) had a positive biopsy. Conclusion: Proceeding to the next dose level (87.4Gy) was justified by the lack of severe chronic toxicity. However, in view of the high rate of histologic sterilization when hyperfractionated irradiation was given in conjunction with neo-adjuvant hormonal therapy, it was felt to be unethical to

  8. Topical administration of regorafenib eye drops: phase I dose-escalation study in healthy volunteers.

    Science.gov (United States)

    Zimmermann, Torsten; Höchel, Joachim; Becka, Michael; Boettger, Michael K; Rohde, Beate; Schug, Barbara; Kunert, Kathleen S; Donath, Frank

    2018-05-01

    Regorafenib is a multikinase inhibitor under investigation for use in neovascular age-related macular degeneration. In this phase I study, regorafenib eye drops were administered to healthy volunteers to provide information on safety, tolerability and systemic exposure. This was a single-centre, randomized, double-masked, parallel-group, dose-escalation, placebo-controlled study. Subjects received regorafenib eye drops (30 mg ml -1 , 25 μl) as a 0.75 mg single dose (Cohort 1), 0.75 mg twice daily (bid) or thrice daily (tid) over 14 days (Cohorts 2 and 3, respectively), 1.5 mg tid unilaterally for 3 days, then bilaterally for up to 14 days (Cohort 4), or placebo. Plasma samples were taken to estimate systemic exposure. Safety and functional assessments were performed throughout the study. Thirty-six subjects received regorafenib and 12 received placebo. Regorafenib was safe and well tolerated over the dose range. No pathological changes occurred in the anterior, vitreous or posterior eye compartments. Mild eyelid redness, oedema and conjunctival hyperaemia were observed across all regorafenib cohorts; these were comparable with the effects seen with placebo. Predominant symptoms were blurred vision in the active and placebo groups. Systemic safety evaluations showed no clinically relevant findings. Absolute systemic exposure after multiple administrations of regorafenib eye drops at a dose of 0.75 mg was 600-700-fold lower than after multiple oral administration of 160 mg day -1 , the dose approved in cancer indications. These results indicate a favourable safety and tolerability profile of regorafenib eye drops up to 30 mg ml -1 tid for use in clinical studies. © 2018 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

  9. PET-guided dose escalation tomotherapy in malignant pleural mesothelioma

    Energy Technology Data Exchange (ETDEWEB)

    Fodor, Andrei; Dell' Oca, Italo; Pasetti, Marcella; Di Muzio, Nadia Gisella [San Raffaele Scientific Institute, Milan (Italy). Dept. of Radiotherapy; Fiorino, Claudio; Broggi, Sara; Cattaneo, Giovanni Mauro; Calandrino, Riccardo [San Raffaele Scientific Institute, Milan (Italy). Medical Physics; Gianolli, Luigi [San Raffaele Scientific Institute, Milan (Italy). Dept. of Nuclear Medicine

    2011-11-15

    To test the feasibility of salvage radiotherapy using PET-guided helical tomotherapy in patients with progressive malignant pleural mesothelioma (MPM). A group of 12 consecutive MPM patients was treated with 56 Gy/25 fractions to the planning target volume (PTV); FDG-PET/CT simulation was always performed to include all positive lymph nodes and MPM infiltrations. Subsequently, a second group of 12 consecutive patients was treated with the same dose to the whole pleura adding a simultaneous integrated boost of 62.5 Gy to the FDG-PET/CT positive areas (BTV). Good dosimetric results were obtained in both groups. No grade 3 (RTOG/EORTC) acute or late toxicities were reported in the first group, while 3 cases of grade 3 late pneumonitis were registered in the second group: the duration of symptoms was 2-10 weeks. Median overall survival was 8 months (1.2-50.5 months) and 20 months (4.3-33.8 months) from the beginning of radiotherapy, for groups I and II, respectively (p = 0.19). A significant impact on local relapse from radiotherapy was seen (median time to local relapse: 8 vs 17 months; 1-year local relapse-free rate: 16% vs 81%, p = 0.003). The results of this pilot study support the planning of a phase III study of combined sequential chemoradiotherapy with dose escalation to BTV in patients not able to undergo resection. (orig.)

  10. A systematic methodology review of phase I radiation dose escalation trials

    International Nuclear Information System (INIS)

    Pijls-Johannesma, Madelon; Mastrigt, Ghislaine van; Hahn, Steve M.; De Ruysscher, Dirk; Baumert, Brigitta G.; Lammering, Guido; Buijsen, Jeroen; Bentzen, Soren M.; Lievens, Yolande; Kramar, Andrew; Lambin, Philippe

    2010-01-01

    Background and purpose: The purpose of this review is to evaluate the methodology used in published phase I radiotherapy (RT) dose escalation trials. A specific emphasis was placed on the frequency of reporting late complications as endpoint. Materials and methods: We performed a systematic literature review using a predefined search strategy to identify all phase I trials reporting on external radiotherapy dose escalation in cancer patients. Results: Fifty-three trials (phase I: n = 36, phase I-II: n = 17) fulfilled the inclusion criteria. Of these, 20 used a modified Fibonacci design for the RT dose escalation, but 32 did not specify a design. Late toxicity was variously defined as >3 months (n = 43) or > 6 months (n = 3) after RT, or not defined (n = 7). In only nine studies the maximum tolerated dose (MTD) was related to late toxicity, while only half the studies reported the minimum follow-up period for dose escalation (n = 26). Conclusion: In phase I RT trials, late complications are often not taken into account and there is currently no consensus on the methodology used for radiation dose escalation studies. We therefore propose a decision-tree algorithm which depends on the endpoint selected and whether a validated early surrogate endpoint is available, in order to choose the most appropriate study design.

  11. Innovative design for a phase 1 trial with intra-patient dose escalation: The Crotoxin study

    Directory of Open Access Journals (Sweden)

    Jacques Medioni

    2017-09-01

    Full Text Available Introduction: Crotoxin has a broad antitumor activity but has shown frequent neurotoxic toxicity. To induce tolerance and limit this toxicity, we propose a new design with intra-patient dose escalation. Methods: A new Dose Limiting Toxicity definition was used. The concept of Target Ceiling Dose was introduced. Results: Dose Limiting Toxicity was the inability to dose escalate twice. Target Ceiling Dose was the highest planned dose to be administered to a patient and could change for patients along time. Recommended Dose was defined similarly as in a (3 + 3 conventional design. Conclusion: This innovant design was used and the clinical trial is now closed for inclusions. Results will be presented later. Keywords: Clinical trial, Phase 1, Intra-patient dose escalation, Cancer

  12. SYSTEMS-2: A randomised phase II study of radiotherapy dose escalation for pain control in malignant pleural mesothelioma

    Directory of Open Access Journals (Sweden)

    M. Ashton

    2018-01-01

    Full Text Available SYSTEMS-2 is a randomised study of radiotherapy dose escalation for pain control in 112 patients with malignant pleural mesothelioma (MPM. Standard palliative (20 Gy/5# or dose escalated treatment (36 Gy/6# will be delivered using advanced radiotherapy techniques and pain responses will be compared at week 5. Data will guide optimal palliative radiotherapy in MPM.

  13. Adalimumab dose escalation and dose de-escalation success rate and predictors in a large national cohort of Crohn's patients

    NARCIS (Netherlands)

    Baert, Filip; Glorieus, Elien; Reenaers, Cathérine; D'Haens, Geert; Peeters, Harald; Franchimont, Dennis; Dewit, Olivier; Caenepeel, Philippe; Louis, Edouard; van Assche, Gert; D'Heygere, F.; George, C.; van Hootegem, P.; Ilegems, S.; Fontaine, F.; Colard, A.; Schoofs, N.; Belaiche, J.; Louis, E.; Reenaers, C.; van Kemseke, C.; Coche, J. C.; Dewit, O.; Rahier, J. F.; de Reuck, M.; Baert, F.; Decaestecker, J.; de Wulf, D.; Amininejad, L.; Franchimont, D.; van Gossum, A.; Du Ville, L.; Hendrickx, K.; Lepoutre, L.; Vandervoort, J.; van der Spek, P.; Sprengers, D.; van de Mierop, F.; Potvin, P.; Bontems, P.; Moreels, T.; van Outryve, M.; Mana, F.; de Looze, D.; de Vos, M.; Peeters, H.; Ferrante, M.; Rutgeerts, P.; van Assche, G.; Vermeire, S.

    2013-01-01

    Adalimumab is efficacious in inducing and maintaining remission in Crohn's disease but dose escalation is needed in 30-40% after 1 year. Attempts for dose de-escalation have not been studied. This study aimed to assess the need for, predictors, and outcome of dose escalation and de-escalation in a

  14. Safety of polyethylene glycol 3350 solution in chronic constipation: randomized, placebo-controlled trial

    OpenAIRE

    McGraw, Thomas

    2016-01-01

    Thomas McGraw Global Medical Affairs, Merck & Co., Inc., Kenilworth, NJ, USA Purpose: To evaluate the safety and tolerability of aqueous solution concentrate (ASC) of polyethylene glycol (PEG) 3350 in patients with functional constipation.Patients and methods: The patients who met Rome III diagnostic criteria for functional constipation were randomized in this multicenter, randomized, placebo-controlled, single-blind study to receive once daily dose of PEG 3350 (17 g) ASC or ...

  15. Pharmacological cardioversion of atrial fibrillation--a double-blind, randomized, placebo-controlled, multicentre, dose-escalation study of AZD1305 given intravenously

    DEFF Research Database (Denmark)

    Rónaszéki, Aladár; Alings, Marco; Egstrup, Kenneth

    2011-01-01

    AZD1305 is a combined ion channel blocker developed for the treatment of atrial fibrillation (AF). The aim of this study was to determine whether AZD1305 was effective in converting AF to sinus rhythm (SR)....

  16. Resolution of methylphenidate osmotic release oral system-induced hair loss in two siblings after dose escalation.

    Science.gov (United States)

    Ardic, Ulku Akyol; Ercan, Eyup Sabri

    2017-11-01

    This report describes the cases of two siblings who experienced hair loss after treatment with methylphenidate (MPH) osmotic release oral system (OROS). Hair loss was resolved after discontinuation of the drug, but the children re-initiated treatment, after which hair loss again occurred, but they continued the treatment. After dose escalation, the hair loss resolved. This is the first report to describe resolution of OROS-MPH-induced hair loss after dose escalation. © 2017 Japan Pediatric Society.

  17. Radiobiological Determination of Dose Escalation and Normal Tissue Toxicity in Definitive Chemoradiation Therapy for Esophageal Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Warren, Samantha, E-mail: Samantha.warren@oncology.ox.ac.uk [Department of Oncology, Gray Institute of Radiation Oncology and Biology, University of Oxford, Oxford (United Kingdom); Partridge, Mike [Department of Oncology, Gray Institute of Radiation Oncology and Biology, University of Oxford, Oxford (United Kingdom); Carrington, Rhys [Velindre Cancer Centre, Velindre Hospital, Cardiff (United Kingdom); Hurt, Chris [Wales Cancer Trials Unit, School of Medicine, Heath Park, Cardiff (United Kingdom); Crosby, Thomas [Velindre Cancer Centre, Velindre Hospital, Cardiff (United Kingdom); Hawkins, Maria A. [Department of Oncology, Gray Institute of Radiation Oncology and Biology, University of Oxford, Oxford (United Kingdom)

    2014-10-01

    Purpose: This study investigated the trade-off in tumor coverage and organ-at-risk sparing when applying dose escalation for concurrent chemoradiation therapy (CRT) of mid-esophageal cancer, using radiobiological modeling to estimate local control and normal tissue toxicity. Methods and Materials: Twenty-one patients with mid-esophageal cancer were selected from the SCOPE1 database (International Standard Randomised Controlled Trials number 47718479), with a mean planning target volume (PTV) of 327 cm{sup 3}. A boost volume, PTV2 (GTV + 0.5 cm margin), was created. Radiobiological modeling of tumor control probability (TCP) estimated the dose required for a clinically significant (+20%) increase in local control as 62.5 Gy/25 fractions. A RapidArc (RA) plan with a simultaneously integrated boost (SIB) to PTV2 (RA{sub 62.5}) was compared to a standard dose plan of 50 Gy/25 fractions (RA{sub 50}). Dose-volume metrics and estimates of normal tissue complication probability (NTCP) for heart and lungs were compared. Results: Clinically acceptable dose escalation was feasible for 16 of 21 patients, with significant gains (>18%) in tumor control from 38.2% (RA{sub 50}) to 56.3% (RA{sub 62.5}), and only a small increase in predicted toxicity: median heart NTCP 4.4% (RA{sub 50}) versus 5.6% (RA{sub 62.5}) P<.001 and median lung NTCP 6.5% (RA{sub 50}) versus 7.5% (RA{sub 62.5}) P<.001. Conclusions: Dose escalation to the GTV to improve local control is possible when overlap between PTV and organ-at-risk (<8% heart volume and <2.5% lung volume overlap for this study) generates only negligible increase in lung or heart toxicity. These predictions from radiobiological modeling should be tested in future clinical trials.

  18. Does selective pleural irradiation of malignant pleural mesothelioma allow radiation dose escalation. A planning study

    International Nuclear Information System (INIS)

    Botticella, A.; Defraene, G.; Nackaerts, K.; Deroose, C.; Coolen, J.; Nafteux, P.; Vanstraelen, B.; Joosten, S.; Michiels, L.A.W.; Peeters, S.; Ruysscher, D. de

    2017-01-01

    After lung-sparing radiotherapy for malignant pleural mesothelioma (MPM), local failure at sites of previous gross disease represents the dominant form of failure. Our aim is to investigate if selective irradiation of the gross pleural disease only can allow dose escalation. In all, 12 consecutive stage I-IV MPM patients (6 left-sided and 6 right-sided) were retrospectively identified and included. A magnetic resonance imaging-based pleural gross tumor volume (GTV) was contoured. Two sets of planning target volumes (PTV) were generated for each patient: (1) a ''selective'' PTV (S-PTV), originating from a 5-mm isotropic expansion from the GTV and (2) an ''elective'' PTV (E-PTV), originating from a 5-mm isotropic expansion from the whole ipsilateral pleural space. Two sets of volumetric modulated arc therapy (VMAT) treatment plans were generated: a ''selective'' pleural irradiation plan (SPI plan) and an ''elective'' pleural irradiation plan (EPI plan, planned with a simultaneous integrated boost technique [SIB]). In the SPI plans, the average median dose to the S-PTV was 53.6 Gy (range 41-63.6 Gy). In 4 of 12 patients, it was possible to escalate the dose to the S-PTV to >58 Gy. In the EPI plans, the average median doses to the E-PTV and to the S-PTV were 48.6 Gy (range 38.5-58.7) and 49 Gy (range 38.6-59.5 Gy), respectively. No significant dose escalation was achievable. The omission of the elective irradiation of the whole ipsilateral pleural space allowed dose escalation from 49 Gy to more than 58 Gy in 4 of 12 chemonaive MPM patients. This strategy may form the basis for nonsurgical radical combined modality treatment of MPM. (orig.) [de

  19. DOSE-ESCALATED EXTERNAL BEAM RADIOTHERAPY DURING HORMONO-RADIOTHERAPY FOR PROSTATE CANCER

    Directory of Open Access Journals (Sweden)

    Yu. V. Gumenetskaya

    2016-01-01

    Full Text Available Introduction. The introduction of modern technologies of conformal external beam radiotherapy (EBRT into clinical practice for the treatment of prostate cancer requires proper quality assurance measures as well as a careful analysis of both the efficacy and toxicity data of treatments. The purpose of this study was to inves- tigate tolerance and the immediate efficacy of conformal dose-escalated EBRT during hormono-radiotherapy for prostate cancer. material and methods. The study involved 156 prostate cancer patients treated with EBRT. Among them, 30 patients received a total dose of 70 Gy, and in 126 patients the total dose was esca- lated to 72-76 Gy (median total dose - 74.0 Gy. Fifty-nine patients received intensity modulated radiation therapy. Results. The prescribed course of treatment was completed in all the patients with prostate cancer. Acute radiation-induced bladder reactions (RTOG were observed in 50 (32.1 % patients, of whom 48 (30.8 % experienced grade I reactions, and 2 (1.3 % experienced grade II reactions. Eighteen (11.5 % patients had radiation-induced rectum reactions, not above grade I. The development of grade II dysuric phenomena necessitated treatment interruption only in two patients. Of 9 (5.8 % patients who had late bladder complica- tions (RTOG/EORTC, 8 (5.1 % patients developed grade I complications, and one (0.6 % patient developed grade II complications. Of 11 (7.1 % patients who had rectum complications, 8 (5.1 % patients developed grade I complications, and 3 (1.9 % patients developed grade II complications. No patients experienced the increase in toxicity of treatment during dose escalation up to a total dose exceeding 70 Gy. During the follow-up period, only one patient developed recurrent disease. Conclusion. The results of our study suggest acceptable levels of toxicity following a continuous course of dose-escalated EBRT given in conjunction with hormono-radiotherapy to prostate cancer patients. Further

  20. Feasibility of extreme dose escalation for glioblastoma multiforme using 4π radiotherapy

    International Nuclear Information System (INIS)

    Nguyen, Dan; Rwigema, Jean-Claude M; Yu, Victoria Y; Kaprealian, Tania; Kupelian, Patrick; Selch, Michael; Lee, Percy; Low, Daniel A; Sheng, Ke

    2014-01-01

    Glioblastoma multiforme (GBM) frequently recurs at the same location after radiotherapy. Further dose escalation using conventional methods is limited by normal tissue tolerance. 4π non-coplanar radiotherapy has recently emerged as a new potential method to deliver highly conformal radiation dose using the C-arm linacs. We aim to study the feasibility of very substantial GBM dose escalation while maintaining normal tissue tolerance using 4π. 11 GBM patients previously treated with volumetric modulated arc therapy (VMAT/RapidArc) on the NovalisTx™ platform to a prescription dose of either 59.4 Gy or 60 Gy were included. All patients were replanned with 30 non-coplanar beams using a 4π radiotherapy platform, which inverse optimizes both beam angles and fluence maps. Four different prescriptions were used including original prescription dose and PTV (4πPTV PD ), 100 Gy to the PTV and GTV (4πPTV 100Gy ), 100 Gy to the GTV only while maintaining prescription dose to the rest of the PTV (4πGTV 100Gy ), and a 5 mm margin expansion plan (4πPTV PD+5mm ). OARs included in the study are the normal brain (brain – PTV), brainstem, chiasm, spinal cord, eyes, lenses, optical nerves, and cochleae. The 4π plans resulted in superior dose gradient indices, as indicated by >20% reduction in the R50, compared to the clinical plans. Among all of the 4π cases, when compared to the clinical plans, the maximum and mean doses were significantly reduced (p < 0.05) by a range of 47.01-98.82% and 51.87-99.47%, respectively, or unchanged (p > 0.05) for all of the non-brain OARs. Both the 4πPTV PD and 4π GTV 100GY plans reduced the mean normal brain mean doses. 4π non-coplanar radiotherapy substantially increases the dose gradient outside of the PTV and better spares critical organs. Dose escalation to 100 Gy to the GTV or additional margin expansion while meeting clinical critical organ dose constraints is feasible. 100 Gy to the PTV result in higher normal brain doses but may

  1. Dose escalated radiotherapy for T1 and T2 nasopharyngeal carcinoma

    International Nuclear Information System (INIS)

    Lu, J. J.; Zhang, Q.; Lee, K. M.; Loh, K. S.; Tan, K. S.

    2008-01-01

    Nasopharyngeal carcinoma (NPC) is most prevalent in the Guangzhou province in southern China, in Hong Kong and in Singapore. It also occurs in Europe and North America, partly due to its epidemiological association with the woodworking and shoe manufacturing industry. Because of its anatomical location, i.e. so close to vital organs at risk, such as the brain stem and eyes, the technique of radiotherapy and dose/fractionation prescription is of extreme importance. This communication describes our experience with dose escalation radiotherapy for stages T1 and T2 of NPC. (author)

  2. Clinical Outcome of Dose-Escalated Image-Guided Radiotherapy for Spinal Metastases

    International Nuclear Information System (INIS)

    Guckenberger, Matthias; Goebel, Joachim; Wilbert, Juergen; Baier, Kurt; Richter, Anne; Sweeney, Reinhart A.; Bratengeier, Klaus; Flentje, Michael

    2009-01-01

    Purpose: To evaluate the outcomes after dose-escalated radiotherapy (RT) for spinal metastases and paraspinal tumors. Methods and Materials: A total of 14 patients, 12 with spinal metastases and a long life expectancy and 2 with paraspinal tumors, were treated for 16 lesions with intensity-modulated, image-guided RT. A median biologic effective dose of 74 Gy 10 (range, 55-86) in a median of 20 fractions (range, 3-34) was prescribed to the target volume. The spinal canal was treated to 40 Gy in 20 fractions using a second intensity-modulated RT dose level in the case of epidural involvement. Results: After median follow-up of 17 months, one local recurrence was observed, for an actuarial local control rate of 88% after 2 years. Local control was associated with rapid and long-term pain relief. Of 11 patients treated for a solitary spinal metastasis, 6 developed systemic disease progression. The actuarial overall survival rate for metastatic patients was 85% and 63% after 1 and 2 years, respectively. Acute Grade 2-3 skin toxicity was seen in 2 patients with no late toxicity greater than Grade 2. No radiation-induced myelopathy was observed. Conclusion: Dose-escalated irradiation of spinal metastases was safe and resulted in excellent local control. Oligometastatic patients with a long life expectancy and epidural involvement are considered to benefit the most from fractionated RT.

  3. The potential influence of cell protectors for dose escalation in cancer therapy: an analysis of amifostine

    International Nuclear Information System (INIS)

    McCumber, Linda M.

    2004-01-01

    The attempt to increase the therapeutic ratio in an effort to improve survival or quality of life is the goal of modern cancer therapy. It is commonly accepted that local and systemic tumor control would increase if the dose intensity of antineoplastic drugs, radiation therapy, or the combination were increased. Radiation dose escalation using intensity-modulated radiation therapy (IMRT), accelerated or hypofractionated radiation schemes, and multidrug chemotherapy regimens are being used to try to increase tumor kill while inflicting minimal injury to normal tissue. Modern chemoradiation techniques have led to improved local regional control and increased cure rates, but the potentially severe and debilitating adverse effects of the therapies prevent them from reaching the ultimate goal of curing the disease while leaving the patient with a good quality of life. Cell protectants such as amifostine function by reducing the effects of therapy on normal cells while maintaining tumor sensitivity to the therapy. In various studies, amifostine has been analyzed and appears to be a potentially powerful adjuvant to current cancer therapy. Administering amifostine may allow dose escalation with less or equal risk to surrounding normal tissues. This could improve therapeutic efficacy, survival, and quality of life for cancer patients

  4. An Hourly Dose-Escalation Desensitization Protocol for Aspirin-Exacerbated Respiratory Disease.

    Science.gov (United States)

    Chen, Justin R; Buchmiller, Brett L; Khan, David A

    2015-01-01

    Aspirin desensitization followed by maintenance therapy effectively improves symptom control in patients with aspirin exacerbated respiratory disease (AERD). The majority of current desensitization protocols use 3-hour dosing intervals and often require 2 to 3 days to complete. We evaluated hourly dose escalations in a subset of patients with chronic rhinosinusitis, nasal polyps, and asthma who historically reacted to aspirin within 1 hour or were avoiding aspirin with the goal of developing a safe and efficient desensitization protocol. Fifty-seven aspirin desensitizations were performed under the hourly protocol. All patients had refractory nasal polyposis as an indication for aspirin desensitization. The clinical characteristics of each subject were analyzed in relation to aspects of his or her reactions during the procedure. Ninety-eight percent of study patients were successfully treated under the hourly protocol, including those with a history of severe reactions and intubation. None required further medication than is available in an outpatient allergy clinic. A total of 96% of reactors recorded a bronchial or naso-ocular reaction within 1 hour of the preceding dose. Of the total patients on this protocol, 40% were able to complete the procedure in a single day, and 60% within 2 days. Patients with AERD who have a history of symptoms less than 1 hour after aspirin exposure can be safely desensitized with a 1-hour dose-escalation protocol that can often be completed in a single day. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  5. SU-E-T-622: Identification and Improvement of Patients Eligible for Dose Escalation with Matched Plans

    International Nuclear Information System (INIS)

    Bush, K; Holcombe, C; Kapp, D; Buyyounouski, M; Hancock, S; Xing, L; Atwood, T; King, M

    2014-01-01

    Purpose: Radiation-therapy dose-escalation beyond 80Gy may improve tumor control rates for patients with localized prostate cancer. Since toxicity remains a concern, treatment planners must achieve dose-escalation while still adhering to dose-constraints for surrounding structures. Patientmatching is a machine-learning technique that identifies prior patients that dosimetrically match DVH parameters of target volumes and critical structures prior to actual treatment planning. We evaluated the feasibility of patient-matching in (1)identifying candidates for safe dose-escalation; and (2)improving DVH parameters for critical structures in actual dose-escalated plans. Methods: We analyzed DVH parameters from 319 historical treatment plans to determine which plans could achieve dose-escalation (8640cGy) without exceeding Zelefsky dose-constraints (rectal and bladder V47Gy<53%, and V75.6Gy<30%, max-point dose to rectum of 8550cGy, max dose to PTV< 9504cGy). We then estimated the percentage of cases that could achieve safe dose-escalation using software that enables patient matching (QuickMatch, Siris Medical, Mountain View, CA). We then replanned a case that had violated DVH constraints with DVH parameters from patient matching, in order to determine whether this previously unacceptable plan could be made eligible with this automated technique. Results: Patient-matching improved the percentage of patients eligible for dose-escalation from 40% to 63% (p=4.7e-4, t-test). Using a commercial optimizer augmented with patient-matching, we demonstrated a case where patient-matching improved the toxicity-profile such that dose-escalation would have been possible; this plan was rapidly achieved using patientmatching software. In this patient, all lower-dose constraints were met with both the denovo and patient-matching plan. In the patient-matching plan, maximum dose to the rectum was 8385cGy, while the denovo plan failed to meet the maximum rectal constraint at 8571c

  6. Clinical Factors Associated With Dose Escalation of Solifenacin for the Treatment of Overactive Bladder in Real Life Practice

    Directory of Open Access Journals (Sweden)

    Ji-Youn Chun

    2014-03-01

    Full Text Available PurposeTo determine the baseline clinical characteristics associated with dose escalation of solifenacin in patients with overactive bladder (OAB.MethodsWe analyzed the data of patients with OAB (micturition frequency ≥8/day and urgency ≥1/day who were treated with solifenacin and followed up for 24 weeks. According to our department protocol, all the patients kept voiding diaries, and OAB symptom scores (OABSS were monitored at baseline and after 4, 12, and 24 weeks of solifenacin treatment.ResultsIn total, 68 patients (mean age, 60.8±10.0 years were recruited. The dose escalation rate by the end of the study was 41.2%, from 23.5% at 4 weeks and 17.6% at 12 weeks. At baseline, the dose escalator group had significantly more OAB wet patients (53.6% vs. 20.0% and higher total OABSS (10.2±2.4 vs. 7.9±3.5, P=0.032 than the nonescalator group. OAB wet (odds ratio [OR], 4.615; 95% confidence interval [CI], 1.578-13.499; P<0.05 and total OABSS (OR, 1.398; 95% CI, 1.046-1.869; P<0.05 were found to be independently associated with dose escalation.ConclusionsPatients who have urgency urinary incontinence and high total OABSS have a tendency for dose escalation of solifenacin.

  7. Clinical Outcomes With Dose-Escalated Adaptive Radiation Therapy for Urinary Bladder Cancer: A Prospective Study

    Energy Technology Data Exchange (ETDEWEB)

    Murthy, Vedang, E-mail: vmurthy@actrec.gov.in [Department of Radiation Oncology, Tata Memorial Centre, Parel, Mumbai (India); Masodkar, Renuka; Kalyani, Nikhil; Mahantshetty, Umesh [Department of Radiation Oncology, Tata Memorial Centre, Parel, Mumbai (India); Bakshi, Ganesh; Prakash, Gagan [Department of Surgical Oncology, Tata Memorial Centre, Parel, Mumbai (India); Joshi, Amit; Prabhash, Kumar [Department of Medical Oncology, Tata Memorial Centre, Parel, Mumbai (India); Ghonge, Sujata; Shrivastava, Shyamkishore [Department of Radiation Oncology, Tata Memorial Centre, Parel, Mumbai (India)

    2016-01-01

    Purpose: The purpose of this study was to assess feasibility, clinical outcomes, and toxicity in patients with bladder cancer treated with adaptive, image guided radiation therapy (IGRT) for bladder preservation as a part of trimodality treatment. The role of dose escalation was also studied. Methods and Materials: Forty-four patients with localized bladder cancer were enrolled in a prospective study. They underwent maximal safe resection of bladder tumor and concurrent platinum-based chemotherapy. Patients with large tumors were offered induction chemotherapy. Radiation therapy planning was done using either 3 (n=34) or 6 (n=10) concentrically grown planning target volumes (PTV). Patients received 64 Gy in 32 fractions to the whole bladder and 55 Gy to the pelvic nodes and, if appropriate, a simultaneous integrated boost to the tumor bed to 68 Gy (equivalent dose for 2-Gy fractions assuming α/β of 10 [EQD2]{sub 10} = 68.7 Gy). Daily megavoltage (MV) imaging helped to choose the most appropriate PTV encompassing bladder for the particular day (using plan-of-the-day approach). Results: Most patients (88%) had T2 disease. Sixteen patients (36%) received neoadjuvant chemotherapy. A majority of the patients (73%) received prophylactic nodal irradiation, whereas 55% of the patients received escalated dose to the tumor bed. With a median follow-up of 30 months, the 3-year locoregional control (LRC), disease-free survival, and overall survival (OS) were 78%, 66%, and 67%, respectively. The bladder preservation rate was 83%. LRC (87% vs 68%, respectively, P=.748) and OS (74% vs 60%, respectively, P=.36) rates were better in patients receiving dose escalation. Instances of acute and late Radiation Therapy Oncology Group (RTOG) grade 3 genitourinary toxicity was seen in 5 (11%) and 2 (4%) patients, respectively. There was no acute or late RTOG grade 3 or higher gastrointestinal toxicity. Conclusions: Adaptive IGRT using plan-of-the-day approach for bladder

  8. Clinical Outcomes With Dose-Escalated Adaptive Radiation Therapy for Urinary Bladder Cancer: A Prospective Study

    International Nuclear Information System (INIS)

    Murthy, Vedang; Masodkar, Renuka; Kalyani, Nikhil; Mahantshetty, Umesh; Bakshi, Ganesh; Prakash, Gagan; Joshi, Amit; Prabhash, Kumar; Ghonge, Sujata; Shrivastava, Shyamkishore

    2016-01-01

    Purpose: The purpose of this study was to assess feasibility, clinical outcomes, and toxicity in patients with bladder cancer treated with adaptive, image guided radiation therapy (IGRT) for bladder preservation as a part of trimodality treatment. The role of dose escalation was also studied. Methods and Materials: Forty-four patients with localized bladder cancer were enrolled in a prospective study. They underwent maximal safe resection of bladder tumor and concurrent platinum-based chemotherapy. Patients with large tumors were offered induction chemotherapy. Radiation therapy planning was done using either 3 (n=34) or 6 (n=10) concentrically grown planning target volumes (PTV). Patients received 64 Gy in 32 fractions to the whole bladder and 55 Gy to the pelvic nodes and, if appropriate, a simultaneous integrated boost to the tumor bed to 68 Gy (equivalent dose for 2-Gy fractions assuming α/β of 10 [EQD2] 10  = 68.7 Gy). Daily megavoltage (MV) imaging helped to choose the most appropriate PTV encompassing bladder for the particular day (using plan-of-the-day approach). Results: Most patients (88%) had T2 disease. Sixteen patients (36%) received neoadjuvant chemotherapy. A majority of the patients (73%) received prophylactic nodal irradiation, whereas 55% of the patients received escalated dose to the tumor bed. With a median follow-up of 30 months, the 3-year locoregional control (LRC), disease-free survival, and overall survival (OS) were 78%, 66%, and 67%, respectively. The bladder preservation rate was 83%. LRC (87% vs 68%, respectively, P=.748) and OS (74% vs 60%, respectively, P=.36) rates were better in patients receiving dose escalation. Instances of acute and late Radiation Therapy Oncology Group (RTOG) grade 3 genitourinary toxicity was seen in 5 (11%) and 2 (4%) patients, respectively. There was no acute or late RTOG grade 3 or higher gastrointestinal toxicity. Conclusions: Adaptive IGRT using plan-of-the-day approach for bladder preservation

  9. Hyperfractionated conformal radiotherapy in locally advanced prostate cancer: results of a dose escalation study

    International Nuclear Information System (INIS)

    Forman, Jeffrey D.; Duclos, Marie; Shamsa, Falah; Porter, Arthur T.; Orton, Colin

    1996-01-01

    Purpose: This study was initiated to assess the incidence of chronic complications and histologic and biochemical control following hyperfractionated conformal radiotherapy in patients with locally advanced prostate cancer. Methods and Materials: Between October 1991 and October 1994, 49 patients with locally advanced prostate cancer were entered on the first two dose levels of a prospective dose-escalation study using hyperfractionated three dimensional conformal radiotherapy. The first 25 patients received a minimum tumor dose of 78 Gy to the prostate and seminal vesicles in 6 weeks at 1.3 Gy, b.i.d. No increase in chronic toxicity compared with conventional radiotherapy was noted; therefore, an additional 24 patients were treated to a minimum tumor dose of 82.8 Gy to the prostate and seminal vesicles in 7 weeks at 1.15 Gy, b.i.d. Toxicity was scored according to the Radiation Therapy Oncology Group morbidity grading scale. Efficacy was assessed through scheduled postradiation prostate specific antigen values and ultrasound-guided biopsies. The median follow-up for the entire group was 20 months. Results: The hyperfractionated external radiation was well tolerated with minimal acute morbidity. At 30 months, the actuarial probability of Grade 2 gastrointestinal toxicity was 17%. At 30 months, the actuarial probability of Grade 2 genitourinary toxicity was 16%. There was no statistically significant difference between the two dose levels. No Grade 3 or 4 gastrointestinal or genitourinary toxicity was noted. At 12 months, 84% of patients had a prostate specific antigen ≤ 4; and 53%; ≤ 1 ng/ml. At 12 months, 71% of patients had post radiation biopsies that were either negative (55%) or showed a marked therapeutic effect (16%). Conclusion: The use of hyperfractionated conformal radiotherapy facilitated dose escalation with no increase in chronic toxicity compared to standard doses. The initial tumor response based on prostate specific antigen measurements and

  10. Dose-escalated total body irradiation and autologous stem cell transplantation for refractory hematologic malignancy

    International Nuclear Information System (INIS)

    McAfee, Steven L.; Powell, Simon N.; Colby, Christine; Spitzer, Thomas R.

    2002-01-01

    Purpose: To evaluate the feasibility of dose escalation of total body irradiation (TBI) above the previously reported maximally tolerated dose, we have undertaken a Phase I-II trial of dose-escalated TBI with autologous peripheral blood stem cell transplantation (PBSCT) for chemotherapy-refractory lymphoma. Methods and Materials: Nine lymphoma patients with primary refractory disease (PRD) or in resistant relapse (RR) received dose-escalated TBI and PBSCT. The three dose levels of fractionated TBI (200 cGy twice daily) were 1,600 cGy, 1,800 cGy, and 2,000 cGy. Lung blocks were used to reduce the TBI transmission dose by 50%, and the chest wall dose was supplemented to the prescribed dose using electrons. Shielding of the kidneys was performed to keep the maximal renal dose at 1,600 cGy. Three patients, two with non-Hodgkin's lymphoma (NHL) in RR and one with PRD Hodgkin's disease, received 1,600 cGy + PBSCT, three patients (two NHL in RR, one PRD) received 1,800 cGy + PBSCT, and three patients with NHL (two in RR, one PRD) received 2,000 cGy + PBSCT. Results: Toxicities associated with this high-dose TBI regimen included reversible hepatic veno-occlusive disease in 1 patient, Grade 2 mucositis requiring narcotic analgesics in 8 patients, and neurologic toxicities consisting of a symmetrical sensory neuropathy (n=4) and Lhermitte's syndrome (n=1). Interstitial pneumonitis developed in 1 patient who received 1,800 cGy after receiving recombinant α-interferon (with exacerbation after rechallenge with interferon). Six (66%) patients achieved a response. Four (44%) patients achieved complete responses, three of which were of a duration greater than 1 year, and 2 (22%) patients achieved a partial response. One patient remains disease-free more than 5 years posttransplant. Corticosteroid-induced gastritis and postoperative infection resulted in the death of 1 patient in complete response, 429 days posttransplant. Conclusion: TBI in a dose range 1,600-2,000 cGy as

  11. Antipsychotic dose escalation as a trigger for Neuroleptic Malignant Syndrome (NMS: literature review and case series report

    Directory of Open Access Journals (Sweden)

    Langan Julie

    2012-11-01

    Full Text Available Abstract Background “Neuroleptic malignant syndrome” (NMS is a potentially fatal idiosyncratic reaction to any medication which affects the central dopaminergic system. Between 0.5% and 1% of patients exposed to antipsychotics develop the condition. Mortality rates may be as high as 55% and many risk factors have been reported. Although rapid escalation of antipsychotic dose is thought to be an important risk factor, to date it has not been the focus of a published case series or scientifically defined. Description We aimed to identify cases of NMS and review risk factors for its development with a particular focus on rapid dose escalation in the 30 days prior to onset. A review of the literature on rapid dose escalation was undertaken and a pragmatic definition of “rapid dose escalation” was made. NMS cases were defined using DSM-IV criteria and systematically identified within a secondary care mental health service. A ratio of titration rate was calculated for each NMS patient and “rapid escalators” and “non rapid escalators” were compared. 13 cases of NMS were identified. A progressive mean dose increase 15 days prior to the confirmed episode of NMS was observed (241.7 mg/day during days 1–15 to 346.9 mg/day during days 16–30 and the mean ratio of dose escalation for NMS patients was 1.4. Rapid dose escalation was seen in 5/13 cases and non rapid escalators had markedly higher daily cumulative antipsychotic dose compared to rapid escalators. Conclusions Rapid dose escalation occurred in less than half of this case series (n = 5, 38.5%, although there is currently no consensus on the precise definition of rapid dose escalation. Cumulative antipsychotic dose – alongside other known risk factors - may also be important in the development of NMS.

  12. Ewing sarcoma localized on spine: a dose escalation study in child

    International Nuclear Information System (INIS)

    Vogin, G.; Marchesi, V.; Biston, M.C.; Gassa, F.; Amessis, M.; Zefkili, S.; Helfre, S.; De Marzi, L.; Lacroix, F.; Leroy, A.

    2011-01-01

    The authors report the study of dose escalation for the treatment of spinal in two types of Ewing tumours. They used 5 dose levels at the rate of five 1,6 Gy per week. They compare different radiotherapy techniques: three-dimensional conformation radiotherapy, static intensity-modulated conformational radiotherapy, helical tomo-therapy, volume-modulated arc-therapy (VMAT), stereotactic radiotherapy, and proton-therapy (in passive diffusion). It appears that it is possible to safely and efficiently deliver until 70,4 Gy in some Ewing tumours. In child, exclusive radiotherapy might become a local treatment option and would require a clinic trial and comparison with exclusive surgery or post-operative radiotherapy. Short communication

  13. On-line conformal HDR dose escalation trial in prostate cancer

    International Nuclear Information System (INIS)

    Martinez, Alvaro; Stromberg, Jannifer; Edmundson, Gregory; Gustafson, Gary; Vicini, Frank; Brabbins, Donald

    1996-01-01

    Purpose: To improve treatment results on prostatic adenocarcinoma, we began the first prospective Phase I/II dose-escalating clinical trial of conformal brachytherapy (CB) and concurrent external beam irradiation. Methods and Materials: Fifty-four patients with T2b-T3c prostatic adenocarcinoma received 172 transperineal conformal high-dose rate (HDR) boost implants. All patients received concomitant external beam pelvic irradiation. Dose escalation of the three HDR fractions were: 5.5 Gy (18 patients), 6 Gy (15 patients), and 6.5 Gy (21 patients). The urethra, anterior rectal wall, and prostate boundaries were identified individually and outlined at 5 mm intervals from the base to the apex of the gland. The CB using real-time ultrasound guidance with interactive online isodose distributions was performed on an outpatient basis. As needles were placed into the prostate, corrections for prostate displacement were recorded and the isodose distributions were recalculated to represent the new relationship between the needles, prostate, and normal structures. Results: Craniocaudal motion of the gland ranged from 0.5-2.0 cm (mean=1.0 cm), whereas lateral displacement was 0.1-0.4 cm. With the interactive online planning system, organ motion was immediately detected, accounted for, and corrected prior to each HDR treatment. The rectal dose has ranged from 45 to 87%, and the urethral dose from 97 to 112% of the prostate dose. Negative prostatic biopsies at 18 months were seen in (30(32)) patients. Biochemical (PSA <1.5 ng/ml) control at 36 months is is 89%. It is significant that operator dependence has been completely removed because the interactive online planning system uniformly guides the physicians. Conclusions: With ultrasound guidance and the interactive online dosimetry system, organ motion is insignificant because it can be corrected during the procedure. Common pitfalls of brachytherapy, including operator dependence and difficulty with reproducibility, have been

  14. Radiation Therapy Dose Escalation for Glioblastoma Multiforme in the Era of Temozolomide

    Energy Technology Data Exchange (ETDEWEB)

    Badiyan, Shahed N.; Markovina, Stephanie; Simpson, Joseph R.; Robinson, Clifford G.; DeWees, Todd [Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri (United States); Tran, David D.; Linette, Gerry [Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri (United States); Jalalizadeh, Rohan [Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri (United States); Dacey, Ralph; Rich, Keith M.; Chicoine, Michael R.; Dowling, Joshua L.; Leuthardt, Eric C.; Zipfel, Gregory J.; Kim, Albert H. [Department of Neurosurgery, Washington University School of Medicine, St. Louis, Missouri (United States); Huang, Jiayi, E-mail: jhuang@radonc.wustl.edu [Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri (United States)

    2014-11-15

    Purpose: To review clinical outcomes of moderate dose escalation using high-dose radiation therapy (HDRT) in the setting of concurrent temozolomide (TMZ) in patients with newly diagnosed glioblastoma multiforme (GBM), compared with standard-dose radiation therapy (SDRT). Methods and Materials: Adult patients aged <70 years with biopsy-proven GBM were treated with SDRT (60 Gy at 2 Gy per fraction) or with HDRT (>60 Gy) and TMZ from 2000 to 2012. Biological equivalent dose at 2-Gy fractions was calculated for the HDRT assuming an α/β ratio of 5.6 for GBM. Results: Eighty-one patients received SDRT, and 128 patients received HDRT with a median (range) biological equivalent dose at 2-Gy fractions of 64 Gy (61-76 Gy). Overall median follow-up time was 1.10 years, and for living patients it was 2.97 years. Actuarial 5-year overall survival (OS) and progression-free survival (PFS) rates for patients that received HDRT versus SDRT were 12.4% versus 13.2% (P=.71), and 5.6% versus 4.1% (P=.54), respectively. Age (P=.001) and gross total/near-total resection (GTR/NTR) (P=.001) were significantly associated with PFS on multivariate analysis. Younger age (P<.0001), GTR/NTR (P<.0001), and Karnofsky performance status ≥80 (P=.001) were associated with improved OS. On subset analyses, HDRT failed to improve PFS or OS for those aged <50 years or those who had GTR/NTR. Conclusion: Moderate radiation therapy dose escalation above 60 Gy with concurrent TMZ does not seem to improve clinical outcomes for patients with GBM.

  15. Effect of a simple dose-escalation schedule on tramadol tolerability : assessment in the clinical setting.

    Science.gov (United States)

    Tagarro, I; Herrera, J; Barutell, C; Díez, M C; Marín, M; Samper, D; Busquet, C; Rodríguez, M J

    2005-01-01

    To assess the effect of a very simple dose-escalation schedule on tramadol tolerability in clinical practice. This schedule consists of starting treatment with sustained-release tramadol 50mg twice daily, and escalating the dose around 7 days later to 100mg twice daily. Data from 1925 outpatients with non-malignant chronic pain were collected in this multicentre, prospective, comparative, non-randomised, open, observational study. A total of 1071 patients (55.6%) were included in the dose-escalation group (50mg group) and 854 patients (44.4%) in the control group (sustained-release tramadol 100mg twice daily; 100mg group). The proportion of patients who interrupted tramadol treatment due to the occurrence of adverse reactions was significantly lower in the 50mg group (5.6%) than in the 100mg group (12.6%) [p = 0.001]. In line with this, the proportion of patients who experienced at least one adverse reaction was significantly lower in the 50mg group (18.4%) than in the 100mg group (30.4%) [p = 0.001] and, interestingly, the two most frequently reported adverse reactions, nausea and dizziness, were found with a significantly lower frequency in the 50mg group (p < 0.001). Multivariate analysis showed that the risk of safety-related treatment cessations was 2.3 times higher in the 100mg group than in the 50mg group, and 2.2 times higher in females than in males. The two treatments were equally effective in reducing pain intensity (p = 0.121), measured as a reduction in pain score obtained by means of a visual analogue scale. The instauration of tramadol treatment, starting with sustained-release 50mg capsules twice daily and escalating the dose some days later to 100mg twice daily, was shown to be an effective and easy way to improve tramadol tolerability in clinical practice, whilst maintaining its analgesic efficacy.

  16. Dose escalation for non-small cell lung cancer: Analysis and modelling of published literature

    International Nuclear Information System (INIS)

    Partridge, Mike; Ramos, Monica; Sardaro, Angela; Brada, Michael

    2011-01-01

    Purpose: To review the published clinical data on non-small cell lung cancer treated with radical radiotherapy to confirm a dose-response relationship as a basis for further dose-escalation trials. Methods: Twenty-four published clinical trials were identified, 16 of which - with 29 different standard, hyper- and hypofractionated treatment schedules - were analysed. Prescription doses were converted to biologically-equivalent dose (BED), with a correction for repopulation. Disease-free survival data were corrected for the stage profile of each cohort to allow better comparison of results. We also analysed moderate (grade II and III) lung and oesophageal acute toxicity related to the corrected BED delivered to the tumour. Results: The clinical data analysed showed good agreement between the observed and modelled disease-free survival at 2 years when compared to the published models of Fenwick (correlation coefficient 0.525, p = 0.003) and Martel (correlation coefficient 0.492, p = 0.007), indicating a clear tumour dose-response. In the normally fractionated treatments (∼2 Gy per fraction), improved disease-free survival was generally observed in the shorter schedules (maximum around 6 weeks). However, the best outcomes were obtained for the hypofractionated schedules. No systematic relationship was seen between prescribed dose and lung or oesophageal acute toxicity, possibly due to dose selection depending on V 20 or MLD in some studies and the diversity of the patients analysed. Conclusions: We have demonstrated a dose-response relationship for NSCLC based on clinical data. The clinical data provide a rational basis for selection of dose escalation schedules to be tested in future randomised trials.

  17. Does selective pleural irradiation of malignant pleural mesothelioma allow radiation dose escalation. A planning study

    Energy Technology Data Exchange (ETDEWEB)

    Botticella, A.; Defraene, G. [KU Leuven - University of Leuven, Department of Oncology, Experimental Radiation Oncology, Leuven (Belgium); Nackaerts, K. [KU Leuven - University of Leuven, University Hospitals Leuven, Department of Respiratory Medicine, Leuven (Belgium); Deroose, C. [KU Leuven - University of Leuven, University Hospitals Leuven, Nuclear Medicine, Leuven (Belgium); Coolen, J. [KU Leuven - University of Leuven, University Hospitals Leuven, Radiology Department, Leuven (Belgium); Nafteux, P. [University Hospitals Leuven, Department of Thoracic Surgery, Leuven (Belgium); Vanstraelen, B. [University Hospitals Leuven, Department of Radiation Oncology, Leuven (Belgium); Joosten, S.; Michiels, L.A.W. [Fontys University of Applied Science, Institute Paramedical Studies, Medical Imaging and Radiotherapeutic Techniques, Eindhoven (Netherlands); Peeters, S. [KU Leuven - University of Leuven, Department of Oncology, Experimental Radiation Oncology, Leuven (Belgium); University Hospitals Leuven, Department of Radiation Oncology, Leuven (Belgium); Ruysscher, D. de [KU Leuven - University of Leuven, Department of Oncology, Experimental Radiation Oncology, Leuven (Belgium); Maastricht University Medical Center, GROW - School for Oncology and Developmental Biology, Department of Radiation Oncology (MAASTRO Clinic), Maastricht (Netherlands)

    2017-04-15

    After lung-sparing radiotherapy for malignant pleural mesothelioma (MPM), local failure at sites of previous gross disease represents the dominant form of failure. Our aim is to investigate if selective irradiation of the gross pleural disease only can allow dose escalation. In all, 12 consecutive stage I-IV MPM patients (6 left-sided and 6 right-sided) were retrospectively identified and included. A magnetic resonance imaging-based pleural gross tumor volume (GTV) was contoured. Two sets of planning target volumes (PTV) were generated for each patient: (1) a ''selective'' PTV (S-PTV), originating from a 5-mm isotropic expansion from the GTV and (2) an ''elective'' PTV (E-PTV), originating from a 5-mm isotropic expansion from the whole ipsilateral pleural space. Two sets of volumetric modulated arc therapy (VMAT) treatment plans were generated: a ''selective'' pleural irradiation plan (SPI plan) and an ''elective'' pleural irradiation plan (EPI plan, planned with a simultaneous integrated boost technique [SIB]). In the SPI plans, the average median dose to the S-PTV was 53.6 Gy (range 41-63.6 Gy). In 4 of 12 patients, it was possible to escalate the dose to the S-PTV to >58 Gy. In the EPI plans, the average median doses to the E-PTV and to the S-PTV were 48.6 Gy (range 38.5-58.7) and 49 Gy (range 38.6-59.5 Gy), respectively. No significant dose escalation was achievable. The omission of the elective irradiation of the whole ipsilateral pleural space allowed dose escalation from 49 Gy to more than 58 Gy in 4 of 12 chemonaive MPM patients. This strategy may form the basis for nonsurgical radical combined modality treatment of MPM. (orig.) [German] Beim malignen Pleuramesotheliom (MPM) ist nach lungenschonender Radiotherapie das lokale Scheitern an Stellen eines frueheren, sichtbaren Tumors die dominierende Form des Scheiterns. Unser Ziel ist es, zu untersuchen, ob die selektive

  18. Can we avoid high levels of dose escalation for high-risk prostate cancer in the setting of androgen deprivation?

    Science.gov (United States)

    Shakespeare, Thomas P; Wilcox, Shea W; Aherne, Noel J

    2016-01-01

    Both dose-escalated external beam radiotherapy (DE-EBRT) and androgen deprivation therapy (ADT) improve outcomes in patients with high-risk prostate cancer. However, there is little evidence specifically evaluating DE-EBRT for patients with high-risk prostate cancer receiving ADT, particularly for EBRT doses >74 Gy. We aimed to determine whether DE-EBRT >74 Gy improves outcomes for patients with high-risk prostate cancer receiving long-term ADT. Patients with high-risk prostate cancer were treated on an institutional protocol prescribing 3-6 months neoadjuvant ADT and DE-EBRT, followed by 2 years of adjuvant ADT. Between 2006 and 2012, EBRT doses were escalated from 74 Gy to 76 Gy and then to 78 Gy. We interrogated our electronic medical record to identify these patients and analyzed our results by comparing dose levels. In all, 479 patients were treated with a 68-month median follow-up. The 5-year biochemical disease-free survivals for the 74 Gy, 76 Gy, and 78 Gy groups were 87.8%, 86.9%, and 91.6%, respectively. The metastasis-free survivals were 95.5%, 94.5%, and 93.9%, respectively, and the prostate cancer-specific survivals were 100%, 94.4%, and 98.1%, respectively. Dose escalation had no impact on any outcome in either univariate or multivariate analysis. There was no benefit of DE-EBRT >74 Gy in our cohort of high-risk prostate patients treated with long-term ADT. As dose escalation has higher risks of radiotherapy-induced toxicity, it may be feasible to omit dose escalation beyond 74 Gy in this group of patients. Randomized studies evaluating dose escalation for high-risk patients receiving ADT should be considered.

  19. Post-nerve-sparing prostatectomy, dose-escalated intensity-modulated radiotherapy: effect on erectile function

    International Nuclear Information System (INIS)

    Bastasch, Michael D.; Teh, Bin S.; Mai, W.-Y.; Carpenter, L. Steven; Lu, Hsin H.; Chiu, J. Kam; Woo, Shiao Y.; Grant, Walter H.; Miles, Brian J.; Kadmon, Dov; Butler, E. Brian

    2002-01-01

    Purpose: The advent of widespread prostate-specific antigen screening has resulted in more younger, potent men being diagnosed with early-stage, organ-confined prostate cancer amenable to definitive surgery. Nerve-sparing prostatectomy is a relatively new surgical advance in the treatment of prostate cancer. Very few data exist on the effect of postoperative radiotherapy (RT) on erectile function after nerve-sparing prostatectomy. They are based on conventional techniques using moderate doses of radiation, 45-54 Gy. Intensity-modulated RT (IMRT) is becoming more widespread because it allows dose escalation with increased sparing of the surrounding normal tissue. We investigated the effect of postprostatectomy, high-dose IMRT on patients' erectile function. Methods and Materials: A review of patient records found 51 patients treated between April 1998 and December 2000 with IMRT after unilateral or bilateral nerve-sparing prostatectomy. The pathologic disease stage in these patients was T2 in 47.4% and T3 in 52.6%. Postoperatively, 4 patients received hormonal ablation consisting of one injection of Lupron Depot (30 mg) 2 months before RT. The median age was 65 years (range 46-77) at the time of RT. The prescribed dose was 64 Gy (range 60-66). The mean dose was 69.6 Gy (range 64.0-72.3). Erectile function was assessed before and after RT by questionnaires. Sexual potency was defined as erectile rigidity adequate for vaginal penetration. Results: Of the 51 patients, 18 (35.3%) maintained their potency and 33 (64.7%) became impotent after nerve-sparing prostatectomy. Patients who underwent bilateral nerve-sparing prostatectomy had higher rates of postoperative potency than did those who underwent unilateral nerve-sparing surgery (72.2% vs. 27.8%; p=0.025). The follow-up for the entire group was 19.5 months. All 18 patients (100%) who were potent postoperatively remained potent after RT. The median follow-up for the 18 potent patients was 27.2 months, significantly

  20. Use of radiobiological indices to guide dose escalation of the prostate cancer patients

    International Nuclear Information System (INIS)

    Burman, Chandra; Happersett, Laura; Kutcher, Gerald; Leibel, Steven; Zelefsky, Michael; Fuks, Zvi; Ling, C. Clifton

    1997-01-01

    Purpose: In the radiation treatment of localized prostate carcinoma, a portion of the anterior rectal wall is included in the planning target volume (PTV). Thus, in dose escalation studies, radiation induced rectal complication may limit the dose that can be delivered safely. In this study we investigate the potential of increasing tumor control without increasing rectal complication by limiting the rectal volume receiving the high prescription dose. The evaluation is with the aid of radiobiological indices. Methods and Materials: Two types of 3D conformal treatment plans were performed for a group of ten patients, for prescription doses of 75.6 to 95.0 Gy. Type I plan involved 6 fields (2 lateral, 2 anterior oblique and 2 posterior oblique), with the dose prescribed to the maximum isodose line encompassing the PTV. Type II plan comprised a primary treatment (using the 6 fields of the first plan) of 72 Gy to the PTV, and a boost with 6 posterior obliques to deliver the additional dose, except to the portion of the rectal wall included by the PTV. Based on the composite 3D dose distribution, TCP and rectal NTCP were calculated with the Goitein and Lyman models, respectively, using parameters derived from our clinical experience and from the 1991 NCI Collaborating Work Group publication. Results: In the figure, the calculated values of TCP, NTCP and TCP * [1-NTCP] (or uncomplicated control), averaged over the 10 patients, are plotted against the prescription dose. The dotted and solid lines are for type I (with uniform PTV dose) and type II (with reduction in rectal dose for the boost) plans, respectively, and the error bars represent the range of computed values for the 10 patients. For type I plans, the increase in TCP, from 75% at 75.6 Gy to 98% at 95 Gy, must be balanced against the rise in rectal NTCP to >20%. The TCP for type II plan is slightly less, but with little increase in NTCP with prescription dose. Thus, the uncomplicated control continues to increase

  1. A Pilot Randomized, Single Blind, Placebo-Controlled Trial of Traditional Acupuncture for Vasomotor Symptoms and Mechanistic Pathways of Menopause

    Science.gov (United States)

    Painovich, Jeannette M.; Shufelt, Chrisandra L.; Azziz, Ricardo; Yang, Yuching; Goodarzi, Mark O.; Braunstein, Glenn D.; Karlan, Beth Y.; Stewart, Paul M.; Merz, C. Noel Bairey

    2011-01-01

    Objective To conduct a pilot study for feasibility of planning a definitive clinical trial comparing traditional acupuncture (TA) to sham acupuncture (SA) and waiting control (WC) on menopause related vasomotor symptoms (VMS), quality of life (QOL), and the hypothalamic-pituitary-adrenal (HPA) axis in peri and post-menopausal women. Methods Thirty-three peri and post-menopausal women with at least 7 VMS daily were randomized to TA, SA or WC. The TA and SA groups were given three treatments per week for 12 weeks. Outcomes included the number and severity of VMS, MENQOL questionnaire, Beck Depression Inventory, Spielberg State-Trait Anxiety Instrument, Pittsburgh Quality Sleep Index, 24 hour urine cortisol and metabolites, and ACTH stimulation testing. Results Both TA and SA groups demonstrated improved VMS trends compared to WC (Δ −3.5±3.00 vs. −4.1±3.79 vs. −1.2±2.4, respectively, p=.20), and significantly improved MENQOL vasomotor scores (Δ − 1.5±2.02 vs. −1.8±1.52 vs. 0.3±0.64, respectively, p=.04). There were no psychosocial group differences. Exit 24-hour urinary measures were lower in the TA vs the SA or WC in total cortisol metabolites (4,658.9±1,670.9 vs 7,735.8±3,747.9 vs 5,166.0±2,234.5, p=0.03, respectively) and DHEA (41.4±27.46, 161.2±222.77, 252.4±385.40, respectively, p=0.05). The ACTH stimulation cortisol response data also trended in the hypothesized direction (p=0.17). Conclusion Both TA and SA reduce VMS frequency and severity and improve VMS-related quality of life compared to WC; however, TA alone may impact the HPA axis. This association is viewed as preliminary and hypothesis-generating and should be explored in a large clinical trial. PMID:21968279

  2. Lithium trial in Alzheimer's disease: a randomized, single-blind, placebo-controlled, multicenter 10-week study.

    LENUS (Irish Health Repository)

    Hampel, Harald

    2012-02-01

    OBJECTIVE: Lithium, a first-line drug for the treatment of bipolar depression, has recently been shown to regulate glycogen synthase kinase-3 (GSK-3), a kinase that is involved in the phosphorylation of the tau protein. Since hyperphosphorylation of tau is a core pathological feature in Alzheimer\\'s disease, lithium-induced inhibition of GSK-3 activity may have therapeutic effects in Alzheimer\\'s disease. In the current study, we tested the effect of short-term lithium treatment in patients with Alzheimer\\'s disease. METHOD: A total of 71 patients with mild Alzheimer\\'s disease (Mini-Mental State Examination score > or = 21 and < or = 26) were successfully randomly assigned to placebo (N = 38) or lithium treatment (N = 33) at 6 academic expert memory clinics. The 10-week treatment included a 6-week titration phase to reach the target serum level of lithium (0.5-0.8 mmol\\/L). The primary outcome measures were cerebrospinal fluid (CSF) levels of phosphorylated tau (p-tau) and GSK-3 activity in lymphocytes. Secondary outcome measures were CSF concentration of total tau and beta-amyloid(1-42) (Abeta(1-42)), plasma levels of Abeta(1-42), Alzheimer\\'s Disease Assessment Scale (ADAS)-Cognitive summary scores, MMSE, and Neuropsychiatric Inventory (NPI). Patients were enrolled in the study from November 2004 to July 2005. RESULTS: No treatment effect on GSK-3 activity or CSF-based biomarker concentrations (P > .05) was observed. Lithium treatment did not lead to change in global cognitive performance as measured by the ADAS-Cog subscale (P = .11) or in depressive symptoms. CONCLUSIONS: The current results do not support the notion that lithium treatment may lead to reduced hyperphosphorylation of tau protein after a short 10-week treatment in the Alzheimer\\'s disease target population. TRIAL REGISTRATION: (Controlled-Trials.com) Identifier: ISRCTN72046462.

  3. Ultrasound to stimulate mandibular bone defect healing : A placebo-controlled single-blind study in rats

    NARCIS (Netherlands)

    Schortinghuis, J; Ruben, JL; Raghoebar, GM; Stegenga, B

    Purpose: Because of the limitations of the body to heal large maxillofacial bone defects, an attempt was made to stimulate mandibular defect healing with low intensity pulsed ultrasound in rats. This ultrasound consists of a 1.5-MHz pressure wave administered in pulses of 200 musec, with an average

  4. Dose-Escalated Robotic SBRT for Stage I-II Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Robert eMeier

    2015-04-01

    Full Text Available Abstract: Stereotactic body radiotherapy (SBRT is the precise external delivery of very high-dose radiotherapy to targets in the body, with treatment completed in one to five fractions. SBRT should be an ideal approach for organ-confined prostate cancer because (I dose escalation should yield improved rates of cancer control; (II the unique radiobiology of prostate cancer favors hypofractionation and (III the conformal nature of SBRT minimizes high-dose radiation delivery to immediately adjacent organs, potentially reducing complications. This approach is also more convenient for patients, and is cheaper than intensity modulated radiotherapy (IMRT. Several external beam platforms are capable of delivering SBRT for early-stage prostate cancer, although most of the mature reported series have employed a robotic non-coplanar platform (i.e., CyberKnife. Several large studies report 5-year biochemical relapse rates which compare favorably to IMRT. Rates of late GU toxicity are similar to those seen with IMRT, and rates of late rectal toxicity may be less than with IMRT and low dose rate (LDR brachytherapy. Patient-reported quality of life (QOL outcomes appear similar to IMRT in the urinary domain. Bowel QOL may be less adversely affected by SBRT than with other radiation modalities. After five years of follow-up, SBRT delivered on a robotic platform is yielding outcomes at least as favorable as IMRT, and may be considered appropriate therapy for stage I-II prostate cancer.

  5. ZD0473 pharmacokinetics in Japanese patients: a Phase I dose-escalation study.

    Science.gov (United States)

    Murakami, H; Tamura, T; Yamada, Y; Yamamoto, N; Ueda, Y; Shimoyama, T; Saijo, N

    2002-12-01

    ZD0473 is new platinum agent that was rationally designed to circumvent platinum resistance and reduce the potential for nephro-and neurotoxicity. This Phase I dose-escalating study investigated the pharmacokinetics, tolerability and efficacy of ZD0473 in Japanese patients with solid, refractory tumours. ZD0473 was administered as a 1-h intravenous infusion every 3 weeks. Nine patients received a total of 16 cycles of ZD0473 (median 1 cycle/patient), with 3 patients treated at each of 3 doses (60, 90, 120 mg/m2). The maximum plasma concentration (C(max)) and the area under the concentration-time curve to infinity (AUC(0-infinity)) increased with dose in a linear fashion for both total platinum and ZD0473 in plasma ultrafiltrate, suggesting that the pharmacokinetics of ZD0473 are linear. Haematological and non-haematological toxicities such as nausea and vomiting were mild (grade 1 or 2) and transient. No clinically significant nephro-, oto- or neurotoxicity was observed. Dose-limiting toxicity (DLT) was not observed and the maximum tolerated dose (MTD) was not identified. ZD0473 treatment showed evidence of disease stabilisation in 3 patients (33%). In conclusion, ZD0473 appears to have linear pharmacokinetics, and an acceptable tolerability profile at doses up to 120 mg/m2 in Japanese patients with refractory solid malignancies. Following evaluation of the data from all the Western trials, the ZD0473 development programme changed and this Japanese trial was stopped.

  6. Can we avoid high levels of dose escalation for high-risk prostate cancer in the setting of androgen deprivation?

    Directory of Open Access Journals (Sweden)

    Shakespeare TP

    2016-05-01

    Full Text Available Thomas P Shakespeare,1,2 Shea W Wilcox,1 Noel J Aherne1,2 1Department of Radiation Oncology, North Coast Cancer Institute, 2Rural Clinical School, Faculty of Medicine, University of New South Wales, Coffs Harbour, NSW, Australia Aim: Both dose-escalated external beam radiotherapy (DE-EBRT and androgen deprivation therapy (ADT improve outcomes in patients with high-risk prostate cancer. However, there is little evidence specifically evaluating DE-EBRT for patients with high-risk prostate cancer receiving ADT, particularly for EBRT doses >74 Gy. We aimed to determine whether DE-EBRT >74 Gy improves outcomes for patients with high-risk prostate cancer receiving long-term ADT. Patients and methods: Patients with high-risk prostate cancer were treated on an institutional protocol prescribing 3–6 months neoadjuvant ADT and DE-EBRT, followed by 2 years of adjuvant ADT. Between 2006 and 2012, EBRT doses were escalated from 74 Gy to 76 Gy and then to 78 Gy. We interrogated our electronic medical record to identify these patients and analyzed our results by comparing dose levels. Results: In all, 479 patients were treated with a 68-month median follow-up. The 5-year biochemical disease-free survivals for the 74 Gy, 76 Gy, and 78 Gy groups were 87.8%, 86.9%, and 91.6%, respectively. The metastasis-free survivals were 95.5%, 94.5%, and 93.9%, respectively, and the prostate cancer-specific survivals were 100%, 94.4%, and 98.1%, respectively. Dose escalation had no impact on any outcome in either univariate or multivariate analysis. Conclusion: There was no benefit of DE-EBRT >74 Gy in our cohort of high-risk prostate patients treated with long-term ADT. As dose escalation has higher risks of radiotherapy-induced toxicity, it may be feasible to omit dose escalation beyond 74 Gy in this group of patients. Randomized studies evaluating dose escalation for high-risk patients receiving ADT should be considered. Keywords: radiotherapy, IMRT, dose

  7. Oral sodium phenylbutyrate in patients with recurrent malignant gliomas: a dose escalation and pharmacologic study.

    Science.gov (United States)

    Phuphanich, Surasak; Baker, Sharyn D; Grossman, Stuart A; Carson, Kathryn A; Gilbert, Mark R; Fisher, Joy D; Carducci, Michael A

    2005-04-01

    We determined the maximum tolerated dose (MTD), toxicity profile, pharmacokinetic parameters, and preliminary efficacy data of oral sodium phenylbutyrate (PB) in patients with recurrent malignant gliomas. Twenty-three patients with supratentorial recurrent malignant gliomas were enrolled on this dose escalation trial. Four dose levels of PB were studied: 9, 18, 27, and 36 g/day. Data were collected to assess toxicity, response, survival, and pharmacokinetics. All PB doses of 9, 18, and 27 g/day were well tolerated. At 36 g/day, two of four patients developed dose-limiting grade 3 fatigue and somnolence. At the MTD of 27 g/day, one of seven patients developed reversible grade 3 somnolence. Median survival from time of study entry was 5.4 months. One patient had a complete response for five years, and no partial responses were noted, which yielded an overall response rate of 5%. Plasma concentrations of 706, 818, 1225, and 1605 muM were achieved with doses of 9, 18, 27, and 36 g/day, respectively. The mean value for PB clearance in this patient population was 22 liters/h, which is significantly higher than the 16 liters/h reported in patients with other malignancies who were not receiving P450 enzyme-inducing anticonvulsant drugs (P = 0.038). This study defines the MTD and recommended phase 2 dose of PB at 27 g/day for heavily pretreated patients with recurrent gliomas. The pharmacology of PB appears to be affected by concomitant administration of P450-inducing anticonvulsants.

  8. Oral sodium phenylbutyrate in patients with recurrent malignant gliomas: A dose escalation and pharmacologic study1

    Science.gov (United States)

    Phuphanich, Surasak; Baker, Sharyn D.; Grossman, Stuart A.; Carson, Kathryn A.; Gilbert, Mark R.; Fisher, Joy D.; Carducci, Michael A.

    2005-01-01

    We determined the maximum tolerated dose (MTD), toxicity profile, pharmacokinetic parameters, and preliminary efficacy data of oral sodium phenylbutyrate (PB) in patients with recurrent malignant gliomas. Twenty-three patients with supratentorial recurrent malignant gliomas were enrolled on this dose escalation trial. Four dose levels of PB were studied: 9, 18, 27, and 36 g/day. Data were collected to assess toxicity, response, survival, and pharmacokinetics. All PB doses of 9, 18, and 27 g/day were well tolerated. At 36 g/day, two of four patients developed dose-limiting grade 3 fatigue and somnolence. At the MTD of 27 g/day, one of seven patients developed reversible grade 3 somnolence. Median survival from time of study entry was 5.4 months. One patient had a complete response for five years, and no partial responses were noted, which yielded an overall response rate of 5%. Plasma concentrations of 706, 818, 1225, and 1605 μM were achieved with doses of 9, 18, 27, and 36 g/day, respectively. The mean value for PB clearance in this patient population was 22 liters/h, which is significantly higher than the 16 liters/h reported in patients with other malignancies who were not receiving P450 enzyme–inducing anticonvulsant drugs (P = 0.038). This study defines the MTD and recommended phase 2 dose of PB at 27 g/day for heavily pretreated patients with recurrent gliomas. The pharmacology of PB appears to be affected by concomitant administration of P450-inducing anticonvulsants. PMID:15831235

  9. Decision Regret in Men Undergoing Dose-Escalated Radiation Therapy for Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Steer, Anna N. [Department of Radiation Oncology, North Coast Cancer Institute, Coffs Harbour (Australia); Aherne, Noel J., E-mail: noel.aherne@ncahs.health.nsw.gov.au [Department of Radiation Oncology, North Coast Cancer Institute, Coffs Harbour (Australia); Rural Clinical School Faculty of Medicine, University of New South Wales, Coffs Harbour (Australia); Gorzynska, Karen; Hoffman, Matthew; Last, Andrew; Hill, Jacques [Department of Radiation Oncology, North Coast Cancer Institute, Coffs Harbour (Australia); Shakespeare, Thomas P. [Department of Radiation Oncology, North Coast Cancer Institute, Coffs Harbour (Australia); Rural Clinical School Faculty of Medicine, University of New South Wales, Coffs Harbour (Australia)

    2013-07-15

    Purpose: Decision regret (DR) is a negative emotion associated with medical treatment decisions, and it is an important patient-centered outcome after therapy for localized prostate cancer. DR has been found to occur in up to 53% of patients treated for localized prostate cancer, and it may vary depending on treatment modality. DR after modern dose-escalated radiation therapy (DE-RT) has not been investigated previously, to our knowledge. Our primary aim was to evaluate DR in a cohort of patients treated with DE-RT. Methods and Materials: We surveyed 257 consecutive patients with localized prostate cancer who had previously received DE-RT, by means of a validated questionnaire. Results: There were 220 responses (85.6% response rate). Image-guided intensity modulated radiation therapy was given in 85.0% of patients and 3-dimensional conformal radiation therapy in 15.0%. Doses received included 73.8 Gy (34.5% patients), 74 Gy (53.6%), and 76 Gy (10.9%). Neoadjuvant androgen deprivation (AD) was given in 51.8% of patients and both neoadjuvant and adjuvant AD in 34.5%. The median follow-up time was 23 months (range, 12-67 months). In all, 3.8% of patients expressed DR for their choice of treatment. When asked whether they would choose DE-RT or AD again, only 0.5% probably or definitely would not choose DE-RT again, compared with 8.4% for AD (P<.01). Conclusion: Few patients treated with modern DE-RT express DR, with regret appearing to be lower than in previously published reports of patients treated with radical prostatectomy or older radiation therapy techniques. Patients experienced more regret with the AD component of treatment than with the radiation therapy component, with implications for informed consent. Further research should investigate regret associated with individual components of modern therapy, including AD, radiation therapy and surgery.

  10. A dose escalation study of concurrent chemoradiation therapy with nedaplatin for cervical cancer

    International Nuclear Information System (INIS)

    Hatae, Masayuki; Takahashi, Takeshi; Kodama, Shoji

    2005-01-01

    Doses of nedaplatin (CDGP) were established for concurrent chemoradiation therapy (CCRT) for cervical cancer, and a collaborative dose escalation study involving 8 hospitals was conducted to investigate the safety and efficacy of this therapy. Radiotherapy was performed according to the standard treatment described in the Regulations of Cervical Carcinoma Treatment. CDGP at 80 mg/m 2 as Level 1 or at 90 mg/m 2 as Level 2 was administered on Days 1 and 29 of treatment. Dose-limiting toxicity (DLT) was observed in 1 of 6 patients receiving 80 mg/m 2 of CDGP and in all 2 patients receiving 90 mg/m 2 of CDGP; therefore, Level 2 was regarded as the maximum tolerated dose (MTD), and Level 1 as the recommended dose. DLT signs consisted of delayed improvement in the leukocyte count in 2 patients and anorexia in 1 patient, suggesting that delayed improvement in the leukocyte count is the main DLT of this combination therapy. The main side effects were digestive disorders such as nausea and anorexia and bone marrow suppression, such as leukopenia, neutropenia, and thrombopenia. Side effects in the Level 1 group were more mild than in the Level 2 group. The efficacy was partial response (PR) or better in all patients. The complete response (CR) rates were 60% (6/10) in the Level 1 group and 50% (1/2) in the Level 2 group; there was no marked difference between the two groups. These results suggest that CCRT involving administration CDGP at 80 mg/m 2 on Days 1 and 29 is safe and effective. (author)

  11. Dose escalation of cisplatin with 5-fluorouracil in concurrent chemoradiotherapy for esophageal carcinoma

    International Nuclear Information System (INIS)

    Lin Qiang; Gao Xianshu; Qiao Xueying; Zhou Zhiguo; Zhang Jun; Yang Xiangran; Wan Xin

    2006-01-01

    Objective: To define the maximum-tolerated dose (MTD) and observe the side effect of escalating cisplatin with 5-fluorouracil in concurrent chemoradiotherapy for esophageal carcinoma in Chinese, with toxicity studied. Methods: Previously untreated fifteen Chinese patients suffering from esophageal carcinoma received conventional fractionation radiotherapy, with 5 daily fractions of 2.0 Gy per week. The total radiation dose was 60 Gy. Concurrent chemotherapy dose escalation was given by the relatively safe and kidney-sparing modified Fibonacci sequence. The starting dose was cisplatin 37.5 mg/m 2 D1 and 5-fluorouracil 500 mg/m 2 D1-5, respectively. This regimen was repeated 4 times every 28 days. Escalation dose was cisplatin 7.5 mg/m 2 and 5- fluorouracil 100 mg/m 2 . Every. cohort contained at least 3 patients. If no dose-limiting toxicity(DLT) was observed, the next dose level was opened for entry. These courses were repeated until DLT appeared. MTD was declared as one dose level below which DLT appeared. Results: DLT was defined as grade 3 radiation-induced esophagitis at the level of cisplatin 60 mg/m2, 5-fluorouracil 700 mg/m 2 . MTD was defined as cisplatin 52.5 mg/m 2 , 5- fiuorouracil 700 mg/m 2 . The major side effect were radiation-induced esophagitis, leucopenia, nausea, vomiting and anorexia. Conclusion: Maximun tolerated dose of cisplatin with 5-fiuorouracil in concurrent ehemoradiotherapy in the Chinese people with esophageal carcinoma were eisplatin 52.5 mg/m2 D1,5-fluorouracil 700 mg/m 2 D1-5, repeated 4 times every 28 days. (authors)

  12. Decision Regret in Men Undergoing Dose-Escalated Radiation Therapy for Prostate Cancer

    International Nuclear Information System (INIS)

    Steer, Anna N.; Aherne, Noel J.; Gorzynska, Karen; Hoffman, Matthew; Last, Andrew; Hill, Jacques; Shakespeare, Thomas P.

    2013-01-01

    Purpose: Decision regret (DR) is a negative emotion associated with medical treatment decisions, and it is an important patient-centered outcome after therapy for localized prostate cancer. DR has been found to occur in up to 53% of patients treated for localized prostate cancer, and it may vary depending on treatment modality. DR after modern dose-escalated radiation therapy (DE-RT) has not been investigated previously, to our knowledge. Our primary aim was to evaluate DR in a cohort of patients treated with DE-RT. Methods and Materials: We surveyed 257 consecutive patients with localized prostate cancer who had previously received DE-RT, by means of a validated questionnaire. Results: There were 220 responses (85.6% response rate). Image-guided intensity modulated radiation therapy was given in 85.0% of patients and 3-dimensional conformal radiation therapy in 15.0%. Doses received included 73.8 Gy (34.5% patients), 74 Gy (53.6%), and 76 Gy (10.9%). Neoadjuvant androgen deprivation (AD) was given in 51.8% of patients and both neoadjuvant and adjuvant AD in 34.5%. The median follow-up time was 23 months (range, 12-67 months). In all, 3.8% of patients expressed DR for their choice of treatment. When asked whether they would choose DE-RT or AD again, only 0.5% probably or definitely would not choose DE-RT again, compared with 8.4% for AD (P<.01). Conclusion: Few patients treated with modern DE-RT express DR, with regret appearing to be lower than in previously published reports of patients treated with radical prostatectomy or older radiation therapy techniques. Patients experienced more regret with the AD component of treatment than with the radiation therapy component, with implications for informed consent. Further research should investigate regret associated with individual components of modern therapy, including AD, radiation therapy and surgery

  13. Dose Escalated Liver Stereotactic Body Radiation Therapy at the Mean Respiratory Position

    International Nuclear Information System (INIS)

    Velec, Michael; Moseley, Joanne L.; Dawson, Laura A.; Brock, Kristy K.

    2014-01-01

    Purpose: The dosimetric impact of dose probability based planning target volume (PTV) margins for liver cancer patients receiving stereotactic body radiation therapy (SBRT) was compared with standard PTV based on the internal target volume (ITV). Plan robustness was evaluated by accumulating the treatment dose to ensure delivery of the intended plan. Methods and Materials: Twenty patients planned on exhale CT for 27 to 50 Gy in 6 fractions using an ITV-based PTV and treated free-breathing were retrospectively evaluated. Isotoxic, dose escalated plans were created on midposition computed tomography (CT), representing the mean breathing position, using a dose probability PTV. The delivered doses were accumulated using biomechanical deformable registration of the daily cone beam CT based on liver targeting at the exhale or mean breathing position, for the exhale and midposition CT plans, respectively. Results: The dose probability PTVs were on average 38% smaller than the ITV-based PTV, enabling an average ± standard deviation increase in the planned dose to 95% of the PTV of 4.0 ± 2.8 Gy (9 ± 5%) on the midposition CT (P<.01). For both plans, the delivered minimum gross tumor volume (GTV) doses were greater than the planned nominal prescribed dose in all 20 patients and greater than the planned dose to 95% of the PTV in 18 (90%) patients. Nine patients (45%) had 1 or more GTVs with a delivered minimum dose more than 5 Gy higher with the midposition CT plan using dose probability PTV, compared with the delivered dose with the exhale CT plan using ITV-based PTV. Conclusions: For isotoxic liver SBRT planned and delivered at the mean respiratory, reduced dose probability PTV enables a mean escalation of 4 Gy (9%) in 6 fractions over ITV-based PTV. This may potentially improve local control without increasing the risk of tumor underdosing

  14. Dose-Escalation Study for Cardiac Radiosurgery in a Porcine Model

    Energy Technology Data Exchange (ETDEWEB)

    Blanck, Oliver, E-mail: oliver.blanck@uksh.de [Department of Radiation Oncology, University of Luebeck and University Medical Center Schleswig-Holstein, Campus Luebeck (Germany); CyberKnife Center Northern Germany, Guestrow (Germany); Bode, Frank [Medical Department II, University of Luebeck and University Medical Center Schleswig-Holstein, Campus Luebeck (Germany); Gebhard, Maximilian [Institute of Pathology, University of Luebeck and University Medical Center Schleswig-Holstein, Campus Luebeck (Germany); Hunold, Peter [Department of Radiology and Nuclear Medicine, University of Luebeck and University Medical Center Schleswig-Holstein, Campus Luebeck (Germany); Brandt, Sebastian [Department of Anaesthesiology and Intensive Care Medicine, University of Luebeck and University Medical Center Schleswig-Holstein, Campus Luebeck (Germany); Bruder, Ralf [Institute for Robotics and Cognitive Systems, University of Luebeck and University Medical Center Schleswig-Holstein, Campus Luebeck (Germany); Grossherr, Martin [Department of Anaesthesiology and Intensive Care Medicine, University of Luebeck and University Medical Center Schleswig-Holstein, Campus Luebeck (Germany); Vonthein, Reinhard [Institute of Medical Biometry and Statistics, University of Luebeck and University Medical Center Schleswig-Holstein, Campus Luebeck (Germany); Rades, Dirk [Department of Radiation Oncology, University of Luebeck and University Medical Center Schleswig-Holstein, Campus Luebeck (Germany); Dunst, Juergen [Department of Radiation Oncology, University of Luebeck and University Medical Center Schleswig-Holstein, Campus Luebeck (Germany); University Copenhagen (Denmark)

    2014-07-01

    Purpose: To perform a proof-of-principle dose-escalation study to radiosurgically induce scarring in cardiac muscle tissue to block veno-atrial electrical connections at the pulmonary vein antrum, similar to catheter ablation. Methods and Materials: Nine mini-pigs underwent pretreatment magnetic resonance imaging (MRI) evaluation of heart function and electrophysiology assessment by catheter measurements in the right superior pulmonary vein (RSPV). Immediately after examination, radiosurgery with randomized single-fraction doses of 0 and 17.5-35 Gy in 2.5-Gy steps were delivered to the RSPV antrum (target volume 5-8 cm{sup 3}). MRI and electrophysiology were repeated 6 months after therapy, followed by histopathologic examination. Results: Transmural scarring of cardiac muscle tissue was noted with doses ≥32.5 Gy. However, complete circumferential scarring of the RSPV was not achieved. Logistic regressions showed that extent and intensity of fibrosis significantly increased with dose. The 50% effective dose for intense fibrosis was 31.3 Gy (odds ratio 2.47/Gy, P<.01). Heart function was not affected, as verified by MRI and electrocardiogram evaluation. Adjacent critical structures were not damaged, as verified by pathology, demonstrating the short-term safety of small-volume cardiac radiosurgery with doses up to 35 Gy. Conclusions: Radiosurgery with doses >32.5 Gy in the healthy pig heart can induce circumscribed scars at the RSPV antrum noninvasively, mimicking the effect of catheter ablation. In our study we established a significant dose-response relationship for cardiac radiosurgery. The long-term effects and toxicity of such high radiation doses need further investigation in the pursuit of cardiac radiosurgery for noninvasive treatment of atrial fibrillation.

  15. Decision regret in men undergoing dose-escalated radiation therapy for prostate cancer.

    Science.gov (United States)

    Steer, Anna N; Aherne, Noel J; Gorzynska, Karen; Hoffman, Matthew; Last, Andrew; Hill, Jacques; Shakespeare, Thomas P

    2013-07-15

    Decision regret (DR) is a negative emotion associated with medical treatment decisions, and it is an important patient-centered outcome after therapy for localized prostate cancer. DR has been found to occur in up to 53% of patients treated for localized prostate cancer, and it may vary depending on treatment modality. DR after modern dose-escalated radiation therapy (DE-RT) has not been investigated previously, to our knowledge. Our primary aim was to evaluate DR in a cohort of patients treated with DE-RT. We surveyed 257 consecutive patients with localized prostate cancer who had previously received DE-RT, by means of a validated questionnaire. There were 220 responses (85.6% response rate). Image-guided intensity modulated radiation therapy was given in 85.0% of patients and 3-dimensional conformal radiation therapy in 15.0%. Doses received included 73.8 Gy (34.5% patients), 74 Gy (53.6%), and 76 Gy (10.9%). Neoadjuvant androgen deprivation (AD) was given in 51.8% of patients and both neoadjuvant and adjuvant AD in 34.5%. The median follow-up time was 23 months (range, 12-67 months). In all, 3.8% of patients expressed DR for their choice of treatment. When asked whether they would choose DE-RT or AD again, only 0.5% probably or definitely would not choose DE-RT again, compared with 8.4% for AD (P<.01). Few patients treated with modern DE-RT express DR, with regret appearing to be lower than in previously published reports of patients treated with radical prostatectomy or older radiation therapy techniques. Patients experienced more regret with the AD component of treatment than with the radiation therapy component, with implications for informed consent. Further research should investigate regret associated with individual components of modern therapy, including AD, radiation therapy and surgery. Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.

  16. Dose-escalated simultaneous integrated-boost treatment of prostate cancer patients via helical tomotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Geier, M.; Astner, S.T.; Duma, M.N.; Putzhammer, J.; Winkler, C.; Molls, M.; Geinitz, H. [Technische Univ. Muenchen (Germany). Klinik und Poliklinik fuer Strahlentherapie und Radiologische Onkologie; Jacob, V. [Universitaetsklinikum Freiburg (Germany). Klinik fuer Strahlenheilkunde; Nieder, C. [Nordland Hospital, Bodoe (Norway). Dept. of Oncology and Palliative Care; Tromsoe Univ. (Norway). Inst. of Clinical Medicine

    2012-05-15

    The goal of this work was to assess the feasibility of moderately hypofractionated simultaneous integrated-boost intensity-modulated radiotherapy (SIB-IMRT) with helical tomotherapy in patients with localized prostate cancer regarding acute side effects and dose-volume histogram data (DVH data). Acute side effects and DVH data were evaluated of the first 40 intermediate risk prostate cancer patients treated with a definitive daily image-guided SIB-IMRT protocol via helical tomotherapy in our department. The planning target volume including the prostate and the base of the seminal vesicles with safety margins was treated with 70 Gy in 35 fractions. The boost volume containing the prostate and 3 mm safety margins (5 mm craniocaudal) was treated as SIB to a total dose of 76 Gy (2.17 Gy per fraction). Planning constraints for the anterior rectal wall were set in order not to exceed the dose of 76 Gy prescribed to the boost volume. Acute toxicity was evaluated prospectively using a modified CTCAE (Common Terminology Criteria for Adverse Events) score. SIB-IMRT allowed good rectal sparing, although the full boost dose was permitted to the anterior rectal wall. Median rectum dose was 38 Gy in all patients and the median volumes receiving at least 65 Gy (V65), 70 Gy (V70), and 75 Gy (V75) were 13.5%, 9%, and 3%, respectively. No grade 4 toxicity was observed. Acute grade 3 toxicity was observed in 20% of patients involving nocturia only. Grade 2 acute intestinal and urological side effects occurred in 25% and 57.5%, respectively. No correlation was found between acute toxicity and the DVH data. This institutional SIB-IMRT protocol using daily image guidance as a precondition for smaller safety margins allows dose escalation to the prostate without increasing acute toxicity. (orig.)

  17. Dose escalation using conformal high-dose-rate brachytherapy improves outcome in unfavorable prostate cancer.

    Science.gov (United States)

    Martinez, Alvaro A; Gustafson, Gary; Gonzalez, José; Armour, Elwood; Mitchell, Chris; Edmundson, Gregory; Spencer, William; Stromberg, Jannifer; Huang, Raywin; Vicini, Frank

    2002-06-01

    To overcome radioresistance for patients with unfavorable prostate cancer, a prospective trial of pelvic external beam irradiation (EBRT) interdigitated with dose-escalating conformal high-dose-rate (HDR) prostate brachytherapy was performed. Between November 1991 and August 2000, 207 patients were treated with 46 Gy pelvic EBRT and increasing HDR brachytherapy boost doses (5.50-11.5 Gy/fraction) during 5 weeks. The eligibility criteria were pretreatment prostate-specific antigen level >or=10.0 ng/mL, Gleason score >or=7, or clinical Stage T2b or higher. Patients were divided into 2 dose levels, low-dose biologically effective dose 93 Gy (149 patients). No patient received hormones. We used the American Society for Therapeutic Radiology and Oncology definition for biochemical failure. The median age was 69 years. The mean follow-up for the group was 4.4 years, and for the low and high-dose levels, it was 7.0 and 3.4 years, respectively. The actuarial 5-year biochemical control rate was 74%, and the overall, cause-specific, and disease-free survival rate was 92%, 98%, and 68%, respectively. The 5-year biochemical control rate for the low-dose group was 52%; the rate for the high-dose group was 87% (p failure. The Radiation Therapy Oncology Group Grade 3 gastrointestinal/genitourinary complications ranged from 0.5% to 9%. The actuarial 5-year impotency rate was 51%. Pelvic EBRT interdigitated with transrectal ultrasound-guided real-time conformal HDR prostate brachytherapy boost is both a precise dose delivery system and a very effective treatment for unfavorable prostate cancer. We demonstrated an incremental beneficial effect on biochemical control and cause-specific survival with higher doses. These results, coupled with the low risk of complications, the advantage of not being radioactive after implantation, and the real-time interactive planning, define a new standard for treatment.

  18. Dose escalation with 3D conformal treatment: five year outcomes, treatment optimization, and future directions

    International Nuclear Information System (INIS)

    Hanks, Gerald E.; Hanlon, Alexandra L. M.S.; Schultheiss, Timothy E.; Pinover, Wayne H.; Movsas, Benjamin; Epstein, Barry E.; Hunt, Margie

    1998-01-01

    Purpose: To report the 5-year outcomes of dose escalation with 3D conformal treatment (3DCRT) of prostate cancer. Methods and Materials: Two hundred thirty-two consecutive patients were treated with 3DCRT alone between 6/89 and 10/92 with ICRU reporting point dose that increased from 63 to 79 Gy. The median follow-up was 60 months, and any patient free of clinical or biochemical evidence of disease was termed bNED. Biochemical failure was defined as prostate-specific antigen (PSA) rising on two consecutive recordings and exceeding 1.5 ng/ml. Morbidity was reported by the Radiation Therapy Oncology Group (RTOG) scale, the Late Effects Normal Tissue (LENT) scale, and a Fox Chase modification of the latter (FC-LENT). All patients were treated with a four-field technique with a 1 cm clinical target volume (CTV) to planning target volume (PTV) margin to the prostate or prostate boost; the CTV and gross tumor volume (GTV) were the same. Actuarial rates of outcome were calculated by Kaplan-Meier and cumulative incidence methods and compared using the log rank and Gray's test statistic, respectively. Cox regression models were used to establish prognostic factors predictive of the various measures of outcome. Five-year Kaplan-Meier bNED rates were utilized by dose group to estimate logit response models for bNED and late morbidity. Results: PSA 10 ng/ml based on 5-year bNED results. No dose response was observed for patients with pretreatment PSA 10 ng/ml strongly suggests that clinical trials employing radiation should investigate the use of 3DCRT and prostate doses of 76-80 Gy

  19. Dose escalation to rash for erlotinib plus gemcitabine for metastatic pancreatic cancer: the phase II RACHEL study.

    Science.gov (United States)

    Van Cutsem, E; Li, C-P; Nowara, E; Aprile, G; Moore, M; Federowicz, I; Van Laethem, J-L; Hsu, C; Tham, C K; Stemmer, S M; Lipp, R; Zeaiter, A; Fittipaldo, A; Csutor, Z; Klughammer, B; Meng, X; Ciuleanu, T

    2014-11-25

    This phase II, open-label, randomised study evaluated whether patients with metastatic pancreatic cancer receiving erlotinib/gemcitabine derived survival benefits from increasing the erlotinib dose. After a 4-week run-in period (gemcitabine 1000 mg m(-2) once weekly plus erlotinib 100 mg per day), patients with metastatic pancreatic cancer who developed grade 0/1 rash were randomised to receive gemcitabine plus erlotinib dose escalation (150 mg, increasing by 50 mg every 2 weeks (maximum 250 mg); n=71) or gemcitabine plus standard-dose erlotinib (100 mg per day; n=75). The primary end point was to determine whether overall survival (OS) was improved by increasing the erlotinib dose. Secondary end points included progression-free survival (PFS), incidence of grade ⩾2 rash, and safety. Erlotinib dose escalation induced grade ⩾2 rash in 29 out of 71 (41.4%) patients compared with 7 out of 75 (9.3%) patients on standard dose. Efficacy was not significantly different in the dose-escalation arm compared with the standard-dose arm (OS: median 7.0 vs 8.4 months, respectively, hazard ratio (HR), 1.26, 95% confidence interval (CI): 0.88-1.80; P=0.2026; PFS: median 3.5 vs 4.5 months, respectively, HR, 1.09, 95% CI: 0.77-1.54; P=0.6298). Incidence of adverse events was comparable between randomised arms. The erlotinib dose-escalation strategy induced rash in some patients; there was no evidence that the higher dose translated into increased benefit.

  20. Subgroup analysis of patients with localized prostate cancer treated within the Dutch-randomized dose escalation trial

    International Nuclear Information System (INIS)

    Al-Mamgani, Abrahim; Heemsbergen, Wilma D.; Levendag, Peter C.; Lebesque, Joos V.

    2010-01-01

    Purpose: To investigate the effect of dose escalation within prognostic risk groups in prostate cancer. Patients and methods: Between 1997 and 2003, 664 patients with localized prostate cancer were randomly assigned to receive 68- or 78-Gy of radiotherapy. Two prognostic models were examined: a risk group model (low-, intermediate-, and high-risk) and PSA-level groupings. High-risk patients with hormonal therapy (HT) were analyzed separately. Outcome variable was freedom from failure (FFF) (clinical failure or PSA nadir + 2 μg/L). Results: In relation to the advantage of high-dose radiotherapy, intermediate-risk patients benefited most from dose escalation. However no significant heterogeneity could be demonstrated between the risk groups. For two types of PSA-level groupings: PSA 8 μg/L, the test for heterogeneity was significant (p = 0.03 and 0.05, respectively). Patients with PSA 8-18 μg/L (n = 297, HR = 0.59) derived the greatest benefit from dose escalation. No heterogeneity could be demonstrated for high-risk patients with and without HT. Conclusion: Intermediate-risk group derived the greatest benefit for dose escalation. However, from this trial no indication was found to exclude low-risk or high-risk patients from high-dose radiotherapy. Patients could be selected for high-dose radiotherapy based on PSA-level groupings: for patients with a PSA < 8 μg/L high-dose radiotherapy is probably not indicated, but should be confirmed in other randomized studies.

  1. Intensity-Modulated Radiotherapy for Locally Advanced Non-Small-Cell Lung Cancer: A Dose-Escalation Planning Study

    International Nuclear Information System (INIS)

    Lievens, Yolande; Nulens, An; Gaber, Mousa Amr; Defraene, Gilles; De Wever, Walter; Stroobants, Sigrid; Van den Heuvel, Frank

    2011-01-01

    Purpose: To evaluate the potential for dose escalation with intensity-modulated radiotherapy (IMRT) in positron emission tomography-based radiotherapy planning for locally advanced non-small-cell lung cancer (LA-NSCLC). Methods and Materials: For 35 LA-NSCLC patients, three-dimensional conformal radiotherapy and IMRT plans were made to a prescription dose (PD) of 66 Gy in 2-Gy fractions. Dose escalation was performed toward the maximal PD using secondary endpoint constraints for the lung, spinal cord, and heart, with de-escalation according to defined esophageal tolerance. Dose calculation was performed using the Eclipse pencil beam algorithm, and all plans were recalculated using a collapsed cone algorithm. The normal tissue complication probabilities were calculated for the lung (Grade 2 pneumonitis) and esophagus (acute toxicity, grade 2 or greater, and late toxicity). Results: IMRT resulted in statistically significant decreases in the mean lung (p <.0001) and maximal spinal cord (p = .002 and 0005) doses, allowing an average increase in the PD of 8.6-14.2 Gy (p ≤.0001). This advantage was lost after de-escalation within the defined esophageal dose limits. The lung normal tissue complication probabilities were significantly lower for IMRT (p <.0001), even after dose escalation. For esophageal toxicity, IMRT significantly decreased the acute NTCP values at the low dose levels (p = .0009 and p <.0001). After maximal dose escalation, late esophageal tolerance became critical (p <.0001), especially when using IMRT, owing to the parallel increases in the esophageal dose and PD. Conclusion: In LA-NSCLC, IMRT offers the potential to significantly escalate the PD, dependent on the lung and spinal cord tolerance. However, parallel increases in the esophageal dose abolished the advantage, even when using collapsed cone algorithms. This is important to consider in the context of concomitant chemoradiotherapy schedules using IMRT.

  2. Integrated boost IMRT with FET-PET-adapted local dose escalation in glioblastomas. Results of a prospective phase II study

    International Nuclear Information System (INIS)

    Piroth, M.D.; Pinkawa, M.; Holy, R.; Forschungszentrum Juelich GmbH

    2012-01-01

    Dose escalations above 60 Gy based on MRI have not led to prognostic benefits in glioblastoma patients yet. With positron emission tomography (PET) using [ 18 F]fluorethyl-L-tyrosine (FET), tumor coverage can be optimized with the option of regional dose escalation in the area of viable tumor tissue. In a prospective phase II study (January 2008 to December 2009), 22 patients (median age 55 years) received radiochemotherapy after surgery. The radiotherapy was performed as an MRI and FET-PET-based integrated-boost intensity-modulated radiotherapy (IMRT). The prescribed dose was 72 and 60 Gy (single dose 2.4 and 2.0 Gy, respectively) for the FET-PET- and MR-based PTV-FET (72 Gy) and PTV-MR (60 Gy) . FET-PET and MRI were performed routinely for follow-up. Quality of life and cognitive aspects were recorded by the EORTC-QLQ-C30/QLQ Brain20 and Mini-Mental Status Examination (MMSE), while the therapy-related toxicity was recorded using the CTC3.0 and RTOG scores. Median overall survival (OS) and disease-free survival (DFS) were 14.8 and 7.8 months, respectively. All local relapses were detected at least partly within the 95% dose volume of PTV-MR (60 Gy) . No relevant radiotherapy-related side effects were observed (excepted alopecia). In 2 patients, a pseudoprogression was observed in the MRI. Tumor progression could be excluded by FET-PET and was confirmed in further MRI and FET-PET imaging. No significant changes were observed in MMSE scores and in the EORTC QLQ-C30/QLQ-Brain20 questionnaires. Our dose escalation concept with a total dose of 72 Gy, based on FET-PET, did not lead to a survival benefit. Acute and late toxicity were not increased, compared with historical controls and published dose-escalation studies. (orig.)

  3. Integrated boost IMRT with FET-PET-adapted local dose escalation in glioblastomas. Results of a prospective phase II study

    Energy Technology Data Exchange (ETDEWEB)

    Piroth, M.D.; Pinkawa, M.; Holy, R. [RWTH Aachen University Hospital (Germany). Dept. of Radiation Oncology; Forschungszentrum Juelich GmbH (DE). Juelich-Aachen Research Alliance (JARA) - Section JARA-Brain] (and others)

    2012-04-15

    Dose escalations above 60 Gy based on MRI have not led to prognostic benefits in glioblastoma patients yet. With positron emission tomography (PET) using [{sup 18}F]fluorethyl-L-tyrosine (FET), tumor coverage can be optimized with the option of regional dose escalation in the area of viable tumor tissue. In a prospective phase II study (January 2008 to December 2009), 22 patients (median age 55 years) received radiochemotherapy after surgery. The radiotherapy was performed as an MRI and FET-PET-based integrated-boost intensity-modulated radiotherapy (IMRT). The prescribed dose was 72 and 60 Gy (single dose 2.4 and 2.0 Gy, respectively) for the FET-PET- and MR-based PTV-FET{sub (72 Gy)} and PTV-MR{sub (60 Gy)}. FET-PET and MRI were performed routinely for follow-up. Quality of life and cognitive aspects were recorded by the EORTC-QLQ-C30/QLQ Brain20 and Mini-Mental Status Examination (MMSE), while the therapy-related toxicity was recorded using the CTC3.0 and RTOG scores. Median overall survival (OS) and disease-free survival (DFS) were 14.8 and 7.8 months, respectively. All local relapses were detected at least partly within the 95% dose volume of PTV-MR{sub (60 Gy)}. No relevant radiotherapy-related side effects were observed (excepted alopecia). In 2 patients, a pseudoprogression was observed in the MRI. Tumor progression could be excluded by FET-PET and was confirmed in further MRI and FET-PET imaging. No significant changes were observed in MMSE scores and in the EORTC QLQ-C30/QLQ-Brain20 questionnaires. Our dose escalation concept with a total dose of 72 Gy, based on FET-PET, did not lead to a survival benefit. Acute and late toxicity were not increased, compared with historical controls and published dose-escalation studies. (orig.)

  4. A Randomized, Double-Blind Placebo Controlled Trial of Balapiravir, a Polymerase Inhibitor, in Adult Dengue Patients

    Science.gov (United States)

    Nguyen, Nguyet Minh; Tran, Chau Nguyen Bich; Phung, Lam Khanh; Duong, Kien Thi Hue; Huynh, Huy le Anh; Farrar, Jeremy; Nguyen, Quyen Than Ha; Tran, Hien Tinh; Nguyen, Chau Van Vinh; Merson, Laura; Hoang, Long Truong; Hibberd, Martin L.; Aw, Pauline P. K.; Wilm, Andreas; Nagarajan, Niranjan; Nguyen, Dung Thi; Pham, Mai Phuong; Nguyen, Truong Thanh; Javanbakht, Hassan; Klumpp, Klaus; Hammond, Janet; Petric, Rosemary; Wolbers, Marcel; Nguyen, Chinh Tran; Simmons, Cameron P.

    2013-01-01

    Background. Dengue is the most common arboviral infection of humans. There are currently no specific treatments for dengue. Balapiravir is a prodrug of a nucleoside analogue (called R1479) and an inhibitor of hepatitis C virus replication in vivo. Methods. We conducted in vitro experiments to determine the potency of balapiravir against dengue viruses and then an exploratory, dose-escalating, randomized placebo-controlled trial in adult male patients with dengue with treatment. Conclusions. Although this trial, the first of its kind in dengue, does not support balapiravir as a candidate drug, it does establish a framework for antiviral treatment trials in dengue and provides the field with a clinically evaluated benchmark molecule. Clinical Trials Registration. NCT01096576. PMID:22807519

  5. Radiation Dose Escalation in Esophageal Cancer Revisited: A Contemporary Analysis of the National Cancer Data Base, 2004 to 2012

    Energy Technology Data Exchange (ETDEWEB)

    Brower, Jeffrey V. [Department of Human Oncology, University of Wisconsin Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin (United States); Chen, Shuai [Department of Biostatistics and Medical Informatics, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin (United States); Bassetti, Michael F. [Department of Human Oncology, University of Wisconsin Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin (United States); Yu, Menggang [Department of Biostatistics and Medical Informatics, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin (United States); Harari, Paul M.; Ritter, Mark A. [Department of Human Oncology, University of Wisconsin Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin (United States); Baschnagel, Andrew M., E-mail: baschnagel@humonc.wisc.edu [Department of Human Oncology, University of Wisconsin Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin (United States)

    2016-12-01

    Purpose: To evaluate the effect of radiation dose escalation on overall survival (OS) for patients with nonmetastatic esophageal cancer treated with concurrent radiation and chemotherapy. Methods and Materials: Patients diagnosed with stage I to III esophageal cancer treated from 2004 to 2012 were identified from the National Cancer Data Base. Patients who received concurrent radiation and chemotherapy with radiation doses of ≥50 Gy and did not undergo surgery were included. OS was compared using Cox proportional hazards regression and propensity score matching. Results: A total of 6854 patients were included; 3821 (55.7%) received 50 to 50.4 Gy and 3033 (44.3%) received doses >50.4 Gy. Univariate analysis revealed no significant difference in OS between patients receiving 50 to 50.4 Gy and those receiving >50.4 Gy (P=.53). The dose analysis, binned as 50 to 50.4, 51 to 54, 55 to 60, and >60 Gy, revealed no appreciable difference in OS within any group compared with 50 to 50.4 Gy. Subgroup analyses investigating the effect of dose escalation by histologic type and in the setting of intensity modulated radiation therapy also failed to reveal a benefit. Propensity score matching confirmed the absence of a statistically significant difference in OS among the dose levels. The factors associated with improved OS on multivariable analysis included female sex, lower Charlson-Deyo comorbidity score, private insurance, cervical/upper esophagus location, squamous cell histologic type, lower T stage, and node-negative status (P<.01 for all analyses). Conclusions: In this large national cohort, dose escalation >50.4 Gy did not result in improved OS among patients with stage I to III esophageal cancer treated with definitive concurrent radiation and chemotherapy. These data suggest that despite advanced contemporary treatment techniques, OS for patients with esophageal cancer remains unaltered by escalation of radiation dose >50.4 Gy, consistent with the results of

  6. Dose escalation using conformal high-dose-rate brachytherapy improves outcome in unfavorable prostate cancer

    International Nuclear Information System (INIS)

    Martinez, Alvaro A.; Gustafson, Gary; Gonzalez, Jose; Armour, Elwood; Mitchell, Chris; Edmundson, Gregory; Spencer, William; Stromberg, Jannifer; Huang, Raywin; Vicini, Frank

    2002-01-01

    Purpose: To overcome radioresistance for patients with unfavorable prostate cancer, a prospective trial of pelvic external beam irradiation (EBRT) interdigitated with dose-escalating conformal high-dose-rate (HDR) prostate brachytherapy was performed. Methods and Materials: Between November 1991 and August 2000, 207 patients were treated with 46 Gy pelvic EBRT and increasing HDR brachytherapy boost doses (5.50-11.5 Gy/fraction) during 5 weeks. The eligibility criteria were pretreatment prostate-specific antigen level ≥10.0 ng/mL, Gleason score ≥7, or clinical Stage T2b or higher. Patients were divided into 2 dose levels, low-dose biologically effective dose 93 Gy (149 patients). No patient received hormones. We used the American Society for Therapeutic Radiology and Oncology definition for biochemical failure. Results: The median age was 69 years. The mean follow-up for the group was 4.4 years, and for the low and high-dose levels, it was 7.0 and 3.4 years, respectively. The actuarial 5-year biochemical control rate was 74%, and the overall, cause-specific, and disease-free survival rate was 92%, 98%, and 68%, respectively. The 5-year biochemical control rate for the low-dose group was 52%; the rate for the high-dose group was 87% (p<0.001). Improvement occurred in the cause-specific survival in favor of the brachytherapy high-dose level (p=0.014). On multivariate analysis, a low-dose level, higher Gleason score, and higher nadir value were associated with increased biochemical failure. The Radiation Therapy Oncology Group Grade 3 gastrointestinal/genitourinary complications ranged from 0.5% to 9%. The actuarial 5-year impotency rate was 51%. Conclusion: Pelvic EBRT interdigitated with transrectal ultrasound-guided real-time conformal HDR prostate brachytherapy boost is both a precise dose delivery system and a very effective treatment for unfavorable prostate cancer. We demonstrated an incremental beneficial effect on biochemical control and cause

  7. Pharmacogenetic testing for clopidogrel using the rapid INFINITI analyzer: a dose-escalation study.

    Science.gov (United States)

    Gladding, Patrick; White, Harvey; Voss, Jamie; Ormiston, John; Stewart, Jim; Ruygrok, Peter; Bvaldivia, Badi; Baak, Ruth; White, Catherine; Webster, Mark

    2009-11-01

    Our aim was to assess whether a higher clopidogrel maintenance dose has a greater antiplatelet effect in CYP2C19*2 allele carriers compared with noncarriers. Clopidogrel is a prodrug that is biotransformed by the cytochrome P450 enzymes CYP2C19, 2C9, and 3A4, 2B6, 1A2. The CYPC219*2 loss of function variant has been associated with a reduced antiplatelet response to clopidogrel and a 3-fold risk of stent thrombosis. Forty patients on standard maintenance dosage clopidogrel (75 mg), for 9.4 +/- 9.2 weeks, were enrolled into a dose escalation study. Platelet function was assessed at baseline and after 1 week of 150 mg once daily using the VerifyNow platelet function analyzer (Accumetrics Ltd., San Diego, California). Genomic DNA was hybridized to a BioFilmChip microarray on the INFINITI analyzer (AutoGenomics Inc., Carlsbad, California) and analyzed for the CYP19*2, *4, *17, and CYP2C9*2, *3 polymorphisms. Platelet inhibition increased over 1 week, mean +8.6 +/- 13.5% (p = 0.0003). Carriers of the CYP2C19*2 allele had significantly reduced platelet inhibition at baseline (median 18%, range 0% to 72%) compared with wildtype (wt) (median 59%, range 11% to 95%, p = 0.01) and at 1 week (p = 0.03). CYP2C19*2 allele carriers had an increase in platelet inhibition of (mean +9 +/- 11%, p = 0.03) and reduction in platelet reactivity (mean -26 +/- 38 platelet response unit, p = 0.04) with a higher dose. Together CYP2C19*2 and CYP2C9*3 loss of function carriers had a greater change in platelet inhibition with 150 mg daily than wt/wt (+10.9% vs. +0.7%, p = 0.04). Increasing the dose of clopidogrel in patients with nonresponder polymorphisms can increase antiplatelet response. Personalizing clopidogrel dosing using pharmacogenomics may be an effective method of optimizing treatment.

  8. Dose escalation by hypo fractionation in localized prostate cancer - a large single institution experience

    International Nuclear Information System (INIS)

    Mahadevan, A.; Klein, E.; Kupelian, P.

    2003-01-01

    . Hypofractionation is an effective method to dose escalate in localized prostate cancer. Longer follow-up is needed to further substantiate these results

  9. A randomised controlled trial of the efficacy and safety of allopurinol dose escalation to achieve target serum urate in people with gout.

    Science.gov (United States)

    Stamp, Lisa K; Chapman, Peter T; Barclay, Murray L; Horne, Anne; Frampton, Christopher; Tan, Paul; Drake, Jill; Dalbeth, Nicola

    2017-09-01

    To determine the efficacy and safety of allopurinol dose escalation using a treat-to-target serum urate (SU) approach. A randomised, controlled, parallel-group, comparative clinical trial was undertaken. People with gout receiving at least creatinine clearance (CrCL)-based allopurinol dose for ≥1 month and SU ≥6 mg/dL were recruited. Participants were randomised to continue current dose (control) or allopurinol dose escalation for 12 months. In the dose escalation group, allopurinol was increased monthly until SU was gout. Allopurinol dose escalation is well tolerated. ANZCTR12611000845932; Results. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  10. Tomotherapy PET-guided dose escalation. A dosimetric feasibility study for patients with malignant pleural mesothelioma

    Energy Technology Data Exchange (ETDEWEB)

    Maggio, Angelo; Cutaia, Claudia; Di Dia, Amalia; Bresciani, Sara; Miranti, Anna; Poli, Matteo; Stasi, Michele [Candiolo Cancer Institute - FPO, IRCCS, Medical Physics, Turin (Italy); Del Mastro, Elena; Garibaldi, Elisabetta; Gabriele, Pietro [Candiolo Cancer Institute - FPO, IRCCS, Radiotherapy Department, Turin (Italy)

    2016-02-15

    The aim of this study was to investigate whether a safe escalation of the dose to the pleural cavity and PET/CT-positive areas in patients with unresectable malignant pleural mesothelioma (MPM) is possible using helical tomotherapy (HT). We selected 12 patients with MPM. Three planning strategies were investigated. In the first strategy (standard treatment), treated comprised a prescribed median dose to the planning target volume (PTV) boost (PTV{sub 1}) of 64.5 Gy (range: 56 Gy/28 fractions to 66 Gy/30 fractions) and 51 Gy (range: 50.4 Gy/28 fractions to 54 Gy/30 fractions) to the pleura PTV (PTV{sub 2}). Thereafter, for each patient, two dose escalation plans were generated prescribing 62.5 and 70 Gy (2.5 and 2.8 Gy/fraction, respectively) to the PTV{sub 1} and 56 Gy (2.24 Gy/fraction) to the PTV{sub 2}, in 25 fractions. Dose-volume histogram (DVH) constraints and normal tissue complication probability (NTCP) calculations were used to evaluate the differences between the plans. For all plans, the 95 % PTVs received at least 95 % of the prescribed dose. For all patients, it was possible to perform the dose escalation in accordance with the Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) constraints for organs at risk (OARs). The average contralateral lung dose was < 8 Gy. NTCP values for OARs did not increase significantly compared with the standard treatment (p > 0.05), except for the ipsilateral lung. For all plans, the lung volume ratio was strongly correlated with the V{sub 20}, V{sub 30}, and V{sub 40} DVHs of the lung (p < 0.0003) and with the lung mean dose (p < 0.0001). The results of this study suggest that by using HT it is possible to safely escalate the dose delivery to at least 62.5 Gy in PET-positive areas while treating the pleural cavity to 56 Gy in 25 fractions without significantly increasing the dose to the surrounding normal organs. (orig.) [German] Ziel war es, zu untersuchen, ob mit der helikalen Tomotherapie (HT) eine

  11. Treatment Assignment Guesses by Study Participants in a Double-Blind Dose Escalation Clinical Trial of Saw Palmetto

    OpenAIRE

    Lee, Jeannette Y.; Moore, Page; Kusek, John; Barry, Michael

    2014-01-01

    Objectives: This report assesses participant perception of treatment assignment in a randomized, double-blind, placebo-controlled trial of saw palmetto for the treatment of benign prostatic hyperplasia (BCM).

  12. Focal Radiation Therapy Dose Escalation Improves Overall Survival in Locally Advanced Pancreatic Cancer Patients Receiving Induction Chemotherapy and Consolidative Chemoradiation

    Energy Technology Data Exchange (ETDEWEB)

    Krishnan, Sunil, E-mail: skrishnan@mdanderson.org [Department of Radiation Oncology, The University of Texas, Houston, Texas (United States); Chadha, Awalpreet S. [Department of Radiation Oncology, The University of Texas, Houston, Texas (United States); Suh, Yelin [Department of Radiation Physics, The University of Texas, Houston, Texas (United States); Chen, Hsiang-Chun [Department of Biostatistics, MD Anderson Cancer Center, Houston, Texas (United States); Rao, Arvind [Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, Texas (United States); Das, Prajnan; Minsky, Bruce D.; Mahmood, Usama; Delclos, Marc E. [Department of Radiation Oncology, The University of Texas, Houston, Texas (United States); Sawakuchi, Gabriel O. [Department of Radiation Physics, The University of Texas, Houston, Texas (United States); Graduate School of Biomedical Sciences, The University of Texas, Houston, Texas (United States); Beddar, Sam [Department of Radiation Physics, The University of Texas, Houston, Texas (United States); Katz, Matthew H.; Fleming, Jason B. [Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Javle, Milind M.; Varadhachary, Gauri R.; Wolff, Robert A. [Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Crane, Christopher H. [Department of Radiation Oncology, The University of Texas, Houston, Texas (United States)

    2016-03-15

    Purpose: To review outcomes of locally advanced pancreatic cancer (LAPC) patients treated with dose-escalated intensity modulated radiation therapy (IMRT) with curative intent. Methods and Materials: A total of 200 patients with LAPC were treated with induction chemotherapy followed by chemoradiation between 2006 and 2014. Of these, 47 (24%) having tumors >1 cm from the luminal organs were selected for dose-escalated IMRT (biologically effective dose [BED] >70 Gy) using a simultaneous integrated boost technique, inspiration breath hold, and computed tomographic image guidance. Fractionation was optimized for coverage of gross tumor and luminal organ sparing. A 2- to 5-mm margin around the gross tumor volume was treated using a simultaneous integrated boost with a microscopic dose. Overall survival (OS), recurrence-free survival (RFS), local-regional and distant RFS, and time to local-regional and distant recurrence, calculated from start of chemoradiation, were the outcomes of interest. Results: Median radiation dose was 50.4 Gy (BED = 59.47 Gy) with a concurrent capecitabine-based (86%) regimen. Patients who received BED >70 Gy had a superior OS (17.8 vs 15.0 months, P=.03), which was preserved throughout the follow-up period, with estimated OS rates at 2 years of 36% versus 19% and at 3 years of 31% versus 9% along with improved local-regional RFS (10.2 vs 6.2 months, P=.05) as compared with those receiving BED ≤70 Gy. Degree of gross tumor volume coverage did not seem to affect outcomes. No additional toxicity was observed in the high-dose group. Higher dose (BED) was the only predictor of improved OS on multivariate analysis. Conclusion: Radiation dose escalation during consolidative chemoradiation therapy after induction chemotherapy for LAPC patients improves OS and local-regional RFS.

  13. Radiation Dose Escalation in Esophageal Cancer Revisited: A Contemporary Analysis of the National Cancer Data Base, 2004 to 2012

    International Nuclear Information System (INIS)

    Brower, Jeffrey V.; Chen, Shuai; Bassetti, Michael F.; Yu, Menggang; Harari, Paul M.; Ritter, Mark A.; Baschnagel, Andrew M.

    2016-01-01

    Purpose: To evaluate the effect of radiation dose escalation on overall survival (OS) for patients with nonmetastatic esophageal cancer treated with concurrent radiation and chemotherapy. Methods and Materials: Patients diagnosed with stage I to III esophageal cancer treated from 2004 to 2012 were identified from the National Cancer Data Base. Patients who received concurrent radiation and chemotherapy with radiation doses of ≥50 Gy and did not undergo surgery were included. OS was compared using Cox proportional hazards regression and propensity score matching. Results: A total of 6854 patients were included; 3821 (55.7%) received 50 to 50.4 Gy and 3033 (44.3%) received doses >50.4 Gy. Univariate analysis revealed no significant difference in OS between patients receiving 50 to 50.4 Gy and those receiving >50.4 Gy (P=.53). The dose analysis, binned as 50 to 50.4, 51 to 54, 55 to 60, and >60 Gy, revealed no appreciable difference in OS within any group compared with 50 to 50.4 Gy. Subgroup analyses investigating the effect of dose escalation by histologic type and in the setting of intensity modulated radiation therapy also failed to reveal a benefit. Propensity score matching confirmed the absence of a statistically significant difference in OS among the dose levels. The factors associated with improved OS on multivariable analysis included female sex, lower Charlson-Deyo comorbidity score, private insurance, cervical/upper esophagus location, squamous cell histologic type, lower T stage, and node-negative status (P 50.4 Gy did not result in improved OS among patients with stage I to III esophageal cancer treated with definitive concurrent radiation and chemotherapy. These data suggest that despite advanced contemporary treatment techniques, OS for patients with esophageal cancer remains unaltered by escalation of radiation dose >50.4 Gy, consistent with the results of the INT-0123 trial. Furthermore, these data highlight that many radiation

  14. Dose Escalation for Prostate Cancer Using the Three-Dimensional Conformal Dynamic Arc Technique: Analysis of 542 Consecutive Patients

    International Nuclear Information System (INIS)

    Jereczek-Fossa, Barbara A.; Vavassori, Andrea; Fodor, Cristiana; Santoro, Luigi; Zerini, Dario; Cattani, Federica; Garibaldi, Cristina; Cambria, Raffaella; Fodor, Andrei; Boboc, Genoveva Ionela; Vitolo, Viviana; Ivaldi, Giovanni Battista; Musi, Gennaro; De Cobelli, Ottavio; Orecchia, Roberto

    2008-01-01

    Purpose: To present the results of dose escalation using three-dimensional conformal dynamic arc radiotherapy (3D-ART) for prostate cancer. Methods and Materials: Five hundred and forty two T1-T3N0M0 prostate cancer patients were treated with 3D-ART. Dose escalation (from 76 Gy/38 fractions to 80 Gy/40 fractions) was introduced in September 2003; 32% of patients received 80 Gy. In 366 patients, androgen deprivation was added to 3D-ART. Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria and Houston definition (nadir + 2) were used for toxicity and biochemical failure evaluation, respectively. Median follow-up was 25 months. Results: Acute toxicity included rectal (G1-2 28.9%; G3 0.5%) and urinary events (G1-2 57.9%; G3-4 2.4%). Late toxicity included rectal (G1-2 15.8%; G3-4 3.1%) and urinary events (G1-2 26.9%; G3-4 1.6%). Two-year failure-free survival and overall survival rates were 94.1% and 97.9%, respectively. Poor prognostic group (GS, iPSA, T), transurethral prostate resection, and dose >76 Gy showed significant association to high risk of progression in multivariate analysis (p = 0.014, p = 0.045, and p 0.04, respectively). The negative effect of dose >76 Gy was not observed (p 0.10), when the analysis was limited to 353 patients treated after September 2003 (when dose escalation was introduced). Higher dose was not associated with higher late toxicity. Conclusions: Three-dimensional-ART is a feasible modality allowing for dose escalation (no increase in toxicity has been observed with higher doses). However, the dose increase from 76 to 80 Gy was not associated with better tumor outcome. Further investigation is warranted for better understanding of the dose effect for prostate cancer

  15. Is Androgen Deprivation Therapy Necessary in All Intermediate-Risk Prostate Cancer Patients Treated in the Dose Escalation Era?

    International Nuclear Information System (INIS)

    Castle, Katherine O.; Hoffman, Karen E.; Levy, Lawrence B.; Lee, Andrew K.; Choi, Seungtaek; Nguyen, Quynh N.; Frank, Steven J.; Pugh, Thomas J.; McGuire, Sean E.; Kuban, Deborah A.

    2013-01-01

    Purpose: The benefit of adding androgen deprivation therapy (ADT) to dose-escalated radiation therapy (RT) for men with intermediate-risk prostate cancer is unclear; therefore, we assessed the impact of adding ADT to dose-escalated RT on freedom from failure (FFF). Methods: Three groups of men treated with intensity modulated RT or 3-dimensional conformal RT (75.6-78 Gy) from 1993-2008 for prostate cancer were categorized as (1) 326 intermediate-risk patients treated with RT alone, (2) 218 intermediate-risk patients treated with RT and ≤6 months of ADT, and (3) 274 low-risk patients treated with definitive RT. Median follow-up was 58 months. Recursive partitioning analysis based on FFF using Gleason score (GS), T stage, and pretreatment PSA concentration was applied to the intermediate-risk patients treated with RT alone. The Kaplan-Meier method was used to estimate 5-year FFF. Results: Based on recursive partitioning analysis, intermediate-risk patients treated with RT alone were divided into 3 prognostic groups: (1) 188 favorable patients: GS 6, ≤T2b or GS 3+4, ≤T1c; (2) 71 marginal patients: GS 3+4, T2a-b; and (3) 68 unfavorable patients: GS 4+3 or T2c disease. Hazard ratios (HR) for recurrence in each group were 1.0, 2.1, and 4.6, respectively. When intermediate-risk patients treated with RT alone were compared to intermediate-risk patients treated with RT and ADT, the greatest benefit from ADT was seen for the unfavorable intermediate-risk patients (FFF, 74% vs 94%, respectively; P=.005). Favorable intermediate-risk patients had no significant benefit from the addition of ADT to RT (FFF, 94% vs 95%, respectively; P=.85), and FFF for favorable intermediate-risk patients treated with RT alone approached that of low-risk patients treated with RT alone (98%). Conclusions: Patients with favorable intermediate-risk prostate cancer did not benefit from the addition of ADT to dose-escalated RT, and their FFF was nearly as good as patients with low-risk disease

  16. Inhomogeneous dose escalation increases expected local control for NSCLC patients with lymph node involvement without increased mean lung dose

    DEFF Research Database (Denmark)

    Nielsen, Tine B; Hansen, Olfred; Schytte, Tine

    2014-01-01

    in mediastinum, and the thorax wall. The dose was escalated using a TCP model implemented into the planning system. The difference in TCP values between the homogeneous and inhomogeneous plans were evaluated using two different TCP models. RESULTS: Dose escalation was possible for all patients. TCP values based...... to the mediastinum were observed: 2.5 Gy for aorta, 4.4 Gy for the connective tissue, 1.6 Gy for the heart, and 2.6 Gy for trachea + bronchi. CONCLUSION: Increased target doses and TCP values using inhomogeneous dose distributions could be achieved for all patients, regardless of lymph node involvement, tumour stage...

  17. Optimizing Collimator Margins for Isotoxically Dose-Escalated Conformal Radiation Therapy of Non-Small Cell Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Warren, Samantha, E-mail: Samantha.warren@oncology.ox.ac.uk [Department of Oncology, Gray Institute of Radiation Oncology and Biology, University of Oxford, Oxford (United Kingdom); Oxford Cancer Centre, Oxford University Hospitals, Oxford (United Kingdom); Panettieri, Vanessa [William Buckland Radiotherapy Centre, Alfred Hospital, Commercial Road, Melbourne (Australia); Panakis, Niki; Bates, Nicholas [Oxford Cancer Centre, Oxford University Hospitals, Oxford (United Kingdom); Lester, Jason F. [Velindre Cancer Centre, Velindre Road, Whitchurch, Cardiff (United Kingdom); Jain, Pooja [Clatterbridge Cancer Centre, Clatterbridge Road, Wirral (United Kingdom); Landau, David B. [Department of Radiotherapy, Guy' s and St. Thomas' NHS Foundation Trust, London (United Kingdom); Nahum, Alan E.; Mayles, W. Philip M. [Clatterbridge Cancer Centre, Clatterbridge Road, Wirral (United Kingdom); Fenwick, John D. [Department of Oncology, Gray Institute of Radiation Oncology and Biology, University of Oxford, Oxford (United Kingdom); Oxford Cancer Centre, Oxford University Hospitals, Oxford (United Kingdom)

    2014-04-01

    Purpose: Isotoxic dose escalation schedules such as IDEAL-CRT [isotoxic dose escalation and acceleration in lung cancer chemoradiation therapy] (ISRCTN12155469) individualize doses prescribed to lung tumors, generating a fixed modeled risk of radiation pneumonitis. Because the beam penumbra is broadened in lung, the choice of collimator margin is an important element of the optimization of isotoxic conformal radiation therapy for lung cancer. Methods and Materials: Twelve patients with stage I-III non-small cell lung cancer (NSCLC) were replanned retrospectively using a range of collimator margins. For each plan, the prescribed dose was calculated according to the IDEAL-CRT isotoxic prescription method, and the absolute dose (D{sub 99}) delivered to 99% of the planning target volume (PTV) was determined. Results: Reducing the multileaf collimator margin from the widely used 7 mm to a value of 2 mm produced gains of 2.1 to 15.6 Gy in absolute PTV D{sub 99}, with a mean gain ± 1 standard error of the mean of 6.2 ± 1.1 Gy (2-sided P<.001). Conclusions: For NSCLC patients treated with conformal radiation therapy and an isotoxic dose prescription, absolute doses in the PTV may be increased by using smaller collimator margins, reductions in relative coverage being offset by increases in prescribed dose.

  18. Image-guided adaptive radiation therapy (IGART): Radiobiological and dose escalation considerations for localized carcinoma of the prostate

    International Nuclear Information System (INIS)

    Song, William; Schaly, Bryan; Bauman, Glenn; Battista, Jerry; Van Dyk, Jake

    2005-01-01

    The goal of this work was to evaluate the efficacy of various image-guided adaptive radiation therapy (IGART) techniques to deliver and escalate dose to the prostate in the presence of geometric uncertainties. Five prostate patients with 15-16 treatment CT studies each were retrospectively analyzed. All patients were planned with an 18 MV, six-field conformal technique with a 10 mm margin size and an initial prescription of 70 Gy in 35 fractions. The adaptive strategy employed in this work for patient-specific dose escalation was to increase the prescription dose in 2 Gy-per-fraction increments until the rectum normal tissue complication probability (NTCP) reached a level equal to that of the nominal plan NTCP (i.e., iso-NTCP dose escalation). The various target localization techniques simulated were: (1) daily laser-guided alignment to skin tattoo marks that represents treatment without image-guidance, (2) alignment to bony landmarks with daily portal images, and (3) alignment to the clinical target volume (CTV) with daily CT images. Techniques (1) and (3) were resimulated with a reduced margin size of 5 mm to investigate further dose escalation. When delivering the original clinical prescription dose of 70 Gy in 35 fractions, the 'CTV registration' technique yielded the highest tumor control probability (TCP) most frequently, followed by the 'bone registration' and 'tattoo registration' techniques. However, the differences in TCP among the three techniques were minor when the margin size was 10 mm (≤1.1%). Reducing the margin size to 5 mm significantly degraded the TCP values of the 'tattoo registration' technique in two of the five patients, where a large difference was found compared to the other techniques (≤11.8%). The 'CTV registration' technique, however, did maintain similar TCP values compared to their 10 mm margin counterpart. In terms of normal tissue sparing, the technique producing the lowest NTCP varied from patient to patient. Reducing the

  19. Dose escalation with 3-D CRT in prostate cancer: five year dose responses and optimal treatment

    International Nuclear Information System (INIS)

    Hanks, Gerald; Hanlon, Alexandra; Pinover, Wayne; Hunt, Margie; Movsas, Benjamin; Schultheiss, Timothy

    1997-01-01

    Purpose: To report 5 yr dose responses in prostate cancer patients treated with 3D-CRT and describe optimal treatment based on dose response. Methods: Dose escalation was studied in 233 consecutive patients treated with 3D-CRT between 3/89 and 10/92. All surviving patients have >32 mo follow-up, the median follow-up is 55 mo. Estimated logistic cumulative distribution functions (logit response models) fit to 5 yr actuarial bNED outcome are reported for 3 dose groups in each of 3 pretreatment PSA groupings (10-19.9 ng/ml and 20+ ng/ml); no dose response is observed for patients with pretreatment PSA <10 ng/ml. Logit response models fit to 5 yr actuarial late morbidity rates (grade 2 GI, grade 2 GU, grade 3,4 GI) are also reported for 4 dose groups. Patients are treated with CT planned 4-field conformal technique where the PTV encompasses the CTV by 1.0 cm in all directions including the anterior rectal wall margin. Patients are followed at 6 mo intervals with PSA and DRE, and bNED failure is defined as PSA ≥1.5 ng/ml and rising on two consecutive measures. The Fox Chase modification of the LENT morbidity scale is used for GI morbidity including any blood transfusion and/or more than 2 coagulations as a grade 3 event. GU morbidity follows the RTOG scale. Results: The logit response models based on 5 yr bNED results have slopes of 27% and 18% for pretreatment PSA grouping 10-19.9 ng/ml and 20+ ng/ml, respectively. The 50% bNED response is observed at 71 Gy and 80 Gy respectively, while the 80% bNED response is observed at 76 Gy for the 10-19.9 ng/ml group and estimated at 88 Gy for the 20+ ng/ml group. Logit dose response models for grade 2 GI and grade 2 GU morbidity show markedly different slopes, 23% versus 4%, respectively. The slope for grade 3,4 GI is 12%. The dose response model indicates grade 3,4 GI complication rates at 5 yrs are 8% at 76 Gy and 12% at 80 Gy. Conclusion: Based on 5 yr results, we can draw some conclusions about appropriate dose from these

  20. A randomized placebo-controlled phase Ia malaria vaccine trial of two virosome-formulated synthetic peptides in healthy adult volunteers.

    Directory of Open Access Journals (Sweden)

    Blaise Genton

    2007-10-01

    Full Text Available Influenza virosomes represent an innovative human-compatible antigen delivery system that has already proven its suitability for subunit vaccine design. The aim of the study was to proof the concept that virosomes can also be used to elicit high titers of antibodies against synthetic peptides. The specific objective was to demonstrate the safety and immunogenicity of two virosome-formulated P. falciparum protein derived synthetic peptide antigens given in two different doses alone or in combination.The design was a single blind, randomized, placebo controlled, dose-escalating study involving 46 healthy Caucasian volunteers aged 18-45 years. Five groups of 8 subjects received virosomal formulations containing 10 microg or 50 microg of AMA 49-CPE, an apical membrane antigen-1 (AMA-1 derived synthetic phospatidylethanolamine (PE-peptide conjugate or 10 ug or 50 ug of UK39, a circumsporozoite protein (CSP derived synthetic PE-peptide conjugate or 50 ug of both antigens each. A control group of 6 subjects received unmodified virosomes. Virosomal formulations of the antigens (designated PEV301 and PEV302 for the AMA-1 and the CSP virosomal vaccine, respectively or unmodified virosomes were injected i. m. on days 0, 60 and 180. In terms of safety, no serious or severe adverse events (AEs related to the vaccine were observed. 11/46 study participants reported 16 vaccine related local AEs. Of these 16 events, all being pain, 4 occurred after the 1(st, 7 after the 2(nd and 5 after the 3(rd vaccination. 6 systemic AEs probably related to the study vaccine were reported after the 1(st injection, 10 after the 2(nd and 6 after the 3(rd. Generally, no difference in the distribution of the systemic AEs between either the doses applied (10 respectively 50 microg or the synthetic antigen vaccines (PEV301 and PEV302 used for immunization was found. In terms of immunogenicity, both PEV301 and PEV302 elicited already after two injections a synthetic peptide

  1. Dose Escalation and Healthcare Resource Use among Ulcerative Colitis Patients Treated with Adalimumab in English Hospitals: An Analysis of Real-World Data.

    Directory of Open Access Journals (Sweden)

    Christopher M Black

    Full Text Available To describe the real-world use of adalimumab for maintenance treatment of ulcerative colitis (UC and associated healthcare costs in English hospitals.Retrospective cohort study.Analysis of NHS Hospital Episode Statistics linked with pharmacy dispensing data in English hospitals.Adult UC patients receiving ≥240mg during adalimumab treatment induction, subsequently maintained on adalimumab.Frequency and pattern of adalimumab use and dose escalation during maintenance treatment and associated healthcare costs (prescriptions and hospital visits.191 UC patients completed adalimumab treatment induction. 83 (43.46% dose escalated during maintenance treatment by ≥100% (equivalent to weekly dosing (median time to dose escalation: 139 days. 56 patients (67.47% subsequently de-escalated by ≥50% (median time to dose de-escalation: 21 days. Mean all-cause healthcare costs for all patients ≤12 months of index were £13,892. Dose escalators incurred greater mean healthcare costs than non-escalators ≤12 months of index (£14,596 vs. £13,351. Prescriptions accounted for 96.49% of UC-related healthcare costs (£11,090 of £11,494 in all patients.Within the cohort, 43.46% of UC patients escalated their adalimumab dose by ≥100% and incurred greater costs than non-escalators. The apparent underestimation of adalimumab dose escalation in previous studies may have resulted in underestimated costs in healthcare systems.

  2. Dose Escalation and Quality of Life in Patients With Localized Prostate Cancer Treated With Radiotherapy: Long-Term Results of the Dutch Randomized Dose-Escalation Trial (CKTO 96-10 Trial)

    International Nuclear Information System (INIS)

    Al-Mamgani, Abrahim; Putten, Wim L.J. van; Wielen, Gerard J. van der; Levendag, Peter C.; Incrocci, Luca

    2011-01-01

    Purpose: To assess the impact of dose escalation of radiotherapy on quality of life (QoL) in prostate cancer patients. Patients and Methods: Three hundred prostate cancer patients participating in the Dutch randomized trial (CKTO 69-10) comparing 68 Gy with 78 Gy were the subject of this analysis. These patients filled out the SF-36 QoL questionnaire before radiotherapy (baseline) and 6, 12, 24, and 36 months thereafter. Changes in QoL over time of ≥10 points were considered clinically relevant. Repeated-measures regression analyses were applied to estimate and test the QoL changes over time, the differences between the two arms, and for association with a number of covariates. Results: At 3-year follow-up, the summary score physical health was 73.2 for the 68-Gy arm vs. 71.6 for the 78-Gy arm (p = 0.81), and the summary score mental health was 76.7 for the 68-Gy arm vs. 76.1 for the 78-Gy arm (p = 0.97). Statistically significant (p 10 points) was seen for only two scales. None of the tested covariates were significantly correlated with QoL scores. Conclusion: Dose escalation did not result in significant deterioration of QoL in prostate cancer patients. In both randomization arms, statistically significant decreases in QoL scores over time were seen in six scales. The deterioration of QoL was more pronounced in the physical than in the mental health domain and in some scales more in the high- than in the low-dose arm, but the differences between arms were not statistically significant.

  3. Dose escalation of chart in non-small cell lung cancer: is three-dimensional conformal radiation therapy really necessary?

    International Nuclear Information System (INIS)

    McGibney, Carol; Holmberg, Ola; McClean, Brendan; Williams, Charles; McCrea, Pamela; Sutton, Phil; Armstrong, John

    1999-01-01

    Purpose: To evaluate, pre clinically, the potential for dose escalation of continuous, hyperfractionated, accelerated radiation therapy (CHART) for non small-cell lung cancer (NSCLC), we examined the strategy of omission of elective nodal irradiation with and without the application of three-dimensional conformal radiation technology (3DCRT). Methods and Materials: 2D, conventional therapy plans were designed according to the specifications of CHART for 18 patients with NSCLC (Stages Ib, IIb, IIIa, and IIIb). Further plans were generated with the omission of elective nodal irradiation (ENI) from the treatment portals (2D minus ENI plans [2D-ENI plans]). Both sets were inserted in the patient's planning computed tomographies (CTs). These reconstructed plans were then compared to alternative, three-dimensional treatment plans which had been generated de novo, with the omission of ENI: 3D minus elective nodal irradiation (3D-ENI plans). Dose delivery to the planning target volumes (PTVs) and to the organs at risk were compared between the 3 sets of corresponding plans. The potential for dose escalation of each patient's 2D-ENI and 3D-ENI plan beyond 54 Gy, standard to CHART, was also determined. Results: PTV coverage was suboptimal in the 2D CHART and the 2D-ENI plans. Only in the 3D-ENI plans did 100% of the PTV get ≥95% of the dose prescribed (i.e., 51.5 Gy [51.3-52.2]). Using 3D-ENI plans significantly reduced the dose received by the spinal cord, the mean and median doses to the esophagus and the heart. It did not significantly reduce the lung dose when compared to 2D-ENI plans. Escalation of the dose (minimum ≥1 Gy) with optimal PTV coverage was possible in 55.5% of patients using 3D-ENI, but was possible only in 16.6% when using the 2D-ENI planning strategy. Conclusions: 3DCRT is fundamental to achieving optimal PTV coverage in NSCLC. A policy of omission of elective nodal irradiation alone (and using 2D technology) will not achieve optimal PTV coverage or

  4. Dose Escalation of Total Marrow Irradiation With Concurrent Chemotherapy in Patients With Advanced Acute Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation

    Energy Technology Data Exchange (ETDEWEB)

    Wong, Jeffrey Y.C., E-mail: jwong@coh.org [Department of Radiation Oncology, City of Hope National Medical Center, Duarte, California (United States); Forman, Stephen; Somlo, George [Department of Hematology/Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California (United States); Rosenthal, Joseph [Department of Hematology/Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California (United States); Department of Pediatrics, City of Hope National Medical Center, Duarte, California (United States); Liu An; Schultheiss, Timothy; Radany, Eric [Department of Radiation Oncology, City of Hope National Medical Center, Duarte, California (United States); Palmer, Joycelynne [Department of Biostatistics, City of Hope National Medical Center, Duarte, California (United States); Stein, Anthony [Department of Hematology/Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California (United States)

    2013-01-01

    Purpose: We have demonstrated that toxicities are acceptable with total marrow irradiation (TMI) at 16 Gy without chemotherapy or TMI at 12 Gy and the reduced intensity regimen of fludarabine/melphalan in patients undergoing hematopoietic cell transplantation (HCT). This article reports results of a study of TMI combined with higher intensity chemotherapy regimens in 2 phase I trials in patients with advanced acute myelogenous leukemia or acute lymphoblastic leukemia (AML/ALL) who would do poorly on standard intent-to-cure HCT regimens. Methods and Materials: Trial 1 consisted of TMI on Days -10 to -6, etoposide (VP16) on Day -5 (60 mg/kg), and cyclophosphamide (CY) on Day -3 (100 mg/kg). TMI dose was 12 (n=3 patients), 13.5 (n=3 patients), and 15 (n=6 patients) Gy at 1.5 Gy twice daily. Trial 2 consisted of busulfan (BU) on Days -12 to -8 (800 {mu}M min), TMI on Days -8 to -4, and VP16 on Day -3 (30 mg/kg). TMI dose was 12 (n=18) and 13.5 (n=2) Gy at 1.5 Gy twice daily. Results: Trial 1 had 12 patients with a median age of 33 years. Six patients had induction failures (IF), and 6 had first relapses (1RL), 9 with leukemia blast involvement of bone marrow ranging from 10%-98%, 5 with circulating blasts (24%-85%), and 2 with chloromas. No dose-limiting toxicities were observed. Eleven patients achieved complete remission at Day 30. With a median follow-up of 14.75 months, 5 patients remained in complete remission from 13.5-37.7 months. Trial 2 had 20 patients with a median age of 41 years. Thirteen patients had IF, and 5 had 1RL, 2 in second relapse, 19 with marrow blasts (3%-100%) and 13 with peripheral blasts (6%-63%). Grade 4 dose-limiting toxicities were seen at 13.5 Gy (stomatitis and hepatotoxicity). Stomatitis was the most frequent toxicity in both trials. Conclusions: TMI dose escalation to 15 Gy is possible when combined with CY/VP16 and is associated with acceptable toxicities and encouraging outcomes. TMI dose escalation is not possible with BU/VP16 due to

  5. Dose escalation without split-course chemoradiation for anal cancer: results of a phase II RTOG study

    International Nuclear Information System (INIS)

    John, Madhu; Pajak, Thomas; Kreig, Richard; Pinover, Wayne H.; Myerson, Robert

    1997-01-01

    PURPOSE: An attempt at radiotherapy (RT) dose escalation (from 45 Gy to 59.6 Gy) in a Radiation Therapy Oncology Group (RTOG) chemoradiation protocol for advanced anal cancers had resulted in an unexpectedly high 1-year colostomy rate (23%) and local failure (The Cancer Journal from Scientific American 2 (4):205-211, 1996). This was felt to be probably secondary to the split course chemoradiation (CR) that was mandated in the protocol. A second phase of this dose escalation study was therefore undertaken without a mandatory split and with an identical RT dose (59.6 Gy) and chemotherapy. MATERIALS AND METHODS: Twenty patients with anal cancers ≥2 cms were treated with a concurrent combination of 59.6 Gy to the pelvis and perineum (1.8 Gy daily, 5 times per week in 33 fractions over 6 (1(2)) weeks) and two cycles of 5 fluorouracil infusion (1000 mg/m 2 over 24 hours for 4 days) and mitomycin C (10 mg/m 2 bolus). A 10 day rest period was allowed only for severe skin reactions. A comparative analysis was made with the 47 patients in the earlier phase of this study who were treated with the identical chemoradiation course but with a mandatory 2-week break at the 36.00 Gy level. RESULTS: Predominant Grade 3 and 4 toxicities in 18 evaluable patients with dermatitis ((14(18)) or 78%), hematologic ((14(18)) or 78%), infection ((3(18)) or 17%) and gastrointestinal ((5(18)) or 28%). There were no fatalities. Nine patients (50%) completed the planned course without a break; 9 others (50%) had their treatments interrupted for a median of 11 days (range 7-19 days) at a median dose of 41.4 Gy (range 32.4 to 48.6 Gy). This compared to (40(47)) patients (85%) who had a 12 day treatment interruption at 36 Gy total dose in a planned break group. One patient had an abdomino-perineal resection (APR) for persistent disease and another for an anal fissure for (2(18)) or 11% 1-year colostomy rate. This was again favorably comparable to 23% 1-year colostomy rate for the earlier group of

  6. An accelerated dose escalation with a grass pollen allergoid is safe and well-tolerated: a randomized open label phase II trial.

    Science.gov (United States)

    Chaker, A M; Al-Kadah, B; Luther, U; Neumann, U; Wagenmann, M

    2015-01-01

    The number of injections in the dose escalation of subcutaneous immunotherapy (SCIT) is small for some currently used hypoallergenic allergoids, but can still be inconvenient to patients and can impair compliance. The aim of this trial was to compare safety and tolerability of an accelerated to the conventional dose escalation scheme of a grass pollen allergoid. In an open label phase II trial, 122 patients were 1:1 randomized for SCIT using a grass pollen allergoid with an accelerated dose escalation comprising only 4 weekly injections (Group I) or a conventional dose escalation including 7 weekly injections (Group II). Safety determination included the occurrence of local and systemic adverse events. Tolerability was assessed by patients and physicians. Treatment-related adverse events were observed in 22 (36.1 %) patients in Group I and 15 (24.6 %) in Group II. Local reactions were reported by 18 patients in Group I and 11 in Group II. Five Grade 1 systemic reactions (WAO classification) were observed in Group I and 2 in Group II. Grade 2 reactions occurred 3 times in Group I and 2 times in Group II. Tolerability was rated as "good" or "very good" by 53 (86.9 %) patients in Group I and 59 (100 %) in Group II by investigators. Forty-eight patients in Group I (80.0 %) and 54 in Group II (91.5 %) rated tolerability as "good" or "very good". The dose escalation of a grass pollen allergoid can be accelerated with safety and tolerability profiles comparable to the conventional dose escalation.

  7. Pelvic nodal dose escalation with prostate hypofractionation using conformal avoidance defined (H-CAD) intensity modulated radiation therapy

    International Nuclear Information System (INIS)

    Hong, Theodore S.; Tome, Wolfgang A.; Jaradat, Hazim; Raisbeck, Bridget M.; Ritter, Mark A.

    2006-01-01

    The management of prostate cancer patients with a significant risk of pelvic lymph node involvement is controversial. Both whole pelvis radiotherapy and dose escalation to the prostate have been linked to improved outcome in such patients, but it is unclear whether conventional whole pelvis doses of only 45-50 Gy are optimal for ultimate nodal control. The purpose of this study is to examine the dosimetric and clinical feasibility of combining prostate dose escalation via hypofractionation with conformal avoidance-based IMRT (H-CAD) dose escalation to the pelvic lymph nodes. One conformal avoidance and one conventional plan were generated for each of eight patients. Conformal avoidance-based IMRT plans were generated that specifically excluded bowel, rectum, and bladder. The prostate and lower seminal vesicles (PTV 70) were planned to receive 70 Gy in 2.5 Gy/fraction while the pelvic lymph nodes (PTV 56) were to concurrently receive 56 Gy in 2 Gy/fraction. The volume of small bowel receiving >45 Gy was restricted to 300 ml or less. These conformal avoidance plans were delivered using helical tomotherapy or LINAC-based IMRT with daily imaging localization. All patients received neoadjuvant and concurrent androgen deprivation with a planned total of two years. The conventional, sequential plans created for comparison purposes for all patients consisted of a conventional 4-field pelvic box prescribed to 50.4 Gy (1.8 Gy/fraction) followed by an IMRT boost to the prostate of 25.2 Gy (1.8 Gy/fraction) yielding a final prostate dose of 75.6 Gy. For all plans, the prescription dose was to cover the target structure. Equivalent uniform dose (EUD) analyses were performed on all targets and dose-volume histograms (DVH) were displayed in terms of both physical and normalized total dose (NTD), i.e. dose in 2 Gy fraction equivalents. H-CAD IMRT plans were created for and delivered to all eight patients. Analysis of the H-CAD plans demonstrates prescription dose coverage of >95

  8. Dose-Escalated Hypofractionated Intensity-Modulated Radiotherapy in High-Risk Carcinoma of the Prostate: Outcome and Late Toxicity

    Directory of Open Access Journals (Sweden)

    David Thomson

    2012-01-01

    Results. Median followup was 84 months. Five-year overall survival (OS was 83% and biochemical progression-free survival (bPFS was 50% for 57 Gy. Five-year OS was 75% and bPFS 58% for 60 Gy. At 7 years, toxicity by RTOG criteria was acceptable with no grade 3 or above toxicity. Compared with baseline, there was no significant change in urinary symptoms at 2 or 7 years. Bowel symptoms were stable between 2 and 7 years. All patients continued to have significant sexual dysfunction. Conclusion. In high-risk prostate cancer, dose-escalated hypofractionated radiotherapy using IMRT results in encouraging outcomes and acceptable late toxicity.

  9. A single-blind, dose escalation, phase I study of high-fluence light-emitting diode-red light (LED-RL) on human skin: study protocol for a randomized controlled trial

    OpenAIRE

    Ho, Derek; Kraeva, Ekaterina; Wun, Ted; Isseroff, R. Rivkah; Jagdeo, Jared

    2016-01-01

    Background Skin fibrosis is involved in a variety of pathologic conditions ranging from scar formation secondary to surgery or trauma to immune-mediated processes. Skin fibrosis is a significant international health problem with an estimated incidence of greater than 100 million people affected per year worldwide with few effective treatment options available. Preliminary in vitro data generated by our research group suggests that red light can function as a stand-alone treatment for skin fib...

  10. Perineural Invasion Predicts Increased Recurrence, Metastasis, and Death From Prostate Cancer Following Treatment With Dose-Escalated Radiation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Feng, Felix Y. [University of Michigan Medical Center, Ann Arbor, MI (United States); Ann Arbor Veteran Affairs Medical System, Ann Arbor, MI (United States); Qian Yushen; Stenmark, Matthew H.; Halverson, Schuyler; Blas, Kevin; Vance, Sean [University of Michigan Medical Center, Ann Arbor, MI (United States); Sandler, Howard M. [Cedars Sinai Medical System, Los Angeles, CA (United States); Hamstra, Daniel A., E-mail: dhamm@med.umich.edu [University of Michigan Medical Center, Ann Arbor, MI (United States)

    2011-11-15

    Purpose: To assess the prognostic value of perineural invasion (PNI) for patients treated with dose-escalated external-beam radiation therapy for prostate cancer. Methods and Materials: Outcomes were analyzed for 651 men treated for prostate cancer with EBRT to a minimum dose {>=}75 Gy. We assessed the impact of PNI as well as pretreatment and treatment-related factors on freedom from biochemical failure (FFBF), freedom from metastasis (FFM), cause-specific survival (CSS), and overall survival. Results: PNI was present in 34% of specimens at biopsy and was significantly associated with higher Gleason score (GS), T stage, and prostate-specific antigen level. On univariate and multivariate analysis, the presence of PNI was associated with worse FFBF (hazard ratio = 1.7, p <0.006), FFM (hazard ratio = 1.8, p <0.03), and CSS (HR = 1.4, p <0.05) compared with absence of PNI; there was no difference in overall survival. Seven-year rates of FFBF, FFM, and CCS were 64% vs. 80%, 84% vs. 92%, and 91% vs. 95% for those patients with and without PNI, respectively. On recursive partitioning analysis, PNI predicted for worse FFM and CSS in patients with GS 8-10, with FFM of 67% vs. 89% (p <0.02), and CSS of 69% vs. 91%, (p <0.04) at 7 years for those with and without PNI, respectively. Conclusions: The presence of PNI in the prostate biopsy predicts worse clinical outcome for patients treated with dose-escalated external-beam radiation therapy. Particularly in patients with GS 8-10 disease, the presence of PNI suggests an increased risk of metastasis and prostate cancer death.

  11. Perineural Invasion Predicts Increased Recurrence, Metastasis, and Death From Prostate Cancer Following Treatment With Dose-Escalated Radiation Therapy

    International Nuclear Information System (INIS)

    Feng, Felix Y.; Qian Yushen; Stenmark, Matthew H.; Halverson, Schuyler; Blas, Kevin; Vance, Sean; Sandler, Howard M.; Hamstra, Daniel A.

    2011-01-01

    Purpose: To assess the prognostic value of perineural invasion (PNI) for patients treated with dose-escalated external-beam radiation therapy for prostate cancer. Methods and Materials: Outcomes were analyzed for 651 men treated for prostate cancer with EBRT to a minimum dose ≥75 Gy. We assessed the impact of PNI as well as pretreatment and treatment-related factors on freedom from biochemical failure (FFBF), freedom from metastasis (FFM), cause-specific survival (CSS), and overall survival. Results: PNI was present in 34% of specimens at biopsy and was significantly associated with higher Gleason score (GS), T stage, and prostate-specific antigen level. On univariate and multivariate analysis, the presence of PNI was associated with worse FFBF (hazard ratio = 1.7, p <0.006), FFM (hazard ratio = 1.8, p <0.03), and CSS (HR = 1.4, p <0.05) compared with absence of PNI; there was no difference in overall survival. Seven-year rates of FFBF, FFM, and CCS were 64% vs. 80%, 84% vs. 92%, and 91% vs. 95% for those patients with and without PNI, respectively. On recursive partitioning analysis, PNI predicted for worse FFM and CSS in patients with GS 8–10, with FFM of 67% vs. 89% (p <0.02), and CSS of 69% vs. 91%, (p <0.04) at 7 years for those with and without PNI, respectively. Conclusions: The presence of PNI in the prostate biopsy predicts worse clinical outcome for patients treated with dose-escalated external-beam radiation therapy. Particularly in patients with GS 8–10 disease, the presence of PNI suggests an increased risk of metastasis and prostate cancer death.

  12. A Phase I Dose Escalation Study of Hypofractionated IMRT Field-in-Field Boost for Newly Diagnosed Glioblastoma Multiforme

    Energy Technology Data Exchange (ETDEWEB)

    Monjazeb, Arta M., E-mail: arta.monjazeb@ucdmc.ucdavis.edu [U.C. Davis School of Medicine, Department of Radiation Oncology, Sacramento, CA (United States); Ayala, Deandra; Jensen, Courtney [Radiation Oncology, Wake Forest University Health Sciences, Winston-Salem, NC (United States); Case, L. Douglas [Biostatistical Sciences, Wake Forest University Health Sciences, Winston-Salem, NC (United States); Bourland, J. Daniel; Ellis, Thomas L. [Neurosurgery, Wake Forest University Health Sciences, Winston-Salem, NC (United States); McMullen, Kevin P.; Chan, Michael D. [Radiation Oncology, Wake Forest University Health Sciences, Winston-Salem, NC (United States); Tatter, Stephen B. [Neurosurgery, Wake Forest University Health Sciences, Winston-Salem, NC (United States); Lesser, Glen J. [Hematology Oncology, Wake Forest University Health Sciences, Winston-Salem, NC (United States); Shaw, Edward G. [Radiation Oncology, Wake Forest University Health Sciences, Winston-Salem, NC (United States)

    2012-02-01

    Objectives: To describe the results of a Phase I dose escalation trial for newly diagnosed glioblastoma multiforme (GBM) using a hypofractionated concurrent intensity-modulated radiotherapy (IMRT) boost. Methods: Twenty-one patients were enrolled between April 1999 and August 2003. Radiotherapy consisted of daily fractions of 1.8 Gy with a concurrent boost of 0.7 Gy (total 2.5 Gy daily) to a total dose of 70, 75, or 80 Gy. Concurrent chemotherapy was not permitted. Seven patients were enrolled at each dose and dose limiting toxicities were defined as irreversible Grade 3 or any Grade 4-5 acute neurotoxicity attributable to radiotherapy. Results: All patients experienced Grade 1 or 2 acute toxicities. Acutely, 8 patients experienced Grade 3 and 1 patient experienced Grade 3 and 4 toxicities. Of these, only two reversible cases of otitis media were attributable to radiotherapy. No dose-limiting toxicities were encountered. Only 2 patients experienced Grade 3 delayed toxicity and there was no delayed Grade 4 toxicity. Eleven patients requiring repeat resection or biopsy were found to have viable tumor and radiation changes with no cases of radionecrosis alone. Median overall and progression-free survival for this cohort were 13.6 and 6.5 months, respectively. One- and 2-year survival rates were 57% and 19%. At recurrence, 15 patients received chemotherapy, 9 underwent resection, and 5 received radiotherapy. Conclusions: Using a hypofractionated concurrent IMRT boost, we were able to safely treat patients to 80 Gy without any dose-limiting toxicity. Given that local failure still remains the predominant pattern for GBM patients, a trial of dose escalation with IMRT and temozolomide is warranted.

  13. A Phase I Dose Escalation Study of Hypofractionated IMRT Field-in-Field Boost for Newly Diagnosed Glioblastoma Multiforme

    International Nuclear Information System (INIS)

    Monjazeb, Arta M.; Ayala, Deandra; Jensen, Courtney; Case, L. Douglas; Bourland, J. Daniel; Ellis, Thomas L.; McMullen, Kevin P.; Chan, Michael D.; Tatter, Stephen B.; Lesser, Glen J.; Shaw, Edward G.

    2012-01-01

    Objectives: To describe the results of a Phase I dose escalation trial for newly diagnosed glioblastoma multiforme (GBM) using a hypofractionated concurrent intensity-modulated radiotherapy (IMRT) boost. Methods: Twenty-one patients were enrolled between April 1999 and August 2003. Radiotherapy consisted of daily fractions of 1.8 Gy with a concurrent boost of 0.7 Gy (total 2.5 Gy daily) to a total dose of 70, 75, or 80 Gy. Concurrent chemotherapy was not permitted. Seven patients were enrolled at each dose and dose limiting toxicities were defined as irreversible Grade 3 or any Grade 4–5 acute neurotoxicity attributable to radiotherapy. Results: All patients experienced Grade 1 or 2 acute toxicities. Acutely, 8 patients experienced Grade 3 and 1 patient experienced Grade 3 and 4 toxicities. Of these, only two reversible cases of otitis media were attributable to radiotherapy. No dose-limiting toxicities were encountered. Only 2 patients experienced Grade 3 delayed toxicity and there was no delayed Grade 4 toxicity. Eleven patients requiring repeat resection or biopsy were found to have viable tumor and radiation changes with no cases of radionecrosis alone. Median overall and progression-free survival for this cohort were 13.6 and 6.5 months, respectively. One- and 2-year survival rates were 57% and 19%. At recurrence, 15 patients received chemotherapy, 9 underwent resection, and 5 received radiotherapy. Conclusions: Using a hypofractionated concurrent IMRT boost, we were able to safely treat patients to 80 Gy without any dose-limiting toxicity. Given that local failure still remains the predominant pattern for GBM patients, a trial of dose escalation with IMRT and temozolomide is warranted.

  14. Accelerated hyperfractionated hepatic irradiation in the management of patients with liver metastases: Results of the RTOG dose escalating protocol

    International Nuclear Information System (INIS)

    Russell, A.H.; Clyde, C.; Wasserman, T.H.; Turner, S.S.; Rotman, M.

    1993-01-01

    This study was prepared to address two objectives: (a) to determine whether progressively higher total doses of hepatic irradiation can prolong survival in a selected population of patients with liver metastases and (b) to refine existing concepts of liver tolerance for fractionated external radiation. One hundred seventy-three analyzable patients with computed tomography measurable liver metastases from primary cancers of the gastrointestinal tract were entered on a dose escalating protocol of twice daily hepatic irradiation employing fractions of 1.5 Gy separated by 4 hr or longer. Sequential groups of patients received 27 Gy, 30 Gy, and 33 Gy to the entire liver and were monitored for acute and late toxicities, survival, and cause of death. Dose escalation was implemented following survival of 10 patients at each dose level for a period of 6 months or longer without clinical or biochemical evidence of radiation hepatitis. The use of progressively larger total doses of radiation did not prolong median survival or decrease the frequency with which liver metastases were the cause of death. None of 122 patients entered at the 27 Gy and 30 Gy dose levels revealed clinical or biochemical evidence of radiation induced liver injury. Five of 51 patients entered at the 33 Gy level revealed clinical or biochemical evidence of late liver injury with an actuarial risk of severe (Grade 3) radiation hepatitis of 10.0% at 6 months, resulting in closure of the study to patient entry. The study design could not credibly establish a safe dose for hepatic irradiation, however, it did succeed in determining that 33 Gy in fractions of 1.5 Gy is unsafe, carrying a substantial risk of delayed radiation injury. The absence of apparent late liver injury at the 27 Gy and 30 Gy dose levels suggests that a prior clinical trial of adjuvant hepatic irradiation in patients with resected colon cancer may have employed an insufficient radiation dose (21 Gy) to fully test the question

  15. The role and strategy of IMRT in radiotherapy of pelvic tumors: Dose escalation and critical organ sparing in prostate cancer

    International Nuclear Information System (INIS)

    Liu, Y.-M.; Shiau, C.-Y.; Lee, M.-L.; Huang, P.-I.; Hsieh, C.-M.; Chen, P.-H.; Lin, Y.-H.; Wang, L.-W.; Yen, S.-H.

    2007-01-01

    Purpose: To investigate the intensity-modulated radiotherapy (IMRT) strategy in dose escalation of prostate and pelvic lymph nodes. Methods and Materials: Plan dosimetric data of 10 prostate cancer patients were compared with two-dimensional (2D) or IMRT techniques for pelvis (two-dimensional whole pelvic radiation therapy [2D-WPRT] or IM-WPRT) to receive 50 Gy or 54 Gy and additional prostate boost by three-dimensional conformal radiation therapy or IMRT (3D-PBRT or IM-PBRT) techniques up to 72 Gy or 78 Gy. Dose-volume histograms (DVHs), normal tissue complication probabilities (NTCP) of critical organ, and conformity of target volume in various combinations were calculated. Results: In DVH analysis, the plans with IM-WPRT (54 Gy) and additional boost up to 78 Gy had lower rectal and bladder volume percentage at 50 Gy and 60 Gy, compared with those with 2D-WPRT (50 Gy) and additional boost up to 72 Gy or 78 Gy. Those with IM-WPRT (54 Gy) also had better small bowel sparing at 30 Gy and 50 Gy, compared with those with 2D-WPRT (50 Gy). In NTCP, those with IM-WPRT and total dose of 78 Gy achieved lower complication rates in rectum and small bowel, compared with those of 2D-WPRT with total dose of 72 Gy. In conformity, those with IM-WPRT had better conformity compared with those with 2D-WPRT with significance (p < 0.005). No significant difference in DVHs, NTCP, or conformity was found between IM-PBRT and 3D-PBRT after IM-WPRT. Conclusions: Initial pelvic IMRT is the most important strategy in dose escalation and critical organ sparing. IM-WPRT is recommended for patients requiring WPRT. There is not much benefit for critical organ sparing by IMRT after 2D-WPRT

  16. Phase 1 Study of Dose Escalation in Hypofractionated Proton Beam Therapy for Non-Small Cell Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Gomez, Daniel R., E-mail: dgomez@mdanderson.org [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Gillin, Michael [Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Liao, Zhongxing [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Wei, Caimiao [Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Lin, Steven H.; Swanick, Cameron; Alvarado, Tina; Komaki, Ritsuko; Cox, James D.; Chang, Joe Y. [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States)

    2013-07-15

    Background: Many patients with locally advanced non-small cell lung cancer (NSCLC) cannot undergo concurrent chemotherapy because of comorbidities or poor performance status. Hypofractionated radiation regimens, if tolerable, may provide an option to these patients for effective local control. Methods and Materials: Twenty-five patients were enrolled in a phase 1 dose-escalation trial of proton beam therapy (PBT) from September 2010 through July 2012. Eligible patients had histologically documented lung cancer, thymic tumors, carcinoid tumors, or metastatic thyroid tumors. Concurrent chemotherapy was not allowed, but concurrent treatment with biologic agents was. The dose-escalation schema comprised 15 fractions of 3 Gy(relative biological effectiveness [RBE])/fraction, 3.5 Gy(RBE)/fraction, or 4 Gy(RBE)/fraction. Dose constraints were derived from biologically equivalent doses of standard fractionated treatment. Results: The median follow-up time for patients alive at the time of analysis was 13 months (range, 8-28 months). Fifteen patients received treatment to hilar or mediastinal lymph nodes. Two patients experienced dose-limiting toxicity possibly related to treatment; 1 received 3.5-Gy(RBE) fractions and experienced an in-field tracheoesophageal fistula 9 months after PBT and 1 month after bevacizumab. The other patient received 4-Gy(RBE) fractions and was hospitalized for bacterial pneumonia/radiation pneumonitis 4 months after PBT. Conclusion: Hypofractionated PBT to the thorax delivered over 3 weeks was well tolerated even with significant doses to the lungs and mediastinal structures. Phase 2/3 trials are needed to compare the efficacy of this technique with standard treatment for locally advanced NSCLC.

  17. Towards biologically conformal radiation therapy (BCRT): Selective IMRT dose escalation under the guidance of spatial biology distribution

    International Nuclear Information System (INIS)

    Yang Yong; Xing Lei

    2005-01-01

    It is well known that the spatial biology distribution (e.g., clonogen density, radiosensitivity, tumor proliferation rate, functional importance) in most tumors and sensitive structures is heterogeneous. Recent progress in biological imaging is making the mapping of this distribution increasingly possible. The purpose of this work is to establish a theoretical framework to quantitatively incorporate the spatial biology data into intensity modulated radiation therapy (IMRT) inverse planning. In order to implement this, we first derive a general formula for determining the desired dose to each tumor voxel for a known biology distribution of the tumor based on a linear-quadratic model. The desired target dose distribution is then used as the prescription for inverse planning. An objective function with the voxel-dependent prescription is constructed with incorporation of the nonuniform dose prescription. The functional unit density distribution in a sensitive structure is also considered phenomenologically when constructing the objective function. Two cases with different hypothetical biology distributions are used to illustrate the new inverse planning formalism. For comparison, treatments with a few uniform dose prescriptions and a simultaneous integrated boost are also planned. The biological indices, tumor control probability (TCP) and normal tissue complication probability (NTCP), are calculated for both types of plans and the superiority of the proposed technique over the conventional dose escalation scheme is demonstrated. Our calculations revealed that it is technically feasible to produce deliberately nonuniform dose distributions with consideration of biological information. Compared with the conventional dose escalation schemes, the new technique is capable of generating biologically conformal IMRT plans that significantly improve the TCP while reducing or keeping the NTCPs at their current levels. Biologically conformal radiation therapy (BCRT

  18. Randomized, single blind, controlled trial of inhaled glutathione vs placebo in patients with cystic fibrosis.

    Science.gov (United States)

    Calabrese, C; Tosco, A; Abete, P; Carnovale, V; Basile, C; Magliocca, A; Quattrucci, S; De Sanctis, S; Alatri, F; Mazzarella, G; De Pietro, L; Turino, C; Melillo, E; Buonpensiero, P; Di Pasqua, A; Raia, V

    2015-03-01

    In cystic fibrosis (CF) the defective CF transmembrane conductance regulator protein may be responsible for the impaired transport of glutathione (GSH), the first line defense of the lung against oxidative stress. The aim of this single-blind, randomized, placebo-controlled trial was to evaluate the effect of inhaled GSH in patients with CF. 54 adult and 51 pediatric patients were randomized to receive inhaled GSH or placebo twice daily for 12 months. Twelve month treatment with inhaled GSH did not achieve our predetermined primary outcome measure of 15% improvement in FEV1%. Only in patients with moderate lung disease, 3, 6 and 9 months therapy with GSH resulted in a statistically significant increase of FEV1 values from the baseline. Moreover GSH therapy improved 6-minute walking test in pediatric population. GSH was well tolerated by all patients. Inhaled GSH has slight positive effects in CF patients with moderate lung disease warranting further study. ClinicalTrials.gov; No.: NCT01450267; URL: www.clinicaltrialsgov. Copyright © 2014 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

  19. Prognostic Significance of Carbohydrate Antigen 19-9 in Unresectable Locally Advanced Pancreatic Cancer Treated With Dose-Escalated Intensity Modulated Radiation Therapy and Concurrent Full-Dose Gemcitabine: Analysis of a Prospective Phase 1/2 Dose Escalation Study

    International Nuclear Information System (INIS)

    Vainshtein, Jeffrey M.; Schipper, Matthew; Zalupski, Mark M.; Lawrence, Theodore S.; Abrams, Ross; Francis, Isaac R.; Khan, Gazala; Leslie, William; Ben-Josef, Edgar

    2013-01-01

    Purpose: Although established in the postresection setting, the prognostic value of carbohydrate antigen 19-9 (CA19-9) in unresectable locally advanced pancreatic cancer (LAPC) is less clear. We examined the prognostic utility of CA19-9 in patients with unresectable LAPC treated on a prospective trial of intensity modulated radiation therapy (IMRT) dose escalation with concurrent gemcitabine. Methods and Materials: Forty-six patients with unresectable LAPC were treated at the University of Michigan on a phase 1/2 trial of IMRT dose escalation with concurrent gemcitabine. CA19-9 was obtained at baseline and during routine follow-up. Cox models were used to assess the effect of baseline factors on freedom from local progression (FFLP), distant progression (FFDP), progression-free survival (PFS), and overall survival (OS). Stepwise forward regression was used to build multivariate predictive models for each endpoint. Results: Thirty-eight patients were eligible for the present analysis. On univariate analysis, baseline CA19-9 and age predicted OS, CA19-9 at baseline and 3 months predicted PFS, gross tumor volume (GTV) and black race predicted FFLP, and CA19-9 at 3 months predicted FFDP. On stepwise multivariate regression modeling, baseline CA19-9, age, and female sex predicted OS; baseline CA19-9 and female sex predicted both PFS and FFDP; and GTV predicted FFLP. Patients with baseline CA19-9 ≤90 U/mL had improved OS (median 23.0 vs 11.1 months, HR 2.88, P<.01) and PFS (14.4 vs 7.0 months, HR 3.61, P=.001). CA19-9 progression over 90 U/mL was prognostic for both OS (HR 3.65, P=.001) and PFS (HR 3.04, P=.001), and it was a stronger predictor of death than either local progression (HR 1.46, P=.42) or distant progression (HR 3.31, P=.004). Conclusions: In patients with unresectable LAPC undergoing definitive chemoradiation therapy, baseline CA19-9 was independently prognostic even after established prognostic factors were controlled for, whereas CA19-9 progression

  20. Prognostic Significance of Carbohydrate Antigen 19-9 in Unresectable Locally Advanced Pancreatic Cancer Treated With Dose-Escalated Intensity Modulated Radiation Therapy and Concurrent Full-Dose Gemcitabine: Analysis of a Prospective Phase 1/2 Dose Escalation Study

    Energy Technology Data Exchange (ETDEWEB)

    Vainshtein, Jeffrey M., E-mail: jvainsh@med.umich.edu [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Schipper, Matthew [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Zalupski, Mark M. [Division of Hematology Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan (United States); Lawrence, Theodore S. [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Abrams, Ross [Department of Radiation Oncology, Rush Medical Center, Chicago, Illinois (United States); Francis, Isaac R. [Department of Radiology, University of Michigan, Ann Arbor, Michigan (United States); Khan, Gazala [Division of Hematology Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan (United States); Leslie, William [Division of Hematology Oncology, Department of Internal Medicine, Rush Medical Center, Chicago, Illinois (United States); Ben-Josef, Edgar [Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania (United States)

    2013-05-01

    Purpose: Although established in the postresection setting, the prognostic value of carbohydrate antigen 19-9 (CA19-9) in unresectable locally advanced pancreatic cancer (LAPC) is less clear. We examined the prognostic utility of CA19-9 in patients with unresectable LAPC treated on a prospective trial of intensity modulated radiation therapy (IMRT) dose escalation with concurrent gemcitabine. Methods and Materials: Forty-six patients with unresectable LAPC were treated at the University of Michigan on a phase 1/2 trial of IMRT dose escalation with concurrent gemcitabine. CA19-9 was obtained at baseline and during routine follow-up. Cox models were used to assess the effect of baseline factors on freedom from local progression (FFLP), distant progression (FFDP), progression-free survival (PFS), and overall survival (OS). Stepwise forward regression was used to build multivariate predictive models for each endpoint. Results: Thirty-eight patients were eligible for the present analysis. On univariate analysis, baseline CA19-9 and age predicted OS, CA19-9 at baseline and 3 months predicted PFS, gross tumor volume (GTV) and black race predicted FFLP, and CA19-9 at 3 months predicted FFDP. On stepwise multivariate regression modeling, baseline CA19-9, age, and female sex predicted OS; baseline CA19-9 and female sex predicted both PFS and FFDP; and GTV predicted FFLP. Patients with baseline CA19-9 ≤90 U/mL had improved OS (median 23.0 vs 11.1 months, HR 2.88, P<.01) and PFS (14.4 vs 7.0 months, HR 3.61, P=.001). CA19-9 progression over 90 U/mL was prognostic for both OS (HR 3.65, P=.001) and PFS (HR 3.04, P=.001), and it was a stronger predictor of death than either local progression (HR 1.46, P=.42) or distant progression (HR 3.31, P=.004). Conclusions: In patients with unresectable LAPC undergoing definitive chemoradiation therapy, baseline CA19-9 was independently prognostic even after established prognostic factors were controlled for, whereas CA19-9 progression

  1. Suicide risk in placebo-controlled studies of major depression

    NARCIS (Netherlands)

    Storosum, J. G.; van Zwieten, B. J.; van den Brink, W.; Gersons, B. P.; Broekmans, A. W.

    2001-01-01

    The purpose of this study was to determine if fear of an increased risk of attempted suicide in placebo groups participating in placebo-controlled studies is an argument against the performance of placebo-controlled trials in studies of major depression. All short-term and long-term,

  2. Phase 1 dose-escalation study of the antiplacental growth factor monoclonal antibody RO5323441 combined with bevacizumab in patients with recurrent glioblastoma

    DEFF Research Database (Denmark)

    Lassen, Ulrik; Chinot, Olivier L; McBain, Catherine

    2015-01-01

    BACKGROUND: We conducted a phase 1 dose-escalation study of RO5323441, a novel antiplacental growth factor (PlGF) monoclonal antibody, to establish the recommended dose for use with bevacizumab and to investigate the pharmacokinetics, pharmacodynamics, safety/tolerability, and preliminary clinica...

  3. A phase I, dose-escalation study of TB-403, a monoclonal antibody directed against PlGF, in patients with advanced solid tumours

    DEFF Research Database (Denmark)

    Lassen, U; Nielsen, D L; Sørensen, M

    2012-01-01

    BACKGROUND: TB-403 (RO 5323441), a humanised monoclonal antibody, is a novel antiangiogenesis agent directed against placental growth factor. The safety, pharmacokinetics (PK), and antitumour activity of TB-403 were assessed in a phase I, dose-escalation study in patients with advanced solid...

  4. Isotoxic dose escalation in the treatment of lung cancer by means of heterogeneous dose distributions in the presence of respiratory motion

    DEFF Research Database (Denmark)

    Baker, Mariwan; Nielsen, Morten; Hansen, Olfred

    2011-01-01

    To test, in the presence of intrafractional respiration movement, a margin recipe valid for a homogeneous and conformal dose distribution and to test whether the use of smaller margins combined with heterogeneous dose distributions allows an isotoxic dose escalation when respiratory motion...

  5. Radioimmunotherapy (RIT) Dose-Escalation Studies in Prostate Cancer Using Anti-PSMA Antibody 177Lu-J591: RIT Alone and RIT in Combination with Docetaxel

    National Research Council Canada - National Science Library

    Vallabhajosula, Shankar

    2007-01-01

    Phase I dose escalation studies with 177Lu-DOTA-huJ591 using dose fractionation regimen will be performed in patients with PCa and who have recurrent and/or metastatic disease. The 177Lu dose (20-45 mCi/m2...

  6. Radioimmunotherapy (RIT) Dose-Escalation Studies in Prostate Cancer Using Anti-PSMA Antibody 177Lu-J591: RIT Alone and RIT in Combination With Docetaxel

    National Research Council Canada - National Science Library

    Vallabhajosula, Shankar

    2006-01-01

    Phase I dose escalation studies with 177Lu-DOTA-huJ591 using dose fractionation regimen will be performed in patients with PCa and who have recurrent and/or metastatic disease. The 177Lu dose (20-45 mCi/m2...

  7. Lack of benefit for the addition of androgen deprivation therapy to dose-escalated radiotherapy in the treatment of intermediate- and high-risk prostate cancer.

    LENUS (Irish Health Repository)

    Krauss, Daniel

    2012-02-01

    PURPOSE: Assessment of androgen deprivation therapy (ADT) benefits for prostate cancer treated with dose-escalated radiotherapy (RT). METHODS AND MATERIALS: From 1991 to 2004, 1,044 patients with intermediate- (n = 782) or high-risk (n = 262) prostate cancer were treated with dose-escalated RT at William Beaumont Hospital. Patients received external-beam RT (EBRT) alone, brachytherapy (high or low dose rate), or high dose rate brachytherapy plus pelvic EBRT. Intermediate-risk patients had Gleason score 7, prostate-specific antigen (PSA) 10.0-19.9 ng\\/mL, or Stage T2b-T2c. High-risk patients had Gleason score 8-10, PSA >\\/=20, or Stage T3. Patients were additionally divided specifically by Gleason score, presence of palpable disease, and PSA level to further define subgroups benefitting from ADT. RESULTS: Median follow-up was 5 years; 420 patients received ADT + dose-escalated RT, and 624 received dose-escalated RT alone. For all patients, no advantages in any clinical endpoints at 8 years were associated with ADT administration. No differences in any endpoints were associated with ADT administration based on intermediate- vs. high-risk group or RT modality when analyzed separately. Patients with palpable disease plus Gleason >\\/=8 demonstrated improved clinical failure rates and a trend toward improved survival with ADT. Intermediate-risk patients treated with brachytherapy alone had improved biochemical control when ADT was given. CONCLUSION: Benefits of ADT in the setting of dose-escalated RT remain poorly defined. This question must continue to be addressed in prospective study.

  8. Can we avoid dose escalation for intermediate-risk prostate cancer in the setting of short-course neoadjuvant androgen deprivation?

    Science.gov (United States)

    Shakespeare, Thomas P; Wilcox, Shea W; Aherne, Noel J

    2016-01-01

    Both dose-escalated external beam radiotherapy (DE-EBRT) and androgen deprivation therapy (ADT) improve the outcomes in patients with intermediate-risk prostate cancer. Despite this, there are only few reports evaluating DE-EBRT for patients with intermediate-risk prostate cancer receiving neoadjuvant ADT, and virtually no studies investigating dose escalation >74 Gy in this setting. We aimed to determine whether DE-EBRT >74 Gy improved the outcomes for patients with intermediate-risk prostate cancer who received neoadjuvant ADT. In our institution, patients with intermediate-risk prostate cancer were treated with neoadjuvant ADT and DE-EBRT, with doses sequentially increasing from 74 Gy to 76 Gy and then to 78 Gy between 2006 and 2012. We identified 435 patients treated with DE-EBRT and ADT, with a median follow-up of 70 months. For the 74 Gy, 76 Gy, and 78 Gy groups, five-year biochemical disease-free survival rates were 95.0%, 97.8%, and 95.3%, respectively; metastasis-free survival rates were 99.1%, 100.0%, and 98.6%, respectively; and prostate cancer-specific survival rate was 100% for all three dose levels. There was no significant benefit for dose escalation either on univariate or multivariate analysis for any outcome. There was no benefit for DE-EBRT >74 Gy in our cohort of intermediate-risk prostate cancer patients treated with neoadjuvant ADT. Given the higher risks of toxicity associated with dose escalation, it may be feasible to omit dose escalation in this group of patients. Randomized studies evaluating dose de-escalation should be considered.

  9. SU-C-BRB-02: Automatic Planning as a Potential Strategy for Dose Escalation for Pancreas SBRT?

    International Nuclear Information System (INIS)

    Wang, S; Zheng, D; Ma, R; Lin, C; Zhu, X; Lei, Y; Enke, C; Zhou, S

    2016-01-01

    Purpose: Stereotactic body radiation therapy (SBRT) has been suggested to provide high rates of local control for locally advanced pancreatic cancer. However, the close proximity of highly radiosensitive normal tissues usually causes the labor-intensive planning process, and may impede further escalation of the prescription dose. The present study evaluates the potential of an automatic planning system as a dose escalation strategy. Methods: Ten pancreatic cancer patients treated with SBRT were studied retrospectively. SBRT was delivered over 5 consecutive fractions with 6 ∼ 8Gy/fraction. Two plans were generated by Pinnacle Auto-Planning with the original prescription and escalated prescription, respectively. Escalated prescription adds 1 Gy/fraction to the original prescription. Manually-created planning volumes were excluded in the optimization goals in order to assess the planning efficiency and quality simultaneously. Critical organs with closest proximity were used to determine the plan normalization to ensure the OAR sparing. Dosimetric parameters including D100, and conformity index (CI) were assessed. Results: Auto-plans directly generate acceptable plans for 70% of the cases without necessity of further improvement, and two more iterations at most are necessary for the rest of the cases. For the pancreas SBRT plans with the original prescription, autoplans resulted in favorable target coverage and PTV conformity (D100 = 96.3% ± 1.48%; CI = 0.88 ± 0.06). For the plans with the escalated prescriptions, no significant target under-dosage was observed, and PTV conformity remains reasonable (D100 = 93.3% ± 3.8%, and CI = 0.84 ± 0.05). Conclusion: Automatic planning, without substantial human-intervention process, results in reasonable PTV coverage and PTV conformity on the premise of adequate OAR sparing for the pancreas SBRT plans with escalated prescription. The results highlight the potential of autoplanning as a dose escalation strategy for pancreas

  10. Phase I Trial of Pelvic Nodal Dose Escalation With Hypofractionated IMRT for High-Risk Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Adkison, Jarrod B.; McHaffie, Derek R.; Bentzen, Soren M.; Patel, Rakesh R.; Khuntia, Deepak [Department of Human Oncology, University of Wisconsin Carbone Cancer Center, School of Medicine and Public Health, Madison, WI (United States); Petereit, Daniel G. [Department of Radiation Oncology, John T. Vucurevich Regional Cancer Care Institute, Rapid City Regional Hospital, Rapid City, SD (United States); Hong, Theodore S.; Tome, Wolfgang [Department of Human Oncology, University of Wisconsin Carbone Cancer Center, School of Medicine and Public Health, Madison, WI (United States); Ritter, Mark A., E-mail: ritter@humonc.wisc.edu [Department of Human Oncology, University of Wisconsin Carbone Cancer Center, School of Medicine and Public Health, Madison, WI (United States)

    2012-01-01

    Purpose: Toxicity concerns have limited pelvic nodal prescriptions to doses that may be suboptimal for controlling microscopic disease. In a prospective trial, we tested whether image-guided intensity-modulated radiation therapy (IMRT) can safely deliver escalated nodal doses while treating the prostate with hypofractionated radiotherapy in 5 Vulgar-Fraction-One-Half weeks. Methods and Materials: Pelvic nodal and prostatic image-guided IMRT was delivered to 53 National Comprehensive Cancer Network (NCCN) high-risk patients to a nodal dose of 56 Gy in 2-Gy fractions with concomitant treatment of the prostate to 70 Gy in 28 fractions of 2.5 Gy, and 50 of 53 patients received androgen deprivation for a median duration of 12 months. Results: The median follow-up time was 25.4 months (range, 4.2-57.2). No early Grade 3 Radiation Therapy Oncology Group or Common Terminology Criteria for Adverse Events v.3.0 genitourinary (GU) or gastrointestinal (GI) toxicities were seen. The cumulative actuarial incidence of Grade 2 early GU toxicity (primarily alpha blocker initiation) was 38%. The rate was 32% for Grade 2 early GI toxicity. None of the dose-volume descriptors correlated with GU toxicity, and only the volume of bowel receiving {>=}30 Gy correlated with early GI toxicity (p = 0.029). Maximum late Grades 1, 2, and 3 GU toxicities were seen in 30%, 25%, and 2% of patients, respectively. Maximum late Grades 1 and 2 GI toxicities were seen in 30% and 8% (rectal bleeding requiring cautery) of patients, respectively. The estimated 3-year biochemical control (nadir + 2) was 81.2 {+-} 6.6%. No patient manifested pelvic nodal failure, whereas 2 experienced paraaortic nodal failure outside the field. The six other clinical failures were distant only. Conclusions: Pelvic IMRT nodal dose escalation to 56 Gy was delivered concurrently with 70 Gy of hypofractionated prostate radiotherapy in a convenient, resource-efficient, and well-tolerated 28-fraction schedule. Pelvic nodal dose

  11. SU-E-T-183: Feasibility of Extreme Dose Escalation for Glioblastoma Multiforme Using 4π Radiotherapy

    International Nuclear Information System (INIS)

    Nguyen, D; Rwigema, J; Yu, V; Kaprealian, T; Kupelian, P; Selch, M; Low, D; Sheng, K

    2014-01-01

    Purpose: GBM recurrence primarily occurs inside or near the high-dose radiation field of original tumor site requiring greater than 100 Gy to significantly improve local control. We utilize 4π non-coplanar radiotherapy to test the feasibility of planning target volume (PTV) margin expansions or extreme dose escalations without incurring additional radiation toxicities. Methods: 11 GBM patients treated with VMAT to a prescription dose of 59.4 Gy or 60 Gy were replanned with 4π. Original VMAT plans were created with 2 to 4 coplanar or non-coplanar arcs using 3 mm hi-res MLC. The 4π optimization, using 5 mm MLC, selected and inverse optimized 30 beams from a candidate pool of 1162 beams evenly distributed through 4π steradians. 4π plans were first compared to clinical plans using the same prescription dose. Two more studies were then performed to respectively escalate the GTV and PTV doses to 100 Gy, followed by a fourth plan expanding the PTV by 5 mm and maintaining the prescription dose. Results: The standard 4π plan significantly reduced (p<0.01) max and mean doses to critical structures by a range of 47.0–98.4% and 61.0–99.2%, respectively. The high dose PTV/high dose GTV/expanded PTV studies showed a reduction (p<0.05) or unchanged* (p>0.05) maximum dose of 72.1%/86.7%/77.1% (chiasm), 7.2%*/27.7%*/30.7% (brainstem), 39.8%*/84.2%/51.9%* (spinal cord), 69.0%/87.0%/66.9% (L eye), 76.2%/88.1%/84.1% (R eye), 95.0%/98.6%/97.5% (L lens), 93.9%/98.8%/97.6% (R lens), 74.3%/88.5%/72.4% (L optical nerve), 80.4%/91.3%/75.7% (R optical nerve), 64.8%/84.2%/44.9%* (L cochlea), and 85.2%/93.0%/78.0% (R cochlea), respectively. V30 and V36 for both brain and (brain - PTV) were reduced for all cases except the high dose PTV plan. PTV dose coverage increased for all 4π plans. Conclusion: Extreme dose escalation or further margin expansion is achievable using 4π, maintaining or reducing OAR doses. This study indicates that clinical trials employing 4π delivery using

  12. Trigeminal Neuralgia Treated With Stereotactic Radiosurgery: The Effect of Dose Escalation on Pain Control and Treatment Outcomes

    Energy Technology Data Exchange (ETDEWEB)

    Kotecha, Rupesh [Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio (United States); Kotecha, Ritesh [MidMichigan Medical Center, Midland, Michigan (United States); Modugula, Sujith [Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio (United States); Murphy, Erin S. [Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio (United States); Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio (United States); Jones, Mark; Kotecha, Rajesh [MidMichigan Medical Center, Midland, Michigan (United States); Reddy, Chandana A. [Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio (United States); Suh, John H. [Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio (United States); Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio (United States); Barnett, Gene H. [Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio (United States); Department of Neurosurgery, Neurological Institute, Cleveland Clinic, Cleveland, Ohio (United States); Neyman, Gennady [Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio (United States); Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio (United States); Machado, Andre; Nagel, Sean [Department of Neurosurgery, Neurological Institute, Cleveland Clinic, Cleveland, Ohio (United States); Chao, Samuel T., E-mail: chaos@ccf.org [Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio (United States); Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio (United States)

    2016-09-01

    Purpose: To analyze the effect of dose escalation on treatment outcome in patients undergoing stereotactic radiosurgery (SRS) for trigeminal neuralgia (TN). Methods and Materials: A retrospective review was performed of 870 patients who underwent SRS for a diagnosis of TN from 2 institutions. Patients were typically treated using a single 4-mm isocenter placed at the trigeminal nerve dorsal root entry zone. Patients were divided into groups based on treatment doses: ≤82 Gy (352 patients), 83 to 86 Gy (85 patients), and ≥90 Gy (433 patients). Pain response was classified using a categorical scoring system, with fair or poor pain control representing treatment failure. Treatment-related facial numbness was classified using the Barrow Neurological Institute scale. Log-rank tests were performed to test differences in time to pain failure or development of facial numbness for patients treated with different doses. Results: Median age at first pain onset was 63 years, median age at time of SRS was 71 years, and median follow-up was 36.5 months from the time of SRS. A majority of patients (827, 95%) were clinically diagnosed with typical TN. The 4-year rate of excellent to good pain relief was 87% (95% confidence interval 84%-90%). The 4-year rate of pain response was 79%, 82%, and 92% in patients treated to ≤82 Gy, 83 to 86 Gy, and ≥90 Gy, respectively. Patients treated to doses ≤82 Gy had an increased risk of pain failure after SRS, compared with patients treated to ≥90 Gy (hazard ratio 2.0, P=.0007). Rates of treatment-related facial numbness were similar among patients treated to doses ≥83 Gy. Nine patients (1%) were diagnosed with anesthesia dolorosa. Conclusions: Dose escalation for TN to doses >82 Gy is associated with an improvement in response to treatment and duration of pain relief. Patients treated at these doses, however, should be counseled about the increased risk of treatment-related facial numbness.

  13. SU-C-BRB-02: Automatic Planning as a Potential Strategy for Dose Escalation for Pancreas SBRT?

    Energy Technology Data Exchange (ETDEWEB)

    Wang, S; Zheng, D; Ma, R; Lin, C; Zhu, X; Lei, Y; Enke, C; Zhou, S [University of Nebraska Medical Center, Omaha, NE (United States)

    2016-06-15

    Purpose: Stereotactic body radiation therapy (SBRT) has been suggested to provide high rates of local control for locally advanced pancreatic cancer. However, the close proximity of highly radiosensitive normal tissues usually causes the labor-intensive planning process, and may impede further escalation of the prescription dose. The present study evaluates the potential of an automatic planning system as a dose escalation strategy. Methods: Ten pancreatic cancer patients treated with SBRT were studied retrospectively. SBRT was delivered over 5 consecutive fractions with 6 ∼ 8Gy/fraction. Two plans were generated by Pinnacle Auto-Planning with the original prescription and escalated prescription, respectively. Escalated prescription adds 1 Gy/fraction to the original prescription. Manually-created planning volumes were excluded in the optimization goals in order to assess the planning efficiency and quality simultaneously. Critical organs with closest proximity were used to determine the plan normalization to ensure the OAR sparing. Dosimetric parameters including D100, and conformity index (CI) were assessed. Results: Auto-plans directly generate acceptable plans for 70% of the cases without necessity of further improvement, and two more iterations at most are necessary for the rest of the cases. For the pancreas SBRT plans with the original prescription, autoplans resulted in favorable target coverage and PTV conformity (D100 = 96.3% ± 1.48%; CI = 0.88 ± 0.06). For the plans with the escalated prescriptions, no significant target under-dosage was observed, and PTV conformity remains reasonable (D100 = 93.3% ± 3.8%, and CI = 0.84 ± 0.05). Conclusion: Automatic planning, without substantial human-intervention process, results in reasonable PTV coverage and PTV conformity on the premise of adequate OAR sparing for the pancreas SBRT plans with escalated prescription. The results highlight the potential of autoplanning as a dose escalation strategy for pancreas

  14. Trigeminal Neuralgia Treated With Stereotactic Radiosurgery: The Effect of Dose Escalation on Pain Control and Treatment Outcomes

    International Nuclear Information System (INIS)

    Kotecha, Rupesh; Kotecha, Ritesh; Modugula, Sujith; Murphy, Erin S.; Jones, Mark; Kotecha, Rajesh; Reddy, Chandana A.; Suh, John H.; Barnett, Gene H.; Neyman, Gennady; Machado, Andre; Nagel, Sean; Chao, Samuel T.

    2016-01-01

    Purpose: To analyze the effect of dose escalation on treatment outcome in patients undergoing stereotactic radiosurgery (SRS) for trigeminal neuralgia (TN). Methods and Materials: A retrospective review was performed of 870 patients who underwent SRS for a diagnosis of TN from 2 institutions. Patients were typically treated using a single 4-mm isocenter placed at the trigeminal nerve dorsal root entry zone. Patients were divided into groups based on treatment doses: ≤82 Gy (352 patients), 83 to 86 Gy (85 patients), and ≥90 Gy (433 patients). Pain response was classified using a categorical scoring system, with fair or poor pain control representing treatment failure. Treatment-related facial numbness was classified using the Barrow Neurological Institute scale. Log-rank tests were performed to test differences in time to pain failure or development of facial numbness for patients treated with different doses. Results: Median age at first pain onset was 63 years, median age at time of SRS was 71 years, and median follow-up was 36.5 months from the time of SRS. A majority of patients (827, 95%) were clinically diagnosed with typical TN. The 4-year rate of excellent to good pain relief was 87% (95% confidence interval 84%-90%). The 4-year rate of pain response was 79%, 82%, and 92% in patients treated to ≤82 Gy, 83 to 86 Gy, and ≥90 Gy, respectively. Patients treated to doses ≤82 Gy had an increased risk of pain failure after SRS, compared with patients treated to ≥90 Gy (hazard ratio 2.0, P=.0007). Rates of treatment-related facial numbness were similar among patients treated to doses ≥83 Gy. Nine patients (1%) were diagnosed with anesthesia dolorosa. Conclusions: Dose escalation for TN to doses >82 Gy is associated with an improvement in response to treatment and duration of pain relief. Patients treated at these doses, however, should be counseled about the increased risk of treatment-related facial numbness.

  15. [Placebo-controlled trials in schizophrenia].

    Science.gov (United States)

    Melamed, Yuval; Davidson, Michael; Bleich, Avi

    2004-03-01

    Clinical trials involving human subjects give rise to ethical and medico-legal dilemmas. Essential research of new drugs may potentially expose patients to ineffective medications or to placebo. The complexity of the problem increases when dealing with mentally ill patients, for whom, on the one hand there is no known cure for their disease, and on the other hand, it is sometimes questionable whether or not they are able to provide informed consent to participate in clinical trials. The Israel Psychiatric Association decided to develop a position paper on the subject of placebo-controlled clinical trials in schizophrenia patients. Discussion groups were established, and the available material in the professional literature was examined, with an emphasis on recent developments. The Declaration of Helsinki and its amendments were analyzed, and experts in the field were consulted. Clinical drug trials for development of new medications are essential in all fields of medicine, especially in psychiatry. The requirement for a placebo arm in pharmaceutical trials presents ethical and clinical dilemmas that are especially complicated with regard to mentally ill persons whose free choice and ability to provide informed consent may be questionable. However, we do not believe that this predicament justifies unconditional rejection of placebo use in psychiatry, when it may provide substantial benefit for some patients. Simultaneously, it is our duty to provide stringent restrictions that will enable strict supervision over the scientific, clinical and ethical aspects of the trials. We propose the following criteria for approval of pharmaceutical trials that include a placebo arm: scientific justification; clinical and ethical justification; provision of informed consent; recruitment of patients hospitalized voluntarily; prevention of harm; administration of additional potential therapeutic interventions; benefit to patients participating in the study; control and follow

  16. Sexual Function After Three-Dimensional Conformal Radiotherapy for Prostate Cancer: Results From a Dose-Escalation Trial

    International Nuclear Information System (INIS)

    Wielen, Gerard J. van der; Putten, Wim van; Incrocci, Luca

    2007-01-01

    Purpose: The purpose of this study is to provide information about sexual function (SF) after three-dimensional conformal radiotherapy (3D-CRT) for prostate cancer while taking important factors into account that influence SF. Methods and Materials: Between June 1997 and February 2003, a total of 268 patients from a randomized dose-escalation trial comparing 68 Gy and 78 Gy agreed to participate in an additional part of the trial that evaluated SF. Results: At baseline 28% of patients had erectile dysfunction (ED). After 1 year, 27% of the pretreatment potent patients had developed ED. After 2 years this percentage had increased to 36%. After 3 years it almost stabilized at 38%. Satisfaction with sexual life was significantly correlated with ED. After 2 years one third of the pre-treatment potent patients still had considerable to very much sexual desire and found sex (very) important. No significant differences were found between the two dose-arms. Potency aids were used on a regular base by 14% of the patients. Conclusion: By taking adjuvant hormonal therapy (HT), HT during follow-up and potency aids into account, we found a lower percentage of ED after 3D-CRT than reported in previous prospective studies. A large group of patients still had sexual desire, considered sex important and 14% used potency aids after 3D-CRT

  17. Can we avoid dose escalation for intermediate-risk prostate cancer in the setting of short-course neoadjuvant androgen deprivation?

    Directory of Open Access Journals (Sweden)

    Shakespeare TP

    2016-03-01

    Full Text Available Thomas P Shakespeare,1,2 Shea W Wilcox,1 Noel J Aherne1,2 1Department of Radiation Oncology, North Coast Cancer Institute, 2Faculty of Medicine, Rural Clinical School, The University of New South Wales, Coffs Harbour, New South Wales, Australia Background: Both dose-escalated external beam radiotherapy (DE-EBRT and androgen deprivation therapy (ADT improve the outcomes in patients with intermediate-risk prostate cancer. Despite this, there are only few reports evaluating DE-EBRT for patients with intermediate-risk prostate cancer receiving neoadjuvant ADT, and virtually no studies investigating dose escalation >74 Gy in this setting. We aimed to determine whether DE-EBRT >74 Gy improved the outcomes for patients with intermediate-risk prostate cancer who received neoadjuvant ADT. Findings: In our institution, patients with intermediate-risk prostate cancer were treated with neoadjuvant ADT and DE-EBRT, with doses sequentially increasing from 74 Gy to 76 Gy and then to 78 Gy between 2006 and 2012. We identified 435 patients treated with DE-EBRT and ADT, with a median follow-up of 70 months. For the 74 Gy, 76 Gy, and 78 Gy groups, five-year biochemical disease-free survival rates were 95.0%, 97.8%, and 95.3%, respectively; metastasis-free survival rates were 99.1%, 100.0%, and 98.6%, respectively; and prostate cancer-specific survival rate was 100% for all three dose levels. There was no significant benefit for dose escalation either on univariate or multivariate analysis for any outcome. Conclusion: There was no benefit for DE-EBRT >74 Gy in our cohort of intermediate-risk prostate cancer patients treated with neoadjuvant ADT. Given the higher risks of toxicity associated with dose escalation, it may be feasible to omit dose escalation in this group of patients. Randomized studies evaluating dose de-escalation should be considered. Keywords: radiotherapy, IMRT, dose, dose escalation, dose de-escalation, androgen deprivation therapy

  18. A phase I dose escalation study of hypofractionated stereotactic radiotherapy as salvage therapy for persistent or recurrent malignant glioma

    International Nuclear Information System (INIS)

    Hudes, Richard S.; Corn, Benjamin W.; Werner-Wasik, Maria; Andrews, David; Rosenstock, Jeffrey; Thoron, Louisa; Downes, Beverly; Curran, Walter J.

    1999-01-01

    Purpose: A phase I dose escalation of hypofractionated stereotactic radiotherapy (H-SRT) in recurrent or persistent malignant gliomas as a means of increasing the biologically effective dose and decreasing the high rate of reoperation due to toxicity associated with single-fraction stereotactic radiosurgery (SRS) and brachytherapy. Materials and Methods: From November 1994 to September 1996, 25 lesions in 20 patients with clinical and/or imaging evidence of malignant glioma persistence or recurrence received salvage H-SRT. Nineteen patients at the time of initial diagnosis had glioblastoma multiforme (GBM) and one patient had an anaplastic astrocytoma. All of these patients with tumor persistence or recurrence had received initial fractionated radiation therapy (RT) with a mean and median dose of 60 Gy (44.0-72.0 Gy). The median time from completion of initial RT to H-SRT was 3.1 months (0.7-45.5 months). Salvage H-SRT was delivered using daily 3.0-3.5 Gy fractions (fxs). Three different total dose levels were sequentially evaluated: 24.0 Gy/3.0 Gy fxs (five lesions), 30.0 Gy/3.0 Gy fxs (10 lesions), and 35.0 Gy/3.5 Gy fxs (nine lesions). Median treated tumor volume measured 12.66 cc (0.89-47.5 cc). The median ratio of prescription volume to tumor volume was 2.8 (1.4-5.0). Toxicity was judged by RTOG criteria. Response was determined by clinical neurologic improvement, a decrease in steroid dose without clinical deterioration, and/or radiologic imaging. Results: No grade 3 toxicities were observed and no reoperation due to toxicity was required. At the time of analysis, 13 of 20 patients had died. The median survival time from the completion of H-SRT is 10.5 months with a 1-year survival rate of 20%. Neurological improvement was found in 45% of patients. Decreased steroid requirements occurred in 60% of patients. Minor imaging response was noted in 22% of patients. Using Fisher's exact test, response of any kind correlated strongly to total dose (p = 0.0056). None

  19. Moderate Hypofractionated Protracted Radiation Therapy and Dose Escalation for Prostate Cancer: Do Dose and Overall Treatment Time Matter?

    Energy Technology Data Exchange (ETDEWEB)

    Kountouri, Melpomeni; Zilli, Thomas; Rouzaud, Michel; Dubouloz, Angèle [Department of Radiation Oncology, Geneva University Hospital, Geneva (Switzerland); Linero, Dolors; Escudé, Lluís; Jorcano, Sandra [Radiation Oncology, Teknon Oncologic Institute, Barcelona (Spain); Miralbell, Raymond, E-mail: Raymond.Miralbell@hcuge.ch [Department of Radiation Oncology, Geneva University Hospital, Geneva (Switzerland); Radiation Oncology, Teknon Oncologic Institute, Barcelona (Spain)

    2016-02-01

    Purpose: This was a retrospective study of 2 sequential dose escalation regimens of twice-weekly 4 Gy/fractions hypofractionated intensity modulated radiation therapy (IMRT): 56 Gy and 60 Gy delivered within a protracted overall treatment time (OTT) of 6.5 and 7 weeks, respectively. Methods and Materials: 163 prostate cancer patients with cT1c-T3a disease and nodal involvement risk ≤20% (Roach index) were treated twice weekly to the prostate ± seminal vesicles with 2 sequential dose-escalated IMRT schedules: 56 Gy (14 × 4 Gy, n=81) from 2003 to 2007 and 60 Gy (15 × 4 Gy, n=82) from 2006 to 2010. Patient repositioning was made with bone matching on portal images. Gastrointestinal (GI) and genitourinary (GU) toxicities were scored according to the Common Terminology Criteria for Adverse Events version 3.0 grading scale. Results: There were no significant differences regarding the acute GU and GI toxicities in the 2 dose groups. The median follow-up times were 80.2 months (range, 4.5-121 months) and 56.5 months (range, 1.4-91.2 months) for patients treated to 56 and 60 Gy, respectively. The 5-year grade ≥2 late GU toxicity-free survivals with 56 Gy and 60 Gy were 96 ± 2.3% and 78.2 ± 5.1% (P=.001), respectively. The 5-year grade ≥2 late GI toxicity-free survivals with 56 Gy and 60 Gy were 98.6 ± 1.3% and 85.1 ± 4.5% (P=.005), respectively. Patients treated with 56 Gy showed a 5-year biochemical progression-free survival (bPFS) of 80.8 ± 4.7%, worse than patients treated with 60 Gy (93.2 ± 3.9%, P=.007). A trend for a better 5-year distant metastasis-free survival was observed among patients treated in the high-dose group (95.3 ± 2.7% vs 100%, P=.073, respectively). On multivariate analysis, only the 60-Gy group predicted for a better bPFS (P=.016, hazard ratio = 4.58). Conclusions: A single 4-Gy additional fraction in patients treated with a hypofractionated protracted IMRT schedule of 14 × 4 Gy resulted in

  20. Phase I dose escalation clinical trial of phenylbutyrate sodium administered twice daily to patients with advanced solid tumors.

    Science.gov (United States)

    Camacho, Luis H; Olson, Jon; Tong, William P; Young, Charles W; Spriggs, David R; Malkin, Mark G

    2007-04-01

    Phenylbutyrate (PBA), and its metabolite phenylacetate (PAA), induce growth inhibition and cellular differentiation in multiple tumor models. However, despite their potential anti-cancer properties, several pharmacodynamic aspects remain unknown. We conducted a dose escalating trial to evaluate twice-daily intravenous PBA infusions for two consecutive weeks (Monday through Friday) every month at five dose levels (60-360 mg/kg/day). Twenty-one patients with the following malignancies were treated: colon carcinoma 4, non-small cell lung carcinoma 4; anaplastic astrocytoma 3, glioblastoma multiforme 3, bladder carcinoma 2, sarcoma 2, and ovarian carcinoma, rectal hemangiopericytoma, and pancreatic carcinoma 1 each. Conversion of PBA to PAA and phenylacetylglutamine (PAG) was documented without catabolic saturation. Plasma content of PBA > or =1 mM was documented for only 3 h following each dose at the top two dosages. The therapy was well tolerated overall. Common adverse effects included grade 1 nausea/vomiting, fatigue, and lightheadedness. Dose limiting toxicities were short-term memory loss, sedation, confusion, nausea, and vomiting. Two patients with anaplastic astrocytoma and a patient with glioblastoma remained stable without tumor progression for 5, 7, and 4 months respectively. Administration of PBA in a twice-daily infusion schedule is safe. The maximum tolerated dose is 300 mg/kg/day. Study designs with more convenient treatment schedules and specific molecular correlates may help to further delineate the mechanism of action of this compound. Future studies evaluating PBA's ability to induce histone acetylation and cell differentiation alone or in combination with other anti-neoplastics are recommended.

  1. Questionnaire based quality assurance for the RT01 trial of dose escalation in conformal radiotherapy for prostate cancer (ISRCTN 47772397)

    International Nuclear Information System (INIS)

    Mayles, W.; Moore, A.Rollo; Aird, Edwin G.A.; Bidmead, A. Margaret; Dearnaley, David P.; Griffiths, Sue E.; Stephens, Richard J.; Warrington, A.P. Jim

    2004-01-01

    Background and purpose: In order to ensure the validity of the outcome of the Medical Research Council's 'RT01 trial' of dose escalation in conformal radiotherapy for prostate cancer it was considered important that the quality of treatment delivery should meet an adequate standard across all contributing centres. A questionnaire was therefore devised to ensure that all aspects of the planning and delivery process were adequately covered. Patients and methods: The questionnaire considered each step in the planning and delivery process and drew the attention of the participants to the specific requirements of the trial. Before entering patients into the trial each participating centre had to complete the questionnaire and an outlining exercise (reported elsewhere). Results: It was not practicable to define a detailed universally acceptable protocol for the whole process of delivery of conformal radiotherapy, not least because of the different equipment available for planning and treatment in different centres. The questionnaire identified some areas of difference in practice between centres where there may be a need for the development of a consensus as to best practice, particularly in the area of patient set-up. Occasionally it was necessary to follow up responses to questions that had been misunderstood or inadequately answered, but in most cases these issues proved to be easily resolved. Conclusions: The questionnaire proved to be a useful self-assessment tool as well as enabling the quality assurance group to ensure that the standards of the trial were being met. Subsequent follow-up visits confirmed the usefulness and validity of this self assessment process

  2. A phase I dose-escalation study of lenalidomide in combination with gemcitabine in patients with advanced pancreatic cancer.

    Directory of Open Access Journals (Sweden)

    Gustav J Ullenhag

    Full Text Available Lenalidomide have both immunomodulatory and anti-angiogenic properties which could confer anti-cancer effects. The aim of this study was to assess the feasibility of combining lenalidomide with the standard treatment gemcitabine in pancreatic cancer patients with advanced disease.Eligible patients had locally advanced or metastatic adenocarcinoma of the pancreas. Patients received lenalidomide days 1-21 orally and gemcitabine 1000 mg/m2 intravenously (days 1, 8 and 15, each 28 day cycle. Three cohorts of lenalidomide were examined (Cohort I = 15 mg, Cohort II = 20 mg and Cohort III = 25 mg daily. The maximum tolerated dose (MTD of lenalidomide given in combination with gemcitabine was defined as the highest dose level at which no more than one out of four (25% subjects experiences a dose-limiting toxicity (DLT. Patients should also be able to receive daily low molecular weight heparin (LMWH (e.g. dalteparin 5000 IU s.c. daily as a prophylactic anticoagulant for venous thromboembolic events (VTEs. Twelve patients (n = 4, n = 3 and n = 5 in cohort I, II and III, respectively were enrolled in this study.Median duration of treatment was 11 weeks (range 1-66, and median number of treatment cycles were three (range 1-14. The only DLT was a cardiac failure grade 3 in cohort III. Frequent treatment-related adverse events (AEs (all grades included neutropenia, leucopenia and fatigue (83% each, but there was no febrile neutropenia; thrombocytopenia (75%; dermatological toxicity (75%; diarrhea and nausea (42% each; and neuropathy (42%.This phase I study demonstrates the feasibility of the combination of lenalidomide and gemcitabine as first-line treatment in patients with advanced pancreatic cancer. The tolerability profile demonstrated in the dose escalation schedule of lenalidomide suggests the dosing of lenalidomide to be 25 mg daily on days 1-21 with standard dosing of gemcitabine and merits further evaluation in a phase II trial.ClinicalTrials.gov NCT

  3. A Phase I Dose-Escalation Study (ISIDE-BT-1) of Accelerated IMRT With Temozolomide in Patients With Glioblastoma

    International Nuclear Information System (INIS)

    Morganti, Alessio G.; Balducci, Mario; Salvati, Maurizio; Esposito, Vincenzo; Romanelli, Pantaleo; Ferro, Marica; Calista, Franco; Digesu, Cinzia; Macchia, Gabriella; Ianiri, Massimo; Deodato, Francesco; Cilla, Savino; Piermattei, Angelo M.P.; Valentini, Vincenzo; Cellini, Numa; Cantore, Gian Paolo

    2010-01-01

    Purpose: To determine the maximum tolerated dose (MTD) of fractionated intensity-modulated radiotherapy (IMRT) with temozolomide (TMZ) in patients with glioblastoma. Methods and Materials: A Phase I clinical trial was performed. Eligible patients had surgically resected or biopsy-proven glioblastoma. Patients started TMZ (75 mg/day) during IMRT and continued for 1 year (150-200 mg/day, Days 1-5 every 28 days) or until disease progression. Clinical target volume 1 (CTV1) was the tumor bed ± enhancing lesion with a 10-mm margin; CTV2 was the area of perifocal edema with a 20-mm margin. Planning target volume 1 (PTV1) and PTV2 were defined as the corresponding CTV plus a 5-mm margin. IMRT was delivered in 25 fractions over 5 weeks. Only the dose for PTV1 was escalated (planned dose escalation: 60 Gy, 62.5 Gy, 65 Gy) while maintaining the dose for PTV2 (45 Gy, 1.8 Gy/fraction). Dose limiting toxicities (DLT) were defined as any treatment-related nonhematological adverse effects rated as Grade ≥3 or any hematological toxicity rated as ≥4 by Radiation Therapy Oncology Group (RTOG) criteria. Results: Nineteen consecutive glioblastoma were treated with step-and-shoot IMRT, planned with the inverse approach (dose to the PTV1: 7 patients, 60 Gy; 6 patients, 62.5 Gy; 6 patients, 65 Gy). Five coplanar beams were used to cover at least 95% of the target volume with the 95% isodose line. Median follow-up time was 23 months (range, 8-40 months). No patient experienced DLT. Grade 1-2 treatment-related neurologic and skin toxicity were common (11 and 19 patients, respectively). No Grade >2 late neurologic toxicities were noted. Conclusion: Accelerated IMRT to a dose of 65 Gy in 25 fractions is well tolerated with TMZ at a daily dose of 75 mg.

  4. SU-E-T-500: Dose Escalation Strategy for Lung Cancer Patients Using a Biologically- Guided Target Definition

    International Nuclear Information System (INIS)

    Shusharina, N; Khan, F; Choi, N; Sharp, G

    2014-01-01

    Purpose: Dose escalation strategy for lung cancer patients can lead to late symptoms such as pneumonitis and cardiac injury. We propose a strategy to increase radiation dose for improving local tumor control while simultaneously striving to minimize the injury of organs at risk (OAR). Our strategy is based on defining a small, biologically-guided target volume for receiving additional radiation dose. Methods: 106 patients with lung cancer treated with radiotherapy were selected for patients diagnosed with stage II and III disease. Previous research has shown that 50% of the maximum SUV threshold in FDG-PET imaging is appropriate for delineation of the most aggressive part of a tumor. After PET- and CT-derived targets were contoured, an IMRT treatment plan was designed to deliver 60 Gy to the GTV as delineated on a 4D CT (Plan 1). A second plan was designed with additional dose of 18 Gy to the PET-derived volume (Plan 2). A composite plan was generated by the addition of Plan 1 and Plan 2. Results: Plan 1 was compared to the composite plan and increases in OAR dose were assessed. For seven patients on average, lung V5 was increased by 1.4% and V20 by 4.2% for ipsilateral lung and by 13.5% and 7% for contralateral lung. For total lung, V5 and V20 were increased by 4.5% and 4.8% respectively. Mean lung dose was increased by 9.7% for the total lung. The maximum dose to the spinal cord increased by 16% on average. For the heart, V20 increased by 4.2% and V40 by 5.2%. Conclusion: It seems feasible that an additional 18 Gy of radiation dose can be delivered to FDG PET-derived subvolume of the CT-based GTV of the primary tumor without significant increase in total dose to the critical organs such as lungs, spinal cord and heart

  5. Whole Brain Irradiation With Hippocampal Sparing and Dose Escalation on Multiple Brain Metastases: A Planning Study on Treatment Concepts

    International Nuclear Information System (INIS)

    Prokic, Vesna; Wiedenmann, Nicole; Fels, Franziska; Schmucker, Marianne; Nieder, Carsten; Grosu, Anca-Ligia

    2013-01-01

    Purpose: To develop a new treatment planning strategy in patients with multiple brain metastases. The goal was to perform whole brain irradiation (WBI) with hippocampal sparing and dose escalation on multiple brain metastases. Two treatment concepts were investigated: simultaneously integrated boost (SIB) and WBI followed by stereotactic fractionated radiation therapy sequential concept (SC). Methods and Materials: Treatment plans for both concepts were calculated for 10 patients with 2-8 brain metastases using volumetric modulated arc therapy. In the SIB concept, the prescribed dose was 30 Gy in 12 fractions to the whole brain and 51 Gy in 12 fractions to individual brain metastases. In the SC concept, the prescription was 30 Gy in 12 fractions to the whole brain followed by 18 Gy in 2 fractions to brain metastases. All plans were optimized for dose coverage of whole brain and lesions, simultaneously minimizing dose to the hippocampus. The treatment plans were evaluated on target coverage, homogeneity, and minimal dose to the hippocampus and organs at risk. Results: The SIB concept enabled more successful sparing of the hippocampus; the mean dose to the hippocampus was 7.55 ± 0.62 Gy and 6.29 ± 0.62 Gy, respectively, when 5-mm and 10-mm avoidance regions around the hippocampus were used, normalized to 2-Gy fractions. In the SC concept, the mean dose to hippocampus was 9.8 ± 1.75 Gy. The mean dose to the whole brain (excluding metastases) was 33.2 ± 0.7 Gy and 32.7 ± 0.96 Gy, respectively, in the SIB concept, for 5-mm and 10-mm hippocampus avoidance regions, and 37.23 ± 1.42 Gy in SC. Conclusions: Both concepts, SIB and SC, were able to achieve adequate whole brain coverage and radiosurgery-equivalent dose distributions to individual brain metastases. The SIB technique achieved better sparing of the hippocampus, especially when a10-mm hippocampal avoidance region was used.

  6. SU-E-T-500: Dose Escalation Strategy for Lung Cancer Patients Using a Biologically- Guided Target Definition

    Energy Technology Data Exchange (ETDEWEB)

    Shusharina, N; Khan, F; Choi, N; Sharp, G [Massachusetts General Hospital, Boston, MA (United States)

    2014-06-01

    Purpose: Dose escalation strategy for lung cancer patients can lead to late symptoms such as pneumonitis and cardiac injury. We propose a strategy to increase radiation dose for improving local tumor control while simultaneously striving to minimize the injury of organs at risk (OAR). Our strategy is based on defining a small, biologically-guided target volume for receiving additional radiation dose. Methods: 106 patients with lung cancer treated with radiotherapy were selected for patients diagnosed with stage II and III disease. Previous research has shown that 50% of the maximum SUV threshold in FDG-PET imaging is appropriate for delineation of the most aggressive part of a tumor. After PET- and CT-derived targets were contoured, an IMRT treatment plan was designed to deliver 60 Gy to the GTV as delineated on a 4D CT (Plan 1). A second plan was designed with additional dose of 18 Gy to the PET-derived volume (Plan 2). A composite plan was generated by the addition of Plan 1 and Plan 2. Results: Plan 1 was compared to the composite plan and increases in OAR dose were assessed. For seven patients on average, lung V5 was increased by 1.4% and V20 by 4.2% for ipsilateral lung and by 13.5% and 7% for contralateral lung. For total lung, V5 and V20 were increased by 4.5% and 4.8% respectively. Mean lung dose was increased by 9.7% for the total lung. The maximum dose to the spinal cord increased by 16% on average. For the heart, V20 increased by 4.2% and V40 by 5.2%. Conclusion: It seems feasible that an additional 18 Gy of radiation dose can be delivered to FDG PET-derived subvolume of the CT-based GTV of the primary tumor without significant increase in total dose to the critical organs such as lungs, spinal cord and heart.

  7. Continual reassessment method for dose escalation clinical trials in oncology: a comparison of prior skeleton approaches using AZD3514 data.

    Science.gov (United States)

    James, Gareth D; Symeonides, Stefan N; Marshall, Jayne; Young, Julia; Clack, Glen

    2016-08-31

    The continual reassessment method (CRM) requires an underlying model of the dose-toxicity relationship ("prior skeleton") and there is limited guidance of what this should be when little is known about this association. In this manuscript the impact of applying the CRM with different prior skeleton approaches and the 3 + 3 method are compared in terms of ability to determine the true maximum tolerated dose (MTD) and number of patients allocated to sub-optimal and toxic doses. Post-hoc dose-escalation analyses on real-life clinical trial data on an early oncology compound (AZD3514), using the 3 + 3 method and CRM using six different prior skeleton approaches. All methods correctly identified the true MTD. The 3 + 3 method allocated six patients to both sub-optimal and toxic doses. All CRM approaches allocated four patients to sub-optimal doses. No patients were allocated to toxic doses from sigmoidal, two from conservative and five from other approaches. Prior skeletons for the CRM for phase 1 clinical trials are proposed in this manuscript and applied to a real clinical trial dataset. Highly accurate initial skeleton estimates may not be essential to determine the true MTD, and, as expected, all CRM methods out-performed the 3 + 3 method. There were differences in performance between skeletons. The choice of skeleton should depend on whether minimizing the number of patients allocated to suboptimal or toxic doses is more important. NCT01162395 , Trial date of first registration: July 13, 2010.

  8. Phase 1 Dose Escalation Study of Accelerated Radiation Therapy With Concurrent Chemotherapy for Locally Advanced Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Kelsey, Chris R., E-mail: christopher.kelsey@duke.edu [Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina (United States); Das, Shiva [Department of Radiation Oncology, University of North Carolina School of Medicine, Chapel Hill, North Carolina (United States); Gu, Lin [Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina (United States); Dunphy, Frank R.; Ready, Neal E. [Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, North Carolina (United States); Marks, Lawrence B. [Department of Radiation Oncology, University of North Carolina School of Medicine, Chapel Hill, North Carolina (United States)

    2015-12-01

    Purpose: To determine the maximum tolerated dose of radiation therapy (RT) given in an accelerated fashion with concurrent chemotherapy using intensity modulated RT. Methods and Materials: Patients with locally advanced lung cancer (non-small cell and small cell) with good performance status and minimal weight loss received concurrent cisplatin and etoposide with RT. Intensity modulated RT with daily image guidance was used to facilitate esophageal avoidance and delivered using 6 fractions per week (twice daily on Fridays with a 6-hour interval). The dose was escalated from 58 Gy to a planned maximum dose of 74 Gy in 4 Gy increments in a standard 3 + 3 trial design. Dose-limiting toxicity (DLT) was defined as acute grade 3-5 nonhematologic toxicity attributed to RT. Results: A total of 24 patients were enrolled, filling all dose cohorts, all completing RT and chemotherapy as prescribed. Dose-limiting toxicity occurred in 1 patient at 58 Gy (grade 3 esophagitis) and 1 patient at 70 Gy (grade 3 esophageal fistula). Both patients with DLTs had large tumors (12 cm and 10 cm, respectively) adjacent to the esophagus. Three additional patients were enrolled at both dose cohorts without further DLT. In the final 74-Gy cohort, no DLTs were observed (0 of 6). Conclusions: Dose escalation and acceleration to 74 Gy with intensity modulated RT and concurrent chemotherapy was tolerable, with a low rate of grade ≥3 acute esophageal reactions.

  9. Long-term tolerance and outcomes for dose escalation in early salvage post-prostatectomy radiation therapy

    International Nuclear Information System (INIS)

    Safdieh, Joseph; Schwartz, David; Weiner, Joseph; Weiss, Jeffrey P.; Madeb, Isaac; Rotman, Marvin; Schreiber, David; Rineer, Justin

    2014-01-01

    To study the long-term outcomes and tolerance in our patients who received dose escalated radiotherapy in the early salvage post-prostatectomy setting. The medical records of 54 consecutive patients who underwent radical prostatectomy subsequently followed by salvage radiation therapy (SRT) to the prostate bed between 2003-2010 were analyzed. Patients included were required to have a pre-radiation prostate specific antigen level (PSA) of 2 ng/mL or less. The median SRT dose was 70.2 Gy. Biochemical failure after salvage radiation was defined as a PSA level >0.2 ng/mL. Biochemical control and survival endpoints were analyzed using the Kaplan-Meier method. Univariate and multivariate Cox regression analysis were used to identify the potential impact of confounding factors on outcomes. The median pre-SRT PSA was 0.45 ng/mL and the median follow-up time was 71 months. The 4- and 7-year actuarial biochemical control rates were 75.7% and 63.2%, respectively. The actuarial 4- and 7-year distant metastasis-free survival was 93.7% and 87.0%, respectively, and the actuarial 7-year prostate cancer specific survival was 94.9%. Grade 3 late genitourinary toxicity developed in 14 patients (25.9%), while grade 4 late genitourinary toxicity developed in 2 patients (3.7%). Grade 3 late gastrointestinal toxicity developed in 1 patient (1.9%), and grade 4 late gastrointestinal toxicity developed in 1 patient (1.9%). In this series with long-term follow-up, early SRT provided outcomes and toxicity profiles similar to those reported from the three major randomized trials studying adjuvant radiation therapy.

  10. Phase I dose escalation study of KOS-1584, a novel epothilone, in patients with advanced solid tumors.

    Science.gov (United States)

    Lam, Elaine T; Goel, Sanjay; Schaaf, Larry J; Cropp, Gillian F; Hannah, Alison L; Zhou, Yiqing; McCracken, Barbara; Haley, Brandi I; Johnson, Robert G; Mani, Sridhar; Villalona-Calero, Miguel A

    2012-02-01

    First-in-man study of KOS-1584, a second generation epothilone. Patients with advanced solid malignancies received KOS-1584 every 3 weeks until disease progression. Using a modified Fibonacci dose escalation scheme, one patient was enrolled at each dose level until the first instance of grade 2 toxicity. Thereafter, a standard 3 + 3 design was utilized. Sixty-six patients in 14 cohorts were dosed from 0.8 to 48 mg/m(2). Diarrhea, arthralgias, and encephalopathy were dose-limiting toxicities (DLTs) at doses ≥36 mg/m(2). At the recommended phase II dose (RP2D), the most common adverse effects were peripheral neuropathy (low grade), fatigue, arthralgias/myalgias, and diarrhea (31, 6%). The incidence of neutropenia was low. The overall clearance, volume of distribution, and half-life of KOS-1584 were 11 ± 6.17 L/h/m(2), 327 ± 161 L/m(2), and 21.9 ± 8.75 h, respectively. The half-life for the seco-metabolite (KOS-1891) was 29.6 ± 13.8 h. KOS-1584 exhibited linear pharmacokinetics. A dose-dependent increase in microtubulin bundle formation was observed at doses ≥27 mg/m(2). Two patients achieved partial responses and 24 patients had stable disease (SD). The RP2D of KOS-1584 is 36 mg/m(2). The lack of severe neurologic toxicity, diarrhea, neutropenia, or hypersensitivity reactions; favorable pharmacokinetic profile; and early evidence of activity support further evaluation.

  11. An individualized radiation dose escalation trial in non-small cell lung cancer based on FDG-PET imaging

    Energy Technology Data Exchange (ETDEWEB)

    Wanet, Marie; Goossens, Samuel; Lee, John Aldo; Janssens, Guillaume; Bol, Anne; Geets, Xavier [Universite Catholique de Louvain, Center of Molecular Imaging, Radiotherapy and Oncology (MIRO), Institut de Recherche Experimentale et Clinique, Brussels (Belgium); Delor, Antoine [Cliniques Universitaires Saint-Luc, Department of Radiation Oncology, Brussels (Belgium); Hanin, Francois-Xavier [Cliniques Universitaires Saint-Luc, Department of Nuclear Medicine, Brussels (Belgium); Ghaye, Benoit [Cliniques Universitaires Saint-Luc, Department of Radiology, Brussels (Belgium); Maanen, Aline van [Cliniques Universitaires Saint-Luc, Statistical Support Unit, Cancer Centre, Brussels (Belgium); Remouchamps, Vincent; Clermont, Christian [Clinique et Maternite Sainte Elisabeth, Department of Radiation Oncology, CHU UCL Namur (Belgium)

    2017-10-15

    The aim of the study was to assess the feasibility of an individualized 18F fluorodeoxyglucose positron emission tomography (FDG-PET)-guided dose escalation boost in non-small cell lung cancer (NSCLC) patients and to assess its impact on local tumor control and toxicity. A total of 13 patients with stage II-III NSCLC were enrolled to receive a dose of 62.5 Gy in 25 fractions to the CT-based planning target volume (PTV; primary tumor and affected lymph nodes). The fraction dose was increased within the individual PET-based PTV (PTV{sub PET}) using intensity modulated radiotherapy (IMRT) with a simultaneous integrated boost (SIB) until the predefined organ-at-risk (OAR) threshold was reached. Tumor response was assessed during follow-up by means of repeat FDG-PET/computed tomography. Acute and late toxicity were recorded and classified according to the CTCAE criteria (Version 4.0). Local progression-free survival was determined using the Kaplan-Meier method. The average dose to PTV{sub PET} reached 89.17 Gy for peripheral and 75 Gy for central tumors. After a median follow-up period of 29 months, seven patients were still alive, while six had died (four due to distant progression, two due to grade 5 toxicity). Local progression was seen in two patients in association with further recurrences. One and 2-year local progression free survival rates were 76.9% and 52.8%, respectively. Three cases of acute grade 3 esophagitis were seen. Two patients with central tumors developed late toxicity and died due to severe hemoptysis. These results suggest that a non-uniform and individualized dose escalation based on FDG-PET in IMRT delivery is feasible. The doses reached were higher in patients with peripheral compared to central tumors. This strategy enables good local control to be achieved at acceptable toxicity rates. However, dose escalation in centrally located tumors with direct invasion of mediastinal organs must be performed with great caution in order to avoid severe

  12. Conformal radiotherapy of 450 localized prostate cancers (may 1999 - march 2007): impact of digestive disorders on the quality of life after dose escalation

    International Nuclear Information System (INIS)

    Guerif, S.; Lavigne, B.; Berger, A.

    2007-01-01

    The incidence of digestive toxicity and the impact of quality of life do not depend on dose escalation in our population selected out of the measurement at the end of the treatment. The incidence of rectum hemorrhages does not any impact on the quality of life of patients. The factors linked to digestive toxicity were the 'co morbidities' (cardiopathy, ischemia, diabetes) and a high initial digestive score. (N.C.)

  13. Effects of timolol and atenolol on benign essential tremor: placebo-controlled studies based on quantitative tremor recording.

    Science.gov (United States)

    Dietrichson, P; Espen, E

    1981-08-01

    Two different beta-adrenoreceptor antagonists, atenolol and timolol, were separately compared with a placebo in the suppression of essential tremor. In two-week single-blind placebo-controlled studies with cross-over, timolol (5 mg twice daily) and atenolol (100 mg once daily) produced an equal reduction in sitting heart rate and sitting blood pressure. Timolol was effective in reducing tremor while atenolol failed to reduce tremor amplitude. These results indicate that essential tremor can be reduced but not blocked, by the adrenergic blocker timolol with both beta 1 and beta 2 blocking properties; but not by the relatively selective beta 1 blocking drug atenolol. Possibly, the tremor reduction is medicated by a peripheral effect on beta 2 adrenoreceptors.

  14. [F-18]-fluorodeoxyglucose positron emission tomography for targeting radiation dose escalation for patients with glioblastoma multiforme: Clinical outcomes and patterns of failure

    International Nuclear Information System (INIS)

    Douglas, James G.; Stelzer, Keith J.; Mankoff, David A.; Tralins, Kevin S.; Krohn, Kenneth A.; Muzi, Mark; Silbergeld, Daniel L.; Rostomily, Robert C.; Scharnhorst, Jeffrey B.S.; Spence, Alexander M.

    2006-01-01

    Purpose: [F-18]-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging for brain tumors has been shown to identify areas of active disease. Radiation dose escalation in the treatment of glioblastoma multiforme may lead to improved disease control. Based on these premises, we initiated a prospective study of FDG-PET for the treatment planning of radiation dose escalation for the treatment of glioblastoma multiforme. Methods and Materials: Forty patients were enrolled. Patients were treated with standard conformal fractionated radiotherapy with volumes defined by MRI imaging. When patients reached a dose of 45-50.4 Gy, they underwent FDG-PET imaging for boost target delineation, for an additional 20 Gy (2 Gy per fraction) to a total dose of 79.4 Gy (n = 30). Results: The estimated 1-year and 2-year overall survival (OS) for the entire group was 70% and 17%, respectively, with a median overall survival of 70 weeks. The estimated 1-year and 2-year progression-free survival (PFS) was 18% and 3%, respectively, with a median of 24 weeks. No significant improvements in OS or PFS were observed for the study group in comparison to institutional historical controls. Conclusions: Radiation dose escalation to 79.4 Gy based on FDG-PET imaging demonstrated no improvement in OS or PFS. This study establishes the feasibility of integrating PET metabolic imaging into radiotherapy treatment planning

  15. A 12-week dose-escalating study of etelcalcetide (ONO-5163/AMG 416), a novel intravenous calcimimetic, for secondary hyperparathyroidism in Japanese hemodialysis patients
.

    Science.gov (United States)

    Yokoyama, Keitaro; Fukagawa, Masafumi; Shigematsu, Takashi; Akiba, Takashi; Fujii, Akifumi; Odani, Motoi; Akizawa, Tadao

    2017-08-01

    To evaluate dose-escalation of etelcalcetide (ONO-5163/AMG 416), a novel, intravenous (IV), long-acting calcium-sensing receptor agonist, for treatment of secondary hyperparathyroidism (SHPT) in Japanese hemodialysis patients. In this multicenter study, IV injections of etelcalcetide (3 times a week for 12 weeks) were administered, with dose escalation every 4 weeks depending on changes in serum intact parathyroid hormone (iPTH) and corrected calcium (cCa). A total of 24 patients participated in this study. Serum iPTH was reduced in a time- and dose-dependent manner, with reductions (in pg/mL) at 12 weeks of -226.1 ± 125.3, -362.5 ± 161.5, and -412.4 ± 130.2, respectively, for maximum doses of 5, 10, and 15 mg. At the end of the treatment, 50% of patients had serum iPTH levels within the target range (60 - 240 pg/mL). Serum cCa and phosphorus were reduced in parallel with iPTH. Adverse events (AEs) occurred in 20 patients (83.3%). The most frequently observed AEs (> 10%) were either mild or moderate nasopharyngitis (29.2%), decreased serum calcium (16.7%), and vomiting (12.5%). Dose-escalated triweekly etelcalcetide was effective for SHPT in Japanese hemodialysis patients and was satisfactorily tolerated.
.

  16. Single blinded, randomized, placebo-controlled study on the effects of ciclosporin on cutaneous barrier function and immunological response in atopic beagles.

    Science.gov (United States)

    White, Amelia G; Santoro, Domenico; Ahrens, Kim; Marsella, Rosanna

    2018-03-01

    Ciclosporin (CsA) is a common treatment for canine atopic dermatitis (cAD). cAD is a very common skin disease with a multifactorial pathogenesis due to complex interactions between the host and the environment. The purpose of this study was to describe the physical and immunological effects of CsA in cAD using a canine model of AD. Fourteen beagles were enrolled; seven received CsA orally every 24 h for 28 days, and seven received placebo. All dogs were exposed to relevant allergens, house dust mite solution, one day prior to treatment and once weekly thereafter for 28 consecutive days. Canine atopic dermatitis extent and severity index-03 (CADESI-03) and skin biopsies were performed on day 0, 14, and 28. Quantitative RT-PCR was used to determine levels of cutaneous cytokines and barrier function markers. Indirect immunofluorescence was used to determine protein expression and distribution of nuclear messengers, barrier function and inflammatory [thymic stromal lymphopoietin (TSLP)] markers. The data were tested for normality and then the upaired two samples Student's t-test and the repeated measurements ANOVA, followed by the Dunnett's Multiple Comparison Test as post-hoc analysis, were performed. A P value of immunologic milieu or barrier markers despite evident improvement of physical signs in the treatment group. Although this study confirmed the usefulness of CsA for the treatment of cAD, a clear involvement of CsA on some of the currently known immunological alterations present in cAD was not determined. However, it is important to note that there was no measurable exacerbation of skin barrier dysfunction secondary to CsA administration in this model. Copyright © 2018 Elsevier B.V. All rights reserved.

  17. Lathosterol to cholesterol ratio in serum predicts cholesterol lowering response to plant sterol consumption in a dual center, randomized, single-blind placebo controlled trial

    Science.gov (United States)

    Benefits of plant sterols (PS) for cholesterol lowering are compromised by large variability in efficacy across individuals. High fractional cholesterol synthesis measured by deuterium incorporation has been associated with non-response to PS consumption; however, prospective studies showing this as...

  18. Stress-related psycho-physiological disorders: randomized single blind placebo controlled naturalistic study of psychometric evaluation using a radio electric asymmetric treatment

    Science.gov (United States)

    2011-01-01

    Background The aim of this study is to investigate the effects of a radio electric asymmetric treatment on psycho-physiological disorders (PPD). PPD are often stress related and are under the unconscious control of the patient and cannot be traced back to any serious physical disease. The brain stimulation treatment protocol used is called Neuro Psycho Physical Optimization (NPPO) with a Radio Electric Asymmetric Conveyer (REAC) device. Methods Psychological stress and PPD were measured for a group of 888 subjects using the Psychological Stress Measure (PSM) test, a self-administered questionnaire. Data were collected immediately before and after the 4-weeks of REAC treatment cycle. Results This study showed a significant reduction in scores measuring subjective perceptions of stress for subjects treated with a cycle of NPPO REAC treatment. At the end-point the number of subjects reporting symptoms of stress-related PPD on the PSM test was significantly reduced, whereas in the placebo group the difference was not significant. Conclusion A cycle of NPPO treatment with REAC was shown to reduce subjective perceptions of stress measured by the PSM test and in particular on PPD. Trial Registration This trial has been registered in the Australian New Zealand Clinical Trials Registry (ANZCTR) with the number: ACTRN12607000463471. PMID:21771304

  19. The plaque- and gingivitis-inhibiting capacity of a commercially available essential oil product. A parallel, split-mouth, single blind, randomized, placebo-controlled clinical study.

    Science.gov (United States)

    Preus, Hans Ragnar; Koldsland, Odd Carsten; Aass, Anne Merete; Sandvik, Leiv; Hansen, Bjørn Frode

    2013-11-01

    Studies have reported commercially available essential oils with convincing plaque and gingivitis preventing properties. However, no tests have compared these essential oils, i.e. Listerine(®), against their true vehicle controls. To compare the plaque and gingivitis inhibiting effect of a commercially-available essential oil (Listerine(®) Total Care) to a negative (22% hydro-alcohol solution) and a positive (0.2% chlorhexidine (CHX)) control in an experimental gingivitis model. In three groups of 15 healthy volunteers, experimental gingivitis was induced and monitored over 21 days, simultaneously treated with Listerine(®) Total Care (test), 22% hydro-alcohol solution (negative control) and 0.2% chlorhexidine solution (positive control), respectively. The upper right quadrant of each individual received mouthwash only, whereas the upper left quadrant was subject to both rinses and mechanical oral hygiene. Plaque, gingivitis and side-effects were assessed at day 7, 14 and 21. After 21 days, the chlorhexidine group showed significantly lower average plaque and gingivitis scores than the Listerine(®) and alcohol groups, whereas there was little difference between the two latter. Listerine(®) Total Care had no statistically significant effect on plaque formation as compared to its vehicle control.

  20. Daily electronic self-monitoring in bipolar disorder using smartphones - the MONARCA I trial: a randomized, placebo-controlled, single-blind, parallel group trial.

    Science.gov (United States)

    Faurholt-Jepsen, M; Frost, M; Ritz, C; Christensen, E M; Jacoby, A S; Mikkelsen, R L; Knorr, U; Bardram, J E; Vinberg, M; Kessing, L V

    2015-10-01

    The number of studies on electronic self-monitoring in affective disorder and other psychiatric disorders is increasing and indicates high patient acceptance and adherence. Nevertheless, the effect of electronic self-monitoring in patients with bipolar disorder has never been investigated in a randomized controlled trial (RCT). The objective of this trial was to investigate in a RCT whether the use of daily electronic self-monitoring using smartphones reduces depressive and manic symptoms in patients with bipolar disorder. A total of 78 patients with bipolar disorder according to ICD-10 criteria, aged 18-60 years, and with 17-item Hamilton Depression Rating Scale (HAMD-17) and Young Mania Rating Scale (YMRS) scores ≤17 were randomized to the use of a smartphone for daily self-monitoring including a clinical feedback loop (the intervention group) or to the use of a smartphone for normal communicative purposes (the control group) for 6 months. The primary outcomes were differences in depressive and manic symptoms measured using HAMD-17 and YMRS, respectively, between the intervention and control groups. Intention-to-treat analyses using linear mixed models showed no significant effects of daily self-monitoring using smartphones on depressive as well as manic symptoms. There was a tendency towards more sustained depressive symptoms in the intervention group (B = 2.02, 95% confidence interval -0.13 to 4.17, p = 0.066). Sub-group analysis among patients without mixed symptoms and patients with presence of depressive and manic symptoms showed significantly more depressive symptoms and fewer manic symptoms during the trial period in the intervention group. These results highlight that electronic self-monitoring, although intuitive and appealing, needs critical consideration and further clarification before it is implemented as a clinical tool.

  1. Late toxicity and biochemical control in 554 prostate cancer patients treated with and without dose escalated image guided radiotherapy

    International Nuclear Information System (INIS)

    Kok, David; Gill, Suki; Bressel, Mathias; Byrne, Keelan; Kron, Tomas; Fox, Chris; Duchesne, Gillian; Tai, Keen Hun; Foroudi, Farshad

    2013-01-01

    Background and purpose: To compare rates of late gastrointestinal toxicity, late genitourinary toxicity and biochemical failure between patients treated for prostate cancer with implanted fiducial marker image guided radiotherapy (FMIGRT), and those treated without FMIGRT. Methods and materials: We performed a single institution retrospective study comparing all 311 patients who received 74 Gy without fiducial markers in 2006 versus all 243 patients who received our updated regimen of 78 Gy with FMIGRT in 2008. Patient records were reviewed 27 months after completing radiotherapy. Biochemical failure was defined using the Phoenix definition. Details of late gastrointestinal and genitourinary toxicities were graded according to CTCAEv4. Moderate/severe toxicity was defined as a grade 2 or higher toxicity. Cumulative incidence and prevalence curves for moderate/severe toxicity were constructed and compared using multistate modeling while biochemical failure free survival was compared using the log rank test. A Cox regression model was developed to correct for confounding factors. Results: Median follow-up time for both groups was 22 months. The hazard ratio for moderate/severe late gastrointestinal toxicity in the non-FMIGRT group was 3.66 [95% CI (1.63–8.23), p = 0.003] compared to patients in the FMIGRT group. There was no difference in the hazard ratio of moderate/severe late genitourinary toxicity between the two groups (0.44 [95% CI (0.19–1.00)]), but patients treated with FMIGRT did have a quicker recovery from their genitourinary toxicities HR = 0.24 [95% CI (0.10–0.59)]. We were unable to detect any differences in biochemical failure free survival between the cohorts HR = 0.60 [95% CI (0.30–1.20), p = 0.143]. Conclusion: Despite dose escalation, the use of FMIGRT in radical radiotherapy for prostate cancer significantly reduces the incidence of gastrointestinal toxicity and the duration of late genitourinary toxicity when compared to conventional non

  2. Limits of dose escalation in lung cancer: a dose-volume histogram analysis comparing coplanar and non-coplanar techniques

    Energy Technology Data Exchange (ETDEWEB)

    Derycke, S; Van Duyse, B; Schelfhout, J; De Neve, W

    1995-12-01

    To evaluate the feasibility of dose escalation in radiotherapy of inoperable lung cancer, a dose-volume histogram analysis was performed comparing standard coplanar (2D) with non-coplanar (3D) beam arrangements on a non-selected group of 20 patients planned by Sherouse`s GRATISTM 3D-planning system. Serial CT-scanning was performed and 2 Target Volumes (Tvs) were defined. Gross Tumor Volume (GTV) defined a high-dose Target Volume (TV-1). GTV plus location of node stations with > 10% probability of invasion (Minet et al.) defined an intermediate-dose Target Volume (TV-2). However, nodal regions which are incompatible with cure were excluded from TV-2. These are ATS-regions 1, 8, 9 and 14 all left and right as well as heterolateral regions. For 3D-planning, Beam`s Eye View selected (by an experienced planner) beam arrangements were optimised using Superdot, a method of target dose-gradient annihilation developed by Sherouse. A second 3D-planning was performed using 4 beam incidences with maximal angular separation. The linac`s isocenter for the optimal arrangement was located at the geometrical center of gravity of a tetraheder, the tetraheder`s comers being the consecutive positions of the virtual source. This ideal beam arrangement was approximated as close as possible, taking into account technical limitations (patient-couch-gantry collisions). Criteria for tolerance were met if no points inside the spinal cord exceeded 50 Gy and if at least 50% of the lung volume received less than 20Gy. If dose regions below 50 Gy were judged acceptable at TV-2, 2D- as well as 3D-plans allow safe escalation to 80 Gy at TV-1. When TV-2 needed to be encompassed by isodose surfaces exceeding 50Gy, 3D-plans were necessary to limit dose at the spinal cord below tolerance. For large TVs dose is limited by lung tolerance for 3D-plans. An analysis (including NTCP-TCP as cost functions) of rival 3D-plans is being performed.

  3. Dose escalation of the hypoxic cell sensitizer etanidazole combined with ifosfamide, carboplatin, etoposide, and autologous hematopoietic stem cell support.

    Science.gov (United States)

    Elias, A D; Wheeler, C; Ayash, L J; Schwartz, G; Ibrahim, J; Mills, L; McCauley, M; Coleman, N; Warren, D; Schnipper, L; Antman, K H; Teicher, B A; Frei, E

    1998-06-01

    Multiple mechanisms of drug resistance contribute to treatment failure. Although high-dose therapy attempts to overwhelm these defenses pharmacologically, this approach is only successful in a fraction of treated patients. Many drug resistance mechanisms are shared between malignant and normal cells, but the expression of various drug resistance mechanisms associated with hypoxia is largely confined to tumor tissue. Thus, reversal of this mechanism is likely to provide a therapeutic advantage to the host. This study was designed to define the dose-limiting toxicities and maximum tolerated dose of etanidazole when it is given concurrently with high-dose ifosfamide, carboplatin, and etoposide (ICE), with hematopoietic stem cell support. The maximum tolerated doses of high-dose ICE were administered concurrently with dose escalations of etanidazole, a hypoxic cell sensitizer. All agents were given by 96-h continuous i.v. infusion beginning on day -7. Mesna uroprotection was provided. Autologous marrow and cytokine mobilized peripheral blood progenitor cells were reinfused on day 0. Granulocyte colony-stimulating factor was administered following reinfusion until the granulocytes recovered to > 1000/microliter. Fifty-five adults with advanced malignancies were enrolled in cohorts of five to nine patients. Four dose levels of etanidazole between 3 and 5.5 g/m2/day (12, 16, 20, and 22 g/m2 total doses) and two doses of carboplatin (1600 and 1800 mg/m2 total doses) were evaluated. Seven patients died of organ toxicity (13%); two each from veno-occlusive disease of liver and sepsis; and one each from sudden death, renal failure, and refractory thrombocytopenic hemorrhage. Five deaths occurred at the top dose level. One additional patient suffered a witnessed cardiorespiratory arrest from ventricular fibrillation and was resuscitated. Dose-dependent and largely reversible peripheral neuropathy was observed consisting of two syndromes: severe cramping myalgic/neuralgic pain

  4. Vorinostat and Concurrent Stereotactic Radiosurgery for Non-Small Cell Lung Cancer Brain Metastases: A Phase 1 Dose Escalation Trial.

    Science.gov (United States)

    Choi, Clara Y H; Wakelee, Heather A; Neal, Joel W; Pinder-Schenck, Mary C; Yu, Hsiang-Hsuan Michael; Chang, Steven D; Adler, John R; Modlin, Leslie A; Harsh, Griffith R; Soltys, Scott G

    2017-09-01

    To determine the maximum tolerated dose (MTD) of vorinostat, a histone deacetylase inhibitor, given concurrently with stereotactic radiosurgery (SRS) to treat non-small cell lung cancer (NSCLC) brain metastases. Secondary objectives were to determine toxicity, local failure, distant intracranial failure, and overall survival rates. In this multicenter study, patients with 1 to 4 NSCLC brain metastases, each ≤2 cm, were enrolled in a phase 1, 3 + 3 dose escalation trial. Vorinostat dose levels were 200, 300, and 400 mg orally once daily for 14 days. Single-fraction SRS was delivered on day 3. A dose-limiting toxicity (DLT) was defined as any Common Terminology Criteria for Adverse Events version 3.0 grade 3 to 5 acute nonhematologic adverse event related to vorinostat or SRS occurring within 30 days. From 2009 to 2014, 17 patients were enrolled and 12 patients completed study treatment. Because no DLTs were observed, the MTD was established as 400 mg. Acute adverse events were reported by 10 patients (59%). Five patients discontinued vorinostat early and withdrew from the study. The most common reasons for withdrawal were dyspnea (n=2), nausea (n=1), and fatigue (n=2). With a median follow-up of 12 months (range, 1-64 months), Kaplan-Meier overall survival was 13 months. There were no local failures. One patient (8%) at the 400-mg dose level with a 2.0-cm metastasis developed histologically confirmed grade 4 radiation necrosis 2 months after SRS. The MTD of vorinostat with concurrent SRS was established as 400 mg. Although no DLTs were observed, 5 patients withdrew before completing the treatment course, a result that emphasizes the need for supportive care during vorinostat administration. There were no local failures. A larger, randomized trial may evaluate both the tolerability and potential local control benefit of vorinostat concurrent with SRS for brain metastases. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. [Extracorporeal shockwave therapy (ESWT) as therapeutic option in supraspinatus tendon syndrome? One year results of a placebo controlled study].

    Science.gov (United States)

    Schmitt, J; Tosch, A; Hünerkopf, M; Haake, M

    2002-07-01

    Extracorporeal shock wave therapy (ESWT) is seen as a therapeutic option in the treatment of chronic supraspinatus tendinitis by some authors. To test whether ESWT comprising 3 x 2000 pulses with the positive energy flux density ED+ of 0.33 mJ/mm2 is clinically superior to a sham ESWT treatment, a prospective, randomized, single-blinded, placebo-controlled study with an independent observer was performed. Forty patients were treated either by verum ESWT or sham ESWT under local anesthesia. Target criteria were the age-corrected Constant score, pain at rest and during activity on a visual analogue scale, and subjective improvement. Patients who reported no subjective improvement after 12 weeks were deblinded and received verum ESWT if they had belonged to the placebo group (partial crossover). The results of the verum group lie within the range of results for ESWT published by other authors. Patients in the placebo group with local anesthetic showed equally good results. At 12 weeks, and 1 year after intervention, no difference could be found between the verum and placebo groups regarding Constant score, pain, shoulder function, or subjective improvement. The nonresponders to the placebo ESWT continued to show no improvement after receiving verum ESWT. This contradicts a specific ESWT effect. Based on the results of this placebo-controlled study, ESWT appears to have no clinically relevant effect on supraspinatus tendinitis. The study underlines the importance of a control group in evaluating new treatment methods for diseases with unknown natural history.

  6. A Phase Ib dose-escalation study to evaluate safety and tolerability of the addition of the aminopeptidase inhibitor tosedostat (CHR-2797) to paclitaxel in patients with advanced solid tumours

    NARCIS (Netherlands)

    C.M.L. Herpen (Carla); F.A.L.M. Eskens (Ferry); M.J.A. de Jonge (Maja); I.M.E. Desar (Ingrid); L. Hooftman (Leon); E. Bone (Elisabeth); J.N.H. Timmerbonte (Johanna); J. Verweij (Jaap)

    2010-01-01

    textabstractBackground: This Phase Ib dose-escalating study investigated safety, maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK) and clinical antitumour activity of tosedostat (CHR-2797), an orally bioavailable aminopeptidase inhibitor, in combination with

  7. A Phase Ib dose-escalation study to evaluate safety and tolerability of the addition of the aminopeptidase inhibitor tosedostat (CHR-2797) to paclitaxel in patients with advanced solid tumours.

    NARCIS (Netherlands)

    Herpen, C.M.L. van; Eskens, F.A.; Jonge, M. de; Desar, I.M.E.; Hooftman, L.; Bone, E.A.; Timmer-Bonte, J.N.H.; Verweij, J.

    2010-01-01

    BACKGROUND: This Phase Ib dose-escalating study investigated safety, maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK) and clinical antitumour activity of tosedostat (CHR-2797), an orally bioavailable aminopeptidase inhibitor, in combination with paclitaxel. METHODS:

  8. Final toxicity results of a radiation-dose escalation study in patients with non-small-cell lung cancer (NSCLC): Predictors for radiation pneumonitis and fibrosis

    International Nuclear Information System (INIS)

    Kong, F.-M.; Hayman, James A.; Griffith, Kent A.; Kalemkerian, Gregory P.; Arenberg, Douglas; Lyons, Susan; Turrisi, Andrew; Lichter, Allen; Fraass, Benedick; Eisbruch, Avraham; Lawrence, Theodore S.; Haken, Randall K. ten

    2006-01-01

    Purpose: We aimed to report the final toxicity results on a radiation-dose escalation trial designed to test a hypothesis that very high doses of radiation could be safely administered to patients with non-small-cell lung cancer (NSCLC) by quantifying the dose-volume toxicity relationship of the lung. Methods and Materials: A total of 109 patients with unresectable or medically inoperable NSCLC were enrolled and treated with radiation-dose escalation (on the basis of predicted normal-lung toxicity) either alone or with neoadjuvant chemotherapy by use of 3D conformal techniques. Eighty-four patients (77%) received more than 69 Gy, the trial was stopped after the dose reached 103 Gy. Estimated median follow-up was 110 months. Results: There were 17 (14.6%) Grade 2 to 3 pneumonitis and 15 (13.8%) Grade 2 to 3 fibrosis and no Grade 4 to 5 lung toxicity. Multivariate analyses showed them to be (1) not associated with the dose prescribed to the tumor, and (2) significantly (p < 0.001) associated with lung-dosimetric parameters such as the mean lung dose (MLD), volume of lung that received at least 20 Gy (V20), and the normal-tissue complication probability (NTCP) of the lung. If cutoffs are 30% for V20, 20 Gy for MLD, and 10% for NTCP, these factors have positive predictive values of 50% to 71% and negative predictive value of 85% to 89%. Conclusions: With long-term follow-up for toxicity, we have demonstrated that much higher doses of radiation than are traditionally administered can be safely delivered to a majority of patients with NSCLC. Quantitative lung dose-volume toxicity-based dose escalation can form the basis for individualized high-dose radiation treatment to maximize the therapeutic ratio in these patients

  9. A phase I study of dose-escalated chemoradiation with accelerated intensity modulated radiotherapy in locally advanced head and neck cancer

    International Nuclear Information System (INIS)

    Guerrero Urbano, Teresa; Clark, Catharine H.; Hansen, Vibeke N.; Adams, Elizabeth J.; A'Hern, Roger; Miles, Elizabeth A.; McNair, Helen; Bidmead, Margaret; Warrington, Alan P.; Dearnaley, David P.; Harrington, Kevin J.; Nutting, Christopher M.

    2007-01-01

    Background and purpose: Intensity modulated radiotherapy (IMRT) allows the delivery of higher and more homogeneous radiation dose to head and neck tumours. This study aims to determine the safety of dose-escalated chemo-IMRT for larynx preservation in locally advanced head and neck cancer. Methods: Patients with T2-4, N1-3, M0 squamous cell carcinoma of the larynx or hypopharynx were treated with a simultaneous-boost IMRT. Two radiation dose levels (DL) were tested: In DL 1, 63 Gy/28F was delivered to primary tumour and involved nodes and 51.8 Gy/28F to elective nodes. In DL 2, the doses were 67.2 Gy/28F and 56 Gy/28F, respectively, representing a 9% dose escalation for the primary. All patients received 2 cycles of neoadjuvant cisplatin and 5-fluorouracil, and concomitant cisplatin. Acute (NCICTCv.2.0) and late toxicity (RTOG and modified LENTSOM) were collected. Results: Thirty patients were entered, 15 in each dose level. All patients completed the treatment schedule. In DL 1, the incidences of acute G3 toxicities were 27% (pain), 20% (radiation dermatitis), 0% (xerostomia) and 67% required gastrostomy tubes. For DL 2 the corresponding incidences were 40%, 20%, 7%, and 87%. G3 dysphagia and pain persisted longer in DL 2. With regard to mucositis, a prolonged healing time for DL 2 was found, with prevalence of G2 of 58% in week 10. No acute grade 4 toxicity was observed. At 6 months, 1 patient in DL 2 had G3 late toxicity (dysphagia). No dose limiting toxicity was found. Complete response rates were 80% in DL 1, and 87% in DL 2. Conclusion: Moderately accelerated chemo-IMRT is safe and feasible with good compliance and acceptable acute toxicity. Dose escalation was possible without a significant difference in acute toxicity. Longer follow-up is required to determine the incidence of late radiation toxicities, and tumour control rates

  10. Late Gastrointestinal Toxicity After Dose-Escalated Conformal Radiotherapy for Early Prostate Cancer: Results From the UK Medical Research Council RT01 Trial (ISRCTN47772397)

    International Nuclear Information System (INIS)

    Syndikus, Isabel; Morgan, Rachel C.; Sydes, Matthew R.; Graham, John D.; Dearnaley, David P.

    2010-01-01

    Purpose: In men with localized prostate cancer, dose-escalated conformal radiotherapy (CFRT) improves efficacy outcomes at the cost of increased toxicity. We present a detailed analysis to provide further information about the incidence and prevalence of late gastrointestinal side effects. Methods and Materials: The UK Medical Research Council RT01 trial included 843 men with localized prostate cancer, who were treated for 6 months with neoadjuvant radiotherapy and were randomly assigned to either 64-Gy or 74-Gy CFRT. Toxicity was evaluated before CFRT and during long-term follow-up using Radiation Therapy Oncology Group (RTOG) grading, the Late Effects on Normal Tissue: Subjective, Objective, Management (LENT/SOM) scale, and Royal Marsden Hospital assessment scores. Patients regularly completed Functional Assessment of Cancer Therapy--Prostate (FACT-P) and University of California, Los Angeles, Prostate Cancer Index (UCLA-PCI) questionnaires. Results: In the dose-escalated group, the hazard ratio (HR) for rectal bleeding (LENT/SOM grade ≥2) was 1.55 (95% CI, 1.17-2.04); for diarrhea (LENT/SOM grade ≥2), the HR was 1.79 (95% CI, 1.10-2.94); and for proctitis (RTOG grade ≥2), the HR was 1.64 (95% CI, 1.20-2.25). Compared to baseline scores, the prevalence of moderate and severe toxicities generally increased up to 3 years and than lessened. At 5 years, the cumulative incidence of patient-reported severe bowel problems was 6% vs. 8% (standard vs. escalated, respectively) and severe distress was 4% vs. 5%, respectively. Conclusions: There is a statistically significant increased risk of various adverse gastrointestinal events with dose-escalated CFRT. This remains at clinically acceptable levels, and overall prevalence ultimately decreases with duration of follow-up.

  11. Once daily controlled-release pregabalin in the treatment of patients with fibromyalgia: a phase III, double-blind, randomized withdrawal, placebo-controlled study.

    Science.gov (United States)

    Arnold, Lesley M; Arsenault, Pierre; Huffman, Cynthia; Patrick, Jeffrey L; Messig, Michael; Chew, Marci L; Sanin, Luis; Scavone, Joseph M; Pauer, Lynne; Clair, Andrew G

    2014-10-01

    Safety and efficacy of a once daily controlled-released (CR) formulation of pregabalin was evaluated in patients with fibromyalgia using a placebo-controlled, randomized withdrawal design. This multicenter study included 6 week single-blind pregabalin CR treatment followed by 13 week double-blind treatment with placebo or pregabalin CR. The starting dose of 165 mg/day was escalated during the first 3 weeks, up to 495 mg/day based on efficacy and tolerability. Patients with ≥50% reduction in average daily pain score at the end of the single-blind phase were randomized to continue pregabalin CR at the optimized dose (330-495 mg/day) or to placebo. The primary endpoint was time to loss of therapeutic response (LTR), defined as treatment' (Benefit, Satisfaction, and Willingness to Continue Scale) in the pregabalin CR group; no other secondary endpoints were statistically significant. Most AEs were mild to moderate in severity (most frequent: dizziness, somnolence). The percentage of pregabalin CR patients discontinuing because of AEs was 12.2% and 4.8% in the single-blind and double-blind phases, respectively (placebo, 0%). Time to LTR was significantly longer with pregabalin CR versus placebo in fibromyalgia patients who initially showed improvement with pregabalin CR, indicating maintenance of response. Pregabalin CR was well tolerated in most patients. Generalizability may be limited by study duration and selective population.

  12. First-in-Man Dose-Escalation Study of the Selective BRAF Inhibitor RG7256 in Patients with BRAF V600-Mutated Advanced Solid Tumors

    DEFF Research Database (Denmark)

    Dienstmann, Rodrigo; Lassen, Ulrik; Cebon, Jonathan

    2016-01-01

    V600-mutated advanced solid tumors. PATIENTS AND METHODS: Patients received RG7256 orally over 8 dose levels from 200 mg once a day (QD) to 2400 mg twice a day (BID) (50-, 100- and 150-mg tablets) using a classic 3 + 3 dose escalation design. RESULTS: In total, 45 patients were enrolled; most (87...... %) had advanced melanoma (94 % BRAF V600E). RG7256 was rapidly absorbed, with limited accumulation and dose-proportional increase in exposure up to 1950 mg BID. The maximal tolerated dose (MTD) was not reached. The most common drug-related adverse events (AEs) were dyspepsia (20 %), dry skin (18 %), rash...

  13. SU-C-202-04: Adapting Biologically Optimized Dose Escalation Based On Mid-Treatment PET/CT for Non-Small-Cell Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, P; Kuo, L; Yorke, E; Hu, Y; Lockney, N; Mageras, G; Deasy, J; Rimner, A [Memorial Sloan Kettering Cancer Center, New York, NY (United States)

    2016-06-15

    Purpose: To develop a biological modeling strategy which incorporates the response observed on the mid-treatment PET/CT into a dose escalation design for adaptive radiotherapy of non-small-cell lung cancer. Method: FDG-PET/CT was acquired midway through standard fractionated treatment and registered to pre-treatment planning PET/CT to evaluate radiation response of lung cancer. Each mid-treatment PET voxel was assigned the median SUV inside a concentric 1cm-diameter sphere to account for registration and imaging uncertainties. For each voxel, the planned radiation dose, pre- and mid-treatment SUVs were used to parameterize the linear-quadratic model, which was then utilized to predict the SUV distribution after the full prescribed dose. Voxels with predicted post-treatment SUV≥2 were identified as the resistant target (response arm). An adaptive simultaneous integrated boost was designed to escalate dose to the resistant target as high as possible, while keeping prescription dose to the original target and lung toxicity intact. In contrast, an adaptive target volume was delineated based only on the intensity of mid-treatment PET/CT (intensity arm), and a similar adaptive boost plan was optimized. The dose escalation capability of the two approaches was compared. Result: Images of three patients were used in this planning study. For one patient, SUV prediction indicated complete response and no necessary dose escalation. For the other two, resistant targets defined in the response arm were multifocal, and on average accounted for 25% of the pre-treatment target, compared to 67% in the intensity arm. The smaller response arm targets led to a 6Gy higher mean target dose in the adaptive escalation design. Conclusion: This pilot study suggests that adaptive dose escalation to a biologically resistant target predicted from a pre- and mid-treatment PET/CT may be more effective than escalation based on the mid-treatment PET/CT alone. More plans and ultimately clinical

  14. Safety of polyethylene glycol 3350 solution in chronic constipation: randomized, placebo-controlled trial.

    Science.gov (United States)

    McGraw, Thomas

    2016-01-01

    To evaluate the safety and tolerability of aqueous solution concentrate (ASC) of polyethylene glycol (PEG) 3350 in patients with functional constipation. The patients who met Rome III diagnostic criteria for functional constipation were randomized in this multicenter, randomized, placebo-controlled, single-blind study to receive once daily dose of PEG 3350 (17 g) ASC or placebo solution for 14 days. The study comprised a screening period (visit 1), endoscopy procedure (visits 2 and 3), and followup telephone calls 30 days post-treatment. Safety end points included adverse events (AEs), clinical laboratory evaluations, vital signs, and others. The primary end points were the proportion of patients with abnormalities of the oral and esophageal mucosa, detected by visual and endoscopic examination of the oral cavity and esophagus, respectively, compared with placebo. A secondary objective was to compare the safety and tolerability of ASC by evaluating AEs or adverse drug reactions. A total of 65 patients were enrolled in this study, 31 were randomized to PEG 3350 ASC and 34 were randomized to placebo, of which 62 patients completed the study. No patients in either group showed abnormalities in inflammation of the oral mucosa during visit 2 (before treatment) or visit 3 (after treatment). Fewer abnormalities of the esophageal mucosa were observed in the PEG 3350 ASC group than in the placebo group on visit 3, with no significant difference in the proportion of abnormalities between the treatment groups. Overall, 40 treatment-emergent AEs were observed in 48.4% of patients treated with PEG 3350 ASC, and 41 treatment-emergent AEs were observed in 55.9% of patients treated with placebo - nonsignificant difference of -7.5% (95% CI: -21.3, 6.3) between treatment groups. No serious AEs or deaths were reported, and no patient discontinued because of an AE. PEG 3350 ASC is safe and well tolerated in patients with functional constipation (NCT01885104).

  15. Treatment assignment guesses by study participants in a double-blind dose escalation clinical trial of saw palmetto.

    Science.gov (United States)

    Lee, Jeannette Y; Moore, Page; Kusek, John; Barry, Michael

    2014-01-01

    This report assesses participant perception of treatment assignment in a randomized, double-blind, placebo-controlled trial of saw palmetto for the treatment of benign prostatic hyperplasia (BCM). Participants randomized to receive saw palmetto were instructed to take one 320 mg gelcap daily for the first 24 weeks, two 320 mg gelcaps daily for the second 24 weeks, and three 320 mg gelcaps daily for the third 24 weeks. Study participants assigned to placebo were instructed to take the same number of matching placebo gelcaps in each time period. At 24, 48, and 72 weeks postrandomization, the American Urological Association Symptom Index (AUA-SI) was administered and participants were asked to guess their treatment assignment. The study was conducted at 11 clinical centers in North America. Study participants were men, 45 years and older, with moderate to low severe BPH symptoms, randomized to saw palmetto (N=151) or placebo (N=155). Treatment arms were compared with respect to the distribution of participant guesses of treatment assignment. For participants assigned to saw palmetto, 22.5%, 24.7%, and 29.8% correctly thought they were taking saw palmetto, and 37.3%, 40.0%, and 44.4% incorrectly thought they were on placebo at 24, 48, and 72 weeks, respectively. For placebo participants, 21.8%, 27.4%, and 25.2% incorrectly thought they were on saw palmetto, and 41.6%, 39.9%, and 42.6% correctly thought they were on placebo at 24, 48, and 72 weeks, respectively. The treatment arms did not vary with respect to the distributions of participants who guessed they were on saw palmetto (p=0.823) or placebo (p=0.893). Participants who experienced an improvement in AUA-SI were 2.16 times more likely to think they were on saw palmetto. Blinding of treatment assignment was successful in this study. Improvement in BPH-related symptoms was associated with the perception that participants were taking saw palmetto.

  16. Dose-escalated intensity-modulated radiotherapy is feasible and may improve locoregional control and laryngeal preservation in laryngo-hypopharyngeal cancers.

    Science.gov (United States)

    Miah, Aisha B; Bhide, Shreerang A; Guerrero-Urbano, M Teresa; Clark, Catharine; Bidmead, A Margaret; St Rose, Suzanne; Barbachano, Yolanda; A'hern, Roger; Tanay, Mary; Hickey, Jennifer; Nicol, Robyn; Newbold, Kate L; Harrington, Kevin J; Nutting, Christopher M

    2012-02-01

    To determine the safety and outcomes of induction chemotherapy followed by dose-escalated intensity-modulated radiotherapy (IMRT) with concomitant chemotherapy in locally advanced squamous cell cancer of the larynx and hypopharynx (LA-SCCL/H). A sequential cohort Phase I/II trial design was used to evaluate moderate acceleration and dose escalation. Patients with LA-SCCL/H received IMRT at two dose levels (DL): DL1, 63 Gy/28 fractions (Fx) to planning target volume 1 (PTV1) and 51.8 Gy/28 Fx to PTV2; DL2, 67.2 Gy/28 Fx and 56 Gy/28 Fx to PTV1 and PTV2, respectively. Patients received induction cisplatin/5-fluorouracil and concomitant cisplatin. Acute and late toxicities and tumor control rates were recorded. Between September 2002 and January 2008, 60 patients (29 DL1, 31 DL2) with Stage III (41% DL1, 52% DL2) and Stage IV (52% DL1, 48% DL2) disease were recruited. Median (range) follow-up for DL1 was 51.2 (12.1-77.3) months and for DL2 was 36.2 (4.2-63.3) months. Acute Grade 3 (G3) dysphagia was higher in DL2 (87% DL2 vs. 59% DL1), but other toxicities were equivalent. One patient in DL1 required dilatation of a pharyngeal stricture (G3 dysphagia). In DL2, 2 patients developed benign pharyngeal strictures at 1 year. One underwent a laryngo-pharyngectomy and the other a dilatation. No other G3/G4 toxicities were reported. Overall complete response was 79% (DL1) and 84% (DL2). Two-year locoregional progression-free survival rates were 64.2% (95% confidence interval, 43.5-78.9%) in DL1 and 78.4% (58.1-89.7%) in DL2. Two-year laryngeal preservation rates were 88.7% (68.5-96.3%) in DL1 and 96.4% (77.7-99.5%) in DL2. At a mean follow-up of 36 months, dose-escalated chemotherapy-IMRT at DL2 has so far been safe to deliver. In this study, DL2 delivered high rates of locoregional control, progression-free survival, and organ preservation and has been selected as the experimental arm in a Cancer Research UK Phase III study. Copyright © 2012 Elsevier Inc. All rights

  17. FOLFIRI and regorafenib combination therapy with dose escalation of irinotecan as fourth-line treatment for patients with metastatic colon cancer according to UGT1A1 genotyping

    Directory of Open Access Journals (Sweden)

    Lu CY

    2014-11-01

    Full Text Available Chien-Yu Lu,1,2 Yung-Sung Yeh,3–5 Ching-Wen Huang,5,6, Cheng-Jen Ma,4,5 Fang-Jung Yu,1,2 Jaw-Yuan Wang4–10 1Division of Gastroenterology, Department of Internal Medicine, 2Department of Internal Medicine, Faculty of Medicine, College of Medicine, 3Department of Emergency Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, 4Graduate Institute of Clinical Medicine, College of Medicine, 5Division of Gastroenterology and General Surgery, Department of Surgery, Kaohsiung Medical University Hospital, 6Graduate Institute of Medicine, College of Medicine, 7Cancer Center, Kaohsiung Medical University Hospital, 8Department of Genomic Medicine, 9Department of Surgery, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 10Center for Biomarkers and Biotech Drugs, Kaohsiung Medical University, Kaohsiung, Taiwan Abstract: Here we report a case of metastatic colon cancer treated with 5-fluorouracil, leucovorin, and escalated doses of irinotecan (FOLFIRI combined with regorafenib in the fourth-line setting after uridine diphosphate glucuronosyltransferase (UGT1A1 genotyping analysis. A 66-year-old male was initially diagnosed with Union Internationale Contre le Cancer stage III descending colon cancer and underwent curative surgery. He received postoperative adjuvant chemotherapy; however, liver metastasis developed and a partial hepatectomy was performed thereafter. Unfortunately, pulmonary metastases and recurrent liver tumors were found despite a series of systemic treatments with multiple combinations of cytotoxic and biologic agents. Recently, a novel multikinase inhibitor, regorafenib, was approved for the treatment of metastatic colorectal cancer refractory to other therapeutic modalities. As further treatment, we combined regorafenib with FOLFIRI, which included dose escalations of irinotecan, after UGT1A1 genotyping analysis. The therapeutic results were promising, with the improvement in liver and pulmonary metastases being

  18. SU-G-BRC-12: Isotoxic Dose Escalation for Advanced Lung Cancer: Comparison of Different Boosting Strategiesfor Patients with Recurrent Disease

    Energy Technology Data Exchange (ETDEWEB)

    Shusharina, N; Khan, F; Sharp, G; Choi, N [Massachusetts General Hospital, Boston, MA (United States)

    2016-06-15

    Purpose: To determine the dose level and timing of the boost in locally advanced lung cancer patients with confirmed tumor recurrence by comparing different boosting strategies by an impact of dose escalation in improvement of the therapeutic ratio. Methods: We selected eighteen patients with advanced NSCLC and confirmed recurrence. For each patient, a base IMRT plan to 60 Gy prescribed to PTV was created. Then we compared three dose escalation strategies: a uniform escalation to the original PTV, an escalation to a PET-defined target planned sequentially and concurrently. The PET-defined targets were delineated by biologically-weighed regions on a pre-treatment 18F-FDG PET. The maximal achievable dose, without violating the OAR constraints, was identified for each boosting method. The EUD for the target, spinal cord, combined lung, and esophagus was compared for each plan. Results: The average prescribed dose was 70.4±13.9 Gy for the uniform boost, 88.5±15.9 Gy for the sequential boost and 89.1±16.5 Gy for concurrent boost. The size of the boost planning volume was 12.8% (range: 1.4 – 27.9%) of the PTV. The most prescription-limiting dose constraints was the V70 of the esophagus. The EUD within the target increased by 10.6 Gy for the uniform boost, by 31.4 Gy for the sequential boost and by 38.2 for the concurrent boost. The EUD for OARs increased by the following amounts: spinal cord, 3.1 Gy for uniform boost, 2.8 Gy for sequential boost, 5.8 Gy for concurrent boost; combined lung, 1.6 Gy for uniform, 1.1 Gy for sequential, 2.8 Gy for concurrent; esophagus, 4.2 Gy for uniform, 1.3 Gy for sequential, 5.6 Gy for concurrent. Conclusion: Dose escalation to a biologically-weighed gross tumor volume defined on a pre-treatment 18F-FDG PET may provide improved therapeutic ratio without breaching predefined OAR constraints. Sequential boost provides better sparing of OARs as compared with concurrent boost.

  19. Dose-Escalated Intensity-Modulated Radiotherapy Is Feasible and May Improve Locoregional Control and Laryngeal Preservation in Laryngo-Hypopharyngeal Cancers

    International Nuclear Information System (INIS)

    Miah, Aisha B.; Bhide, Shreerang A.; Guerrero-Urbano, M. Teresa; Clark, Catharine; Bidmead, A. Margaret; St Rose, Suzanne; Barbachano, Yolanda; A’Hern, Roger; Tanay, Mary; Hickey, Jennifer; Nicol, Robyn; Newbold, Kate L.; Harrington, Kevin J.; Nutting, Christopher M.

    2012-01-01

    Purpose: To determine the safety and outcomes of induction chemotherapy followed by dose-escalated intensity-modulated radiotherapy (IMRT) with concomitant chemotherapy in locally advanced squamous cell cancer of the larynx and hypopharynx (LA-SCCL/H). Methods and Materials: A sequential cohort Phase I/II trial design was used to evaluate moderate acceleration and dose escalation. Patients with LA-SCCL/H received IMRT at two dose levels (DL): DL1, 63 Gy/28 fractions (Fx) to planning target volume 1 (PTV1) and 51.8 Gy/28 Fx to PTV2; DL2, 67.2 Gy/28 Fx and 56 Gy/28 Fx to PTV1 and PTV2, respectively. Patients received induction cisplatin/5-fluorouracil and concomitant cisplatin. Acute and late toxicities and tumor control rates were recorded. Results: Between September 2002 and January 2008, 60 patients (29 DL1, 31 DL2) with Stage III (41% DL1, 52% DL2) and Stage IV (52% DL1, 48% DL2) disease were recruited. Median (range) follow-up for DL1 was 51.2 (12.1–77.3) months and for DL2 was 36.2 (4.2–63.3) months. Acute Grade 3 (G3) dysphagia was higher in DL2 (87% DL2 vs. 59% DL1), but other toxicities were equivalent. One patient in DL1 required dilatation of a pharyngeal stricture (G3 dysphagia). In DL2, 2 patients developed benign pharyngeal strictures at 1 year. One underwent a laryngo-pharyngectomy and the other a dilatation. No other G3/G4 toxicities were reported. Overall complete response was 79% (DL1) and 84% (DL2). Two-year locoregional progression-free survival rates were 64.2% (95% confidence interval, 43.5–78.9%) in DL1 and 78.4% (58.1–89.7%) in DL2. Two-year laryngeal preservation rates were 88.7% (68.5–96.3%) in DL1 and 96.4% (77.7–99.5%) in DL2. Conclusions: At a mean follow-up of 36 months, dose-escalated chemotherapy–IMRT at DL2 has so far been safe to deliver. In this study, DL2 delivered high rates of locoregional control, progression-free survival, and organ preservation and has been selected as the experimental arm in a Cancer Research UK

  20. Dose-Escalated Stereotactic Body Radiation Therapy for Patients With Intermediate- and High-Risk Prostate Cancer: Initial Dosimetry Analysis and Patient Outcomes

    International Nuclear Information System (INIS)

    Kotecha, Rupesh; Djemil, Toufik; Tendulkar, Rahul D.; Reddy, Chandana A.; Thousand, Richard A.; Vassil, Andrew; Stovsky, Mark; Berglund, Ryan K.; Klein, Eric A.; Stephans, Kevin L.

    2016-01-01

    Purpose: To report the short-term clinical outcomes and acute and late treatment-related genitourinary (GU) and gastrointestinal (GI) toxicities in patients with intermediate- and high-risk prostate cancer treated with dose-escalated stereotactic body radiation therapy (SBRT). Methods and Materials: Between 2011 and 2014, 24 patients with prostate cancer were treated with SBRT to the prostate gland and proximal seminal vesicles. A high-dose avoidance zone (HDAZ) was created by a 3-mm expansion around the rectum, urethra, and bladder. Patients were treated to a minimum dose of 36.25 Gy in 5 fractions, with a simultaneous dose escalation to a dose of 50 Gy to the target volume away from the HDAZ. Acute and late GU and GI toxicity outcomes were measured according to the National Cancer Institute Common Terminology Criteria for Adverse Events toxicity scale, version 4. Results: The median follow-up was 25 months (range, 18-45 months). Nine patients (38%) experienced an acute grade 2 GU toxicity, which was medically managed, and no patients experienced an acute grade 2 GI toxicity. Two patients (8%) experienced late grade 2 GU toxicity, and 2 patients (8%) experienced late grade 2 GI toxicity. No acute or late grade ≥3 GU or GI toxicities were observed. The 24-month prostate-specific antigen relapse-free survival outcome for all patients was 95.8% (95% confidence interval 75.6%-99.4%), and both biochemical failures occurred in patients with high-risk disease. All patients are currently alive at the time of this analysis and continue to be followed. Conclusions: A heterogeneous prostate SBRT planning technique with differential treatment volumes (low dose: 36.25 Gy; and high dose: 50 Gy) with an HDAZ provides a safe method of dose escalation. Favorable rates of biochemical control and acceptably low rates of acute and long-term GU and GI toxicity can be achieved in patients with intermediate- and high-risk prostate cancer treated with SBRT.

  1. Dose-Escalated Intensity-Modulated Radiotherapy Is Feasible and May Improve Locoregional Control and Laryngeal Preservation in Laryngo-Hypopharyngeal Cancers

    Energy Technology Data Exchange (ETDEWEB)

    Miah, Aisha B; Bhide, Shreerang A; Guerrero-Urbano, M Teresa [Head and Neck Unit, The Royal Marsden National Health Service (NHS) Foundation Trust, London (United Kingdom); Institute of Cancer Research, London (United Kingdom); Clark, Catharine; Bidmead, A Margaret [Institute of Cancer Research, London (United Kingdom); Department of Physics, The Royal Marsden NHS Foundation Trust, London (United Kingdom); St Rose, Suzanne; Barbachano, Yolanda; A' Hern, Roger [Department of Statistics, The Royal Marsden NHS Foundation Trust, London (United Kingdom); Tanay, Mary; Hickey, Jennifer; Nicol, Robyn; Newbold, Kate L [Head and Neck Unit, The Royal Marsden National Health Service (NHS) Foundation Trust, London (United Kingdom); Harrington, Kevin J [Head and Neck Unit, The Royal Marsden National Health Service (NHS) Foundation Trust, London (United Kingdom); Institute of Cancer Research, London (United Kingdom); Nutting, Christopher M., E-mail: chris.nutting@rmh.nhs.uk [Head and Neck Unit, The Royal Marsden National Health Service (NHS) Foundation Trust, London (United Kingdom); Institute of Cancer Research, London (United Kingdom)

    2012-02-01

    Purpose: To determine the safety and outcomes of induction chemotherapy followed by dose-escalated intensity-modulated radiotherapy (IMRT) with concomitant chemotherapy in locally advanced squamous cell cancer of the larynx and hypopharynx (LA-SCCL/H). Methods and Materials: A sequential cohort Phase I/II trial design was used to evaluate moderate acceleration and dose escalation. Patients with LA-SCCL/H received IMRT at two dose levels (DL): DL1, 63 Gy/28 fractions (Fx) to planning target volume 1 (PTV1) and 51.8 Gy/28 Fx to PTV2; DL2, 67.2 Gy/28 Fx and 56 Gy/28 Fx to PTV1 and PTV2, respectively. Patients received induction cisplatin/5-fluorouracil and concomitant cisplatin. Acute and late toxicities and tumor control rates were recorded. Results: Between September 2002 and January 2008, 60 patients (29 DL1, 31 DL2) with Stage III (41% DL1, 52% DL2) and Stage IV (52% DL1, 48% DL2) disease were recruited. Median (range) follow-up for DL1 was 51.2 (12.1-77.3) months and for DL2 was 36.2 (4.2-63.3) months. Acute Grade 3 (G3) dysphagia was higher in DL2 (87% DL2 vs. 59% DL1), but other toxicities were equivalent. One patient in DL1 required dilatation of a pharyngeal stricture (G3 dysphagia). In DL2, 2 patients developed benign pharyngeal strictures at 1 year. One underwent a laryngo-pharyngectomy and the other a dilatation. No other G3/G4 toxicities were reported. Overall complete response was 79% (DL1) and 84% (DL2). Two-year locoregional progression-free survival rates were 64.2% (95% confidence interval, 43.5-78.9%) in DL1 and 78.4% (58.1-89.7%) in DL2. Two-year laryngeal preservation rates were 88.7% (68.5-96.3%) in DL1 and 96.4% (77.7-99.5%) in DL2. Conclusions: At a mean follow-up of 36 months, dose-escalated chemotherapy-IMRT at DL2 has so far been safe to deliver. In this study, DL2 delivered high rates of locoregional control, progression-free survival, and organ preservation and has been selected as the experimental arm in a Cancer Research UK Phase III

  2. Continued Benefit to Androgen Deprivation Therapy for Prostate Cancer Patients Treated With Dose-Escalated Radiation Therapy Across Multiple Definitions of High-Risk Disease

    International Nuclear Information System (INIS)

    Stenmark, Matthew H.; Blas, Kevin; Halverson, Schuyler; Sandler, Howard M.; Feng, Felix Y.; Hamstra, Daniel A.

    2011-01-01

    Purpose: To analyze prognostic factors in patients with high-risk prostate cancer treated with dose-escalated external-beam radiation therapy (EBRT) and androgen deprivation (ADT). Methods and Materials: Between 1998 and 2008 at University of Michigan Medical Center, 718 men were consecutively treated with EBRT to at least 75 Gy. Seven definitions of high-risk prostate cancer, applying to 11–33% of patients, were evaluated. Biochemical failure (BF), salvage ADT use, metastatic progression, and prostate cancer–specific mortality (PCSM) were estimated by the Kaplan-Meier method and Cox proportional hazards regression. Results: Each high-risk definition was associated with increased BF (hazard ratio [HR] 2.8–3.9, p < 0.0001), salvage ADT use (HR 3.9–6.3, p < 0.0001), metastasis (HR 3.7–6.6, p < 0.0001), and PCSM (HR 3.7–16.2, p < 0.0001). Furthermore, an increasing number of high-risk features predicted worse outcome. Adjuvant ADT yielded significant reductions in both metastases (HR 0.19–0.38, p < 0.001) and PCSM (HR 0.38–0.50, p < 0.05) for all high-risk definitions (with the exception of clinical Stage T3–4 disease) but improved BF only for those with elevated Gleason scores (p < 0.03, HR 0.25–0.48). When treated with ADT and dose-escalated EBRT, patients with Gleason scores 8 to 10, without other high-risk features, had 8-year freedom from BF of 74%, freedom from distant metastases of 93%, and cause-specific survival of 92%, with salvage ADT used in 16% of patients. Conclusion: Adjuvant ADT results in a significant improvement in clinical progression and PCSM across multiple definitions of high-risk disease even with dose-escalated EBRT. There is a subset of patients, characterized by multiple high-risk features or the presence of Gleason Pattern 5, who remain at significant risk for metastasis and PCSM despite current treatment.

  3. Dose-Escalated Stereotactic Body Radiation Therapy for Patients With Intermediate- and High-Risk Prostate Cancer: Initial Dosimetry Analysis and Patient Outcomes

    Energy Technology Data Exchange (ETDEWEB)

    Kotecha, Rupesh; Djemil, Toufik; Tendulkar, Rahul D.; Reddy, Chandana A.; Thousand, Richard A.; Vassil, Andrew [Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio (United States); Stovsky, Mark; Berglund, Ryan K.; Klein, Eric A. [Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio (United States); Stephans, Kevin L., E-mail: stephak@ccf.org [Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio (United States)

    2016-07-01

    Purpose: To report the short-term clinical outcomes and acute and late treatment-related genitourinary (GU) and gastrointestinal (GI) toxicities in patients with intermediate- and high-risk prostate cancer treated with dose-escalated stereotactic body radiation therapy (SBRT). Methods and Materials: Between 2011 and 2014, 24 patients with prostate cancer were treated with SBRT to the prostate gland and proximal seminal vesicles. A high-dose avoidance zone (HDAZ) was created by a 3-mm expansion around the rectum, urethra, and bladder. Patients were treated to a minimum dose of 36.25 Gy in 5 fractions, with a simultaneous dose escalation to a dose of 50 Gy to the target volume away from the HDAZ. Acute and late GU and GI toxicity outcomes were measured according to the National Cancer Institute Common Terminology Criteria for Adverse Events toxicity scale, version 4. Results: The median follow-up was 25 months (range, 18-45 months). Nine patients (38%) experienced an acute grade 2 GU toxicity, which was medically managed, and no patients experienced an acute grade 2 GI toxicity. Two patients (8%) experienced late grade 2 GU toxicity, and 2 patients (8%) experienced late grade 2 GI toxicity. No acute or late grade ≥3 GU or GI toxicities were observed. The 24-month prostate-specific antigen relapse-free survival outcome for all patients was 95.8% (95% confidence interval 75.6%-99.4%), and both biochemical failures occurred in patients with high-risk disease. All patients are currently alive at the time of this analysis and continue to be followed. Conclusions: A heterogeneous prostate SBRT planning technique with differential treatment volumes (low dose: 36.25 Gy; and high dose: 50 Gy) with an HDAZ provides a safe method of dose escalation. Favorable rates of biochemical control and acceptably low rates of acute and long-term GU and GI toxicity can be achieved in patients with intermediate- and high-risk prostate cancer treated with SBRT.

  4. Off-label biologic regimens in psoriasis: a systematic review of efficacy and safety of dose escalation, reduction, and interrupted biologic therapy.

    Directory of Open Access Journals (Sweden)

    Elizabeth A Brezinski

    Full Text Available OBJECTIVES: While off-label dosing of biologic treatments may be necessary in selected psoriasis patients, no systematic review exists to date that synthesizes the efficacy and safety of these off-label dosing regimens. The aim of this systematic review is to evaluate efficacy and safety of off-label dosing regimens (dose escalation, dose reduction, and interrupted treatment with etanercept, adalimumab, infliximab, ustekinumab, and alefacept for psoriasis treatment. DATA SOURCES AND STUDY SELECTION: We searched OVID Medline from January 1, 1990 through August 1, 2011 for prospective clinical trials that studied biologic therapy for psoriasis treatment in adults. Individual articles were screened for studies that examined escalated, reduced, or interrupted therapy with etanercept, adalimumab, infliximab, ustekinumab, or alefacept. DATA SYNTHESIS: A total of 23 articles with 12,617 patients matched the inclusion and exclusion criteria for the systematic review. Data were examined for primary and secondary efficacy outcomes and adverse events including infections, malignancies, cardiovascular events, and anti-drug antibodies. The preponderance of data suggests that continuous treatment with anti-TNF agents and anti-IL12/23 agent was necessary for maintenance of disease control. Among non-responders, dose escalation with etanercept, adalimumab, ustekinumab, and alefacept typically resulted in greater efficacy than standard dosing. Dose reduction with etanercept and alefacept resulted in reduced efficacy. Withdrawal of the examined biologics led to an increase in disease activity; efficacy from retreatment did not result in equivalent initial response rates for most biologics. Safety data on off-label dosing regimens are limited. CONCLUSION: Dose escalation in non-responders generally resulted in increased efficacy in the examined biologics used to treat moderate-to-severe psoriasis. Continuous treatment with anti-TNF agents and anti-IL12/23 agent

  5. SU-G-BRC-12: Isotoxic Dose Escalation for Advanced Lung Cancer: Comparison of Different Boosting Strategiesfor Patients with Recurrent Disease

    International Nuclear Information System (INIS)

    Shusharina, N; Khan, F; Sharp, G; Choi, N

    2016-01-01

    Purpose: To determine the dose level and timing of the boost in locally advanced lung cancer patients with confirmed tumor recurrence by comparing different boosting strategies by an impact of dose escalation in improvement of the therapeutic ratio. Methods: We selected eighteen patients with advanced NSCLC and confirmed recurrence. For each patient, a base IMRT plan to 60 Gy prescribed to PTV was created. Then we compared three dose escalation strategies: a uniform escalation to the original PTV, an escalation to a PET-defined target planned sequentially and concurrently. The PET-defined targets were delineated by biologically-weighed regions on a pre-treatment 18F-FDG PET. The maximal achievable dose, without violating the OAR constraints, was identified for each boosting method. The EUD for the target, spinal cord, combined lung, and esophagus was compared for each plan. Results: The average prescribed dose was 70.4±13.9 Gy for the uniform boost, 88.5±15.9 Gy for the sequential boost and 89.1±16.5 Gy for concurrent boost. The size of the boost planning volume was 12.8% (range: 1.4 – 27.9%) of the PTV. The most prescription-limiting dose constraints was the V70 of the esophagus. The EUD within the target increased by 10.6 Gy for the uniform boost, by 31.4 Gy for the sequential boost and by 38.2 for the concurrent boost. The EUD for OARs increased by the following amounts: spinal cord, 3.1 Gy for uniform boost, 2.8 Gy for sequential boost, 5.8 Gy for concurrent boost; combined lung, 1.6 Gy for uniform, 1.1 Gy for sequential, 2.8 Gy for concurrent; esophagus, 4.2 Gy for uniform, 1.3 Gy for sequential, 5.6 Gy for concurrent. Conclusion: Dose escalation to a biologically-weighed gross tumor volume defined on a pre-treatment 18F-FDG PET may provide improved therapeutic ratio without breaching predefined OAR constraints. Sequential boost provides better sparing of OARs as compared with concurrent boost.

  6. Dose escalation by image-guided intensity-modulated radiotherapy leads to an increase in pain relief for spinal metastases: a comparison study with a regimen of 30 Gy in 10 fractions.

    Science.gov (United States)

    He, Jinlan; Xiao, Jianghong; Peng, Xingchen; Duan, Baofeng; Li, Yan; Ai, Ping; Yao, Min; Chen, Nianyong

    2017-12-22

    Under the existing condition that the optimum radiotherapy regimen for spinal metastases is controversial, this study investigates the benefits of dose escalation by image-guided intensity-modulated radiotherapy (IG-IMRT) with 60-66 Gy in 20-30 fractions for spinal metastases. In the dose-escalation group, each D50 of planning gross tumor volume (PGTV) was above 60 Gy and each Dmax of spinal cord planning organ at risk volume (PRV) was below 48 Gy. The median biological effective dose (BED) of Dmax of spinal cord was lower in the dose-escalation group compared with that in the 30-Gy group (69.70 Gy vs. 83.16 Gy, p pain responses were better in the dose-escalation group than those in the 30-Gy group ( p = 0.005 and p = 0.024), and the complete pain relief rates were respectively 73.69% and 34.29% ( p = 0.006), 73.69% and 41.38% ( p = 0.028) in two compared groups. In the dose-escalation group, there is a trend of a longer duration of pain relief, a longer overall survival and a lower incidence of acute radiation toxicities. No late radiation toxicities were observed in both groups. Dosimetric parameters and clinical outcomes, including pain response, duration of pain relief, radiation toxicities and overall survival, were compared among twenty-five metastatic spinal lesions irradiated with the dose-escalation regimen and among forty-four lesions treated with the 30-Gy regimen. Conventionally-fractionated IG-IMRT for spinal metastases could escalate dose to the vertebral lesions while sparing the spinal cord, achieving a better pain relief without increasing radiation complications.

  7. Is it beneficial to selectively boost high-risk tumor subvolumes? A comparison of selectively boosting high-risk tumor subvolumes versus homogeneous dose escalation of the entire tumor based on equivalent EUD plans

    International Nuclear Information System (INIS)

    Kim, Yusung; To me, Wolfgang A.

    2008-01-01

    Purpose. To quantify and compare expected local tumor control and expected normal tissue toxicities between selective boosting IMRT and homogeneous dose escalation IMRT for the case of prostate cancer. Methods. Four different selective boosting scenarios and three different high-risk tumor subvolume geometries were designed to compare selective boosting and homogeneous dose escalation IMRT plans delivering the same equivalent uniform dose (EUD) to the entire PTV. For each scenario, differences in tumor control probability between both boosting strategies were calculated for the high-risk tumor subvolume and remaining low-risk PTV, and were visualized using voxel based iso-TCP maps. Differences in expected rectal and bladder complications were quantified using radiobiological indices (generalized EUD (gEUD) and normal tissue complication probability (NTCP)) as well as %-volumes. Results. For all investigated scenarios and high-risk tumor subvolume geometries, selective boosting IMRT improves expected TCP compared to homogeneous dose escalation IMRT, especially when lack of control of the high-risk tumor subvolume could be the cause for tumor recurrence. Employing, selective boosting IMRT significant increases in expected TCP can be achieved for the high-risk tumor subvolumes. The three conventional selective boosting IMRT strategies, employing physical dose objectives, did not show significant improvement in rectal and bladder sparing as compared to their counterpart homogeneous dose escalation plans. However, risk-adaptive optimization, utilizing radiobiological objective functions, resulted in reduction in NTCP for the rectum when compared to its corresponding homogeneous dose escalation plan. Conclusions. Selective boosting is a more effective method than homogeneous dose escalation for achieving optimal treatment outcomes. Furthermore, risk-adaptive optimization increases the therapeutic ratio as compared to conventional selective boosting IMRT

  8. Hypoxia imaging with [18F]-FMISO-PET for guided dose escalation with intensity-modulated radiotherapy in head-and-neck cancers

    Energy Technology Data Exchange (ETDEWEB)

    Henriques de Figueiredo, B. [Institut Bergonie, Department of Radiotherapy, Bordeaux (France); INCIA UMR-CNRS 5287, Bordeaux (France); Zacharatou, C. [Institut Bergonie, Department of Radiotherapy, Bordeaux (France); Galland-Girodet, S.; Benech, J. [Hospital Haut-Leveque, Department of Radiotherapy, CHRU Bordeaux (France); Clermont-Gallerande, H. de [Hospital Pellegrin, Department of Nuclear Medicine, CHRU Bordeaux (France); Lamare, F. [INCIA UMR-CNRS 5287, Bordeaux (France); Hospital Haut-Leveque, Department of Radiotherapy, CHRU Bordeaux (France); Hatt, M. [LaTIM INSERM U1101, Brest (France); Digue, L. [Hospital Saint-Andre, Department of Clinical Oncology, CHRU Bordeaux (France); Mones del Pujol, E. de [Department of Oto-rhino-laryngology, CHRU Bordeaux (France); Fernandez, P. [INCIA UMR-CNRS 5287, Bordeaux (France); Hospital Pellegrin, Department of Nuclear Medicine, CHRU Bordeaux (France); University Bordeaux 2, Bordeaux (France)

    2014-09-23

    Positron emission tomography (PET) with [{sup 18}F]-fluoromisonidazole ([{sup 18}F]-FMISO) provides a non-invasive assessment of hypoxia. The aim of this study is to assess the feasibility of a dose escalation with volumetric modulated arc therapy (VMAT) guided by [{sup 18}F]-FMISO-PET for head-and-neck cancers (HNC). Ten patients with inoperable stages III-IV HNC underwent [{sup 18}F]-FMISO-PET before radiotherapy. Hypoxic target volumes (HTV) were segmented automatically by using the fuzzy locally adaptive Bayesian method. Retrospectively, two VMAT plans were generated delivering 70 Gy to the gross tumour volume (GTV) defined on computed tomography simulation or 79.8 Gy to the HTV. A dosimetric comparison was performed, based on calculations of tumour control probability (TCP), normal tissue complication probability (NTCP) for the parotid glands and uncomplicated tumour control probability (UTCP). The mean hypoxic fraction, defined as the ratio between the HTV and the GTV, was 0.18. The mean average dose for both parotids was 22.7 Gy and 25.5 Gy without and with dose escalation respectively. FMISO-guided dose escalation led to a mean increase of TCP, NTCP for both parotids and UTCP by 18.1, 4.6 and 8 % respectively. A dose escalation up to 79.8 Gy guided by [{sup 18}F]-FMISO-PET with VMAT seems feasible with improvement of TCP and without excessive increase of NTCP for parotids. (orig.) [German] Die Positronenemissionstomographie (PET) mit [{sup 18}F]-Fluoromisonidazol ([{sup 18}F]-FMISO) ermoeglicht eine nichtinvasive Beurteilung der Hypoxie. Ziel dieser Studie ist es, die Durchfuehrbarkeit einer [{sup 18}F]-FMISO-PET-gefuehrten Dosissteigerung bei volumetrisch modulierter Arc-Therapie (VMAT) von Kopf-Hals-Tumoren (KHT) zu bewerten. Zehn Patienten mit inoperablen KHT der Stadien III-IV erhielten vor der Strahlentherapie eine [{sup 18}F]-FMISO-PET. Hypoxische Zielvolumina (HV) wurden automatisch mit Hilfe des FLAB(Fuzzy Locally Adaptive Bayesian

  9. Gemcitabine and paclitaxel associated pneumonitis in non-small cell lung cancer: report of a phase I/II dose-escalating study.

    Science.gov (United States)

    Thomas, A L; Cox, G; Sharma, R A; Steward, W P; Shields, F; Jeyapalan, K; Muller, S; O'Byrne, K J

    2000-12-01

    The aim of this phase I/II dose escalating study was to establish the maximum tolerated dose (MTD) of gemcitabine and paclitaxel given in combination in non-small cell lung cancer (NSCLC). 12 patients with stage IIIB and IV NSCLC received paclitaxel administered intravenously over 1 h followed by gemcitabine given over 30 min on days 1, 8 and 15 every 28 days. Pneumonitis was the principal side-effect observed with 4 patients affected. Of these, 1 experienced grade 3 toxicity after one cycle of treatment and the others had grade 2 toxicity. All 4 cases responded to prednisolone. No other significant toxicities were observed. Of the 8 evaluable patients, 3 had a partial response and 2 had minor responses. The study was discontinued due to this dose-limiting toxicity. The combination of paclitaxel and gemcitabine shows promising antitumour activity in NSCLC, however, this treatment schedule may predispose to pneumonitis.

  10. Optimization of tolerability and efficacy of the novel dual amylin and calcitonin receptor agonist KBP-089 through dose escalation and combination with a GLP-1 analog

    DEFF Research Database (Denmark)

    Gydesen, Sofie; Andreassen, Kim Vietz; Hjuler, Sara Toftegaard

    2017-01-01

    , and the following treatment with 2.5, 10, and 40 µg/kg resulted in an ~15% vehicle-corrected weight loss, a corresponding reduction in adipose tissue (AT), and, in all treatment groups, improved oral glucose tolerance (P weight evenly with no significant...... second day obtained equal weight loss at study end, albeit with an uneven reduction in both food intake and body weight in rats dosed every second day. In a 4-fold dose escalation, KBP-089 induced a transient reduction in food intake at every escalation step, with reducing magnitude over time...... reduction in food intake at either escalation step. KBP-089 (1.25 µg/kg) and liraglutide (50 µg/kg) reduced 24-h food intake by 29% and 37% compared with vehicle, respectively; however, when they were combined, 24-h food intake was reduced by 87%. Chronically, KBP-089 (1.25 µg/kg) and liraglutide (50 µg...

  11. A dose-escalation trial with the adaptive radiotherapy process as a delivery system in localized prostate cancer: Analysis of chronic toxicity

    International Nuclear Information System (INIS)

    Brabbins, Donald; Martinez, Alvaro; Yan Di; Lockman, David; Wallace, Michell; Gustafson, Gary; Chen, Peter; Vicini, Frank; Wong, John

    2005-01-01

    Purpose: To evaluate the validity of the chosen adaptive radiotherapy (ART) dose-volume constraints while testing the hypothesis that toxicity would not be greater at higher tumor dose levels. Materials and methods: In the ART dose escalation/selection trial, treatment was initiated with a generic planning target volume (PTV) formed as a 1-cm expansion of the clinical target volume (CTV). After the first week of therapy, the patient was replanned with a patient-specific PTV, constructed with CT and electronic portal images obtained in the first 4 days of treatment. A new multileaf collimator beam aperture was used. A minimum dose prescribed to the patient-specific PTV, ranging 70.2-79.2 Gy, was determined on the basis of the following rectal and bladder constraints: 82 Gy, 75.6 Gy, 75.6 Gy, and the maximum bladder dose is 85 Gy. A conformal four-field and/or intensity-modulated radiotherapy (IMRT) technique was used. Independent reviewers scored toxicities. The worst toxicity score seen was used as per the Common Toxicity Criteria grade scale (version 2). We divided the patients into three separate groups: 70.2-72 Gy, >72-75.6 Gy, and >75.6-79.2 Gy. Toxicities in each group were quantified and compared by the Pearson chi-squared test to validate our dose escalation/selection model. Grades 0, 1, 2, and 3 were censored as none vs. each category and none vs. any. Results: We analyzed patients with follow-up greater than 1 year. The mean duration of follow-up was 29 months (range, 12-46 months). We report on 280 patients, mean age 72 years (range, 51-87 years). Only 60 patients received adjuvant hormones. Mean pretreatment prostate-specific antigen level was 9.3 ng/mL (range, 0.6-120 ng/mL). Mean Gleason score was 6 (range, 3-9). The lowest dose level was given to 49 patients, the intermediate dose to 131 patients, and 100 patients received the highest dose escalation. One hundred eighty-one patients (65%) were treated to a prostate field only and 99 patients (35%) to

  12. Improvement in dose escalation using off-line and on-line image feedback in the intensity modulated beam design for prostate cancer treatment

    International Nuclear Information System (INIS)

    Yan, D.; Birkner, M.; Nuesslin, F.; Wong, J.; Martinez, A.

    2001-01-01

    Purpose: To test the capability of dose escalation in the IMRT process where the organ/patient temporal geometric variation, measured using either off-line or on-line treatment CT and portal images, are adapted for the optimal design of intensity modulated beam. Materials and Methods: Retrospective study was performed on five prostate cancer patients with multiple CT scans (14∼17/patient) and daily portal images obtained during the treatment course. These images were used to determine the displacements of each subvolume in the organs of interest caused by the daily patient setup and internal organ motion/deformation. The temporal geometric information was processed in order of treatment time and fed into an inverse planning system. The inverse planning engine was specifically implemented to adapt the design of intensity modulated beam to the temporal subvolume displacement and patient internal density changes. Three image feedback strategies were applied to each patient and evaluated with respect to the capability of safe dose escalation. The first one is off-line image feedback, which designs the beam intensity based on the patient images measured within the first week of treatment. The second is an on-line 'the target of the day' strategy, which designs the beam intensity in daily bases by using 'the image of the day' alone. The last one is also the on-line based. However, it designs the instantaneous beam intensity based on also dose distribution in each organ of interest received prior to the current treatment. For each of the treatment strategies, the minimum dose delivered to the CTV was determined by applying the identical normal tissue constraints of partial dose/volumes. This minimum dose was used to represent the treatment dose for each patient. Results: The off-line strategy appears feasible after 5 days of image feedback. The average treatment dose among the patients can be 10% higher than the one in the conventional IMRT treatment where the inverse

  13. Conformal technique dose escalation in prostate cancer: improved cancer control with higher doses in patients with pretreatment PSA {>=} 10 ngm/ml

    Energy Technology Data Exchange (ETDEWEB)

    Hanks, G E; Lee, W R; Hanlon, A L; Kaplan, E; Epstein, B; Schultheiss, T

    1995-07-01

    Purpose: Single institutions and an NCI supported group of institutions have been investigating the value of dose escalation in patients with prostate cancer treated by conformal treatment techniques. Improvement in morbidity has been previously established, while this report identifies the pretreatment PSA level subgroups of patients who benefitted in cancer control from higher dose. Materials and Methods: We report actuarial bNED survival rates for 375 consecutive patients with known pretreatment PSA levels treated with conformal technique between 5/89 and 12/93. The whole pelvis was treated to 45 Gy in 25 fractions in all T2C,3, all Gleason 8, 9, 10 and all patients with pretreatment PSA {>=}20. The prostate {+-} seminal vesicles was boosted at 2.1 Gy/day to the center of the prostate to 65-79 Gy (65-69 N=50), 70-72.49 N=94, 72.5-74.9 N=82, 75-77.49 N=129 and {>=}77.5 N=20). The median followup is 21 mos with a range of 3 to 67 mos. The highest dose patients have the least followup, reducing the impact of the highest dose levels at this time. Patients are analyzed for the entire group divided at 71 Gy and at 73 Gy calculated at the center of the prostate. Each dose group is then subdivided by pretreatment PSA levels <10, 10-19.9, and {>=}20 ngm/ml and dose levels are compared within pretreatment PSA level group. bNED failure is defined as PSA {>=}1.5 ngm/ml and rising on two consecutive values. Results: Table 1 shows the bNED survival rates at 24 and 36 mos for all patients and the three pretreatment PSA level groups. For all patients pooled, there is an overall advantage to using doses {>=}71 Gy (64% vs 85% at 36 mo, p=.006) and {>=}73 Gy (71% vs 86% at 36 mo, p=.07). The subgroup of PSA <10 ngm/ml, however, shows no benefit in bNED survival when using doses over 71 Gy (90% vs 93% at 36 mo) or 73 Gy (91 vs 94% at 36 mo). The subgroup PSA 10 ngm/ml to 19.9 ngm/ml shows improved cancer control when using doses over 71 Gy (61% vs 88% at 36 mo, p=.03) and over 73

  14. Short-term Androgen-Deprivation Therapy Improves Prostate Cancer-Specific Mortality in Intermediate-Risk Prostate Cancer Patients Undergoing Dose-Escalated External Beam Radiation Therapy

    International Nuclear Information System (INIS)

    Zumsteg, Zachary S.; Spratt, Daniel E.; Pei, Xin; Yamada, Yoshiya; Kalikstein, Abraham; Kuk, Deborah; Zhang, Zhigang; Zelefsky, Michael J.

    2013-01-01

    Purpose: We investigated the benefit of short-term androgen-deprivation therapy (ADT) in patients with intermediate-risk prostate cancer (PC) receiving dose-escalated external beam radiation therapy. Methods and Materials: The present retrospective study comprised 710 intermediate-risk PC patients receiving external beam radiation therapy with doses of ≥81 Gy at a single institution from 1992 to 2005, including 357 patients receiving neoadjuvant and concurrent ADT. Prostate-specific antigen recurrence-free survival (PSA-RFS) and distant metastasis (DM) were compared using the Kaplan-Meier method and Cox proportional hazards models. PC-specific mortality (PCSM) was assessed using competing-risks analysis. Results: The median follow-up was 7.9 years. Despite being more likely to have higher PSA levels, Gleason score 4 + 3 = 7, multiple National Comprehensive Cancer Network intermediate-risk factors, and older age (P≤.001 for all comparisons), patients receiving ADT had improved PSA-RFS (hazard ratio [HR], 0.598; 95% confidence interval [CI], 0.435-0.841; P=.003), DM (HR, 0.424; 95% CI, 0.219-0.819; P=.011), and PCSM (HR, 0.380; 95% CI, 0.157-0.921; P=.032) on univariate analysis. Using multivariate analysis, ADT was an even stronger predictor of improved PSA-RFS (adjusted HR [AHR], 0.516; 95% CI, 0.360-0.739; P<.001), DM (AHR, 0.347; 95% CI, 0.176-0.685; P=.002), and PCSM (AHR, 0.297; 95% CI, 0.128-0.685; P=.004). Gleason score 4 + 3 = 7 and ≥50% positive biopsy cores were other independent predictors of PCSM. Conclusions: Short-term ADT improves PSA-RFS, DM, and PCSM in patients with intermediate-risk PC undergoing dose-escalated external beam radiation therapy

  15. Methods, safety, and early clinical outcomes of dose escalation using simultaneous integrated and sequential boosts in patients with locally advanced gynecologic malignancies.

    Science.gov (United States)

    Boyle, John; Craciunescu, Oana; Steffey, Beverly; Cai, Jing; Chino, Junzo

    2014-11-01

    To evaluate the safety of dose escalated radiotherapy using a simultaneous integrated boost technique in patients with locally advanced gynecological malignancies. Thirty-nine women with locally advanced gynecological malignancies were treated with intensity modulated radiation therapy utilizing a simultaneous integrated boost (SIB) technique for gross disease in the para-aortic and/or pelvic nodal basins, sidewall extension, or residual primary disease. Women were treated to 45Gy in 1.8Gy fractions to elective nodal regions. Gross disease was simultaneously treated to 55Gy in 2.2Gy fractions (n=44 sites). An additional sequential boost of 10Gy in 2Gy fractions was delivered if deemed appropriate (n=29 sites). Acute and late toxicity, local control in the treated volumes (LC), overall survival (OS), and distant metastases (DM) were assessed. All were treated with a SIB to a dose of 55Gy. Twenty-four patients were subsequently treated with a sequential boost to a median dose of 65Gy. Median follow-up was 18months. Rates of acute>grade 2 gastrointestinal (GI), genitourinary (GU), and hematologic (heme) toxicities were 2.5%, 0%, and 30%, respectively. There were no grade 4 acute toxicities. At one year, grade 1-2 late GI toxicities were 24.5%. There were no grade 3 or 4 late GI toxicities. Rates of grade 1-2 late GU toxicities were 12.7%. There were no grade 3 or 4 late GU toxicities. Dose escalated radiotherapy using a SIB results in acceptable rates of acute toxicity. Copyright © 2014 Elsevier Inc. All rights reserved.

  16. Results of a phase I dose escalation study of eltrombopag in patients with advanced soft tissue sarcoma receiving doxorubicin and ifosfamide

    International Nuclear Information System (INIS)

    Chawla, Sant P; Staddon, Arthur; Hendifar, Andrew; Messam, Conrad A; Patwardhan, Rita; Kamel, Yasser Mostafa

    2013-01-01

    The objective of this Phase I dose escalation study was to explore the safety and tolerability of eltrombopag, an oral, nonpeptide, thrombopoietin receptor agonist, in patients with advanced soft tissue sarcoma (STS) and thrombocytopenia due to treatment with doxorubicin and ifosfamide (AI) combination chemotherapy. Patients aged 18 or older with histologically confirmed, locally advanced or metastatic STS were treated with 1 cycle of AI followed by AI with eltrombopag starting at Cycle 2, using 2 different dosing schedules. The study design included an eltrombopag dose escalation phase starting at 75 mg daily to determine the optimal biological dose (OBD). Eighteen patients were enrolled and 15 received at least 1 dose of chemotherapy; 3 patients withdrew prior to receiving eltrombopag. Seven, 4, and 1 patients received 75 mg, 100 mg, and 150 mg eltrombopag daily, respectively. No dose-limiting toxicities were reported. Due to slow recruitment, the study was closed prior to identifying an OBD. The most common hematologic adverse events (AEs) were thrombocytopenia (80%), neutropenia (73%), and anemia (67%). The most common nonhematologic AEs were fatigue (53%), alanine aminotransferase increased, constipation, and nausea (47% each). Eleven of 12 patients who received eltrombopag completed at least 2 chemotherapy cycles; all had increased platelet counts on Day 1 of Cycle 2 (cycle with eltrombopag) compared to Day 1 of Cycle 1 (cycle without eltrombopag). Although data are limited, safety data were consistent with the known toxicities of AI combination chemotherapy or the side effect profile of eltrombopag seen in other studies. Available data suggest a potential pre- and post-chemotherapy dosing scheme for eltrombopag when administered with AI chemotherapy, and support further investigation of eltrombopag treatment in patients with chemotherapy-induced thrombocytopenia

  17. Acute gastrointestinal, genitourinary, and dermatological toxicity during dose-escalated 3D-conformal radiation therapy (3DCRT) using an intrarectal balloon for prostate gland localization and immobilization

    International Nuclear Information System (INIS)

    Woel, Rosemonde; Beard, Clair; Chen, Ming-Hui; Hurwitz, Mark; Loffredo, Marian; McMahon, Elizabeth; Ching, Jane; Lopes, Lynn; D'Amico, Anthony V.

    2005-01-01

    Purpose: We determined the acute gastrointestinal (GI), genitourinary (GU), and dermatologic (D) toxicity during dose-escalated three-dimensional conformal radiation therapy (3DCRT). A modified intrarectal balloon (Medrad) was used for prostate gland localization and immobilization. Methods: Forty-six men with clinical category T1c to T3a, and at least one high-risk feature (PSA >10, Gleason ≥7, or MRI evidence of extracapsular extension or seminal vesical invasion) comprised the study cohort. Treatment consisted of hormonal therapy and 4-field 3DCRT using an intrarectal balloon for the initial 15 of 40 treatments. Planning treatment volume dose was 72 Gy (95% normalization). A Mantel-Haenzel Chi-square test compared the distribution of GU, GI, and D symptoms at baseline and at end of treatment (EOT). Results: There was no significant difference between the 2 time points in the proportion of patients with bowel symptoms (p = 0.73), tenesmus (p = 0.27), nocturia (p = 1.00), or GU urgency (p = 0.40). However, there was a significant decrease in GU frequency (70% vs. 50%, p = 0.46) as a result of medical interventions and a significant increase in hemorrhoidal irritation (4% vs. 20%, p = 0.02) and anal cutaneous skin reaction (0% vs. 70%, p < 0.001). By 3 months after EOT compared to baseline, there was no significant difference in the proportion of patients experiencing hemorrhoidal bleeding (4% vs. 8%, p = 0.52), requiring intervention for hemorrhoidal symptoms (7% vs. 5%, p = 0.8), or experiencing persistent anal cutaneous skin reaction (0% vs. 3%, p = 0.31). Conclusion: Dose-escalated 3DCRT using an intrarectal balloon for prostate localization and immobilization was well tolerated. Acute GU, GI, and D symptoms resolved with standard dietary or medical interventions by the EOT or shortly thereafter

  18. Dose escalation of radical radiation therapy in non-small-cell lung cancer using positron emission tomography/computed tomography-defined target volumes: Are class solutions obsolete?

    International Nuclear Information System (INIS)

    Everitt, S.; Schneider-Kolsky, M.; Budd, R.; Yuen, K.; Manus, M Mac

    2008-01-01

    Full text: This study investigated the maximum theoretical radiation dose that could safely be delivered to 20 patients diagnosed with non-small-cell lung cancer. Two three-dimensional conformal radiation therapy (RT) class-solution techniques (A and B) and an individualized three-dimensional conformal RT technique (C) were compared at the standard dose of 60 Gy (part I). Dose escalation was then attempted for each technique successfully at 60 Gy, constrained by predetermined limits for lung and spinal canal (part II). Part I and part II data were reanalysed to include oesophageal dose constraints (part III). In part I, 60 Gy was successfully planned using techniques A, B and C in 19 (95%), 18 (90%) and 20 (100%) patients, respectively. The mean escalated dose attainable for part II using techniques A, B and C were 76.4, 74 and 97.8 Gy, respectively (P < 0.0005). One (5%) patient was successfully planned for 120 Gy using techniques A and B, whereas four (20%) were successfully planned using technique C. Following the inclusion of additional constraints applied to the oesophagus in part III, the amount of escalated dose remained the same for all patients who were successfully planned at 60 Gy apart from two patients when technique C was applied. In conclusion, individualized three-dimensional conformal RT facilitated greater dose conformation and higher escalation of dose in most patients. With modern planning tools, simple class solutions are obsolete for conventional dose radical RT in non-small-cell lung cancer. Highly individualized conformal planning is essential for dose escalation.

  19. Modelling normal tissue isoeffect distribution in conformal radiotherapy of glioblastoma provides an alternative dose escalation pattern through hypofractionation without reducing the total dose

    International Nuclear Information System (INIS)

    Mangel, L.; Skriba, Z.; Major, T.; Polgar, C.; Fodor, J.; Somogyi, A.; Nemeth, G.

    2002-01-01

    The purpose of this study was to prove that by using conformal external beam radiotherapy (RT) normal brain structures can be protected even when applying an alternative approach of biological dose escalation: hypofractionation (HOF) without total dose reduction (TDR). Traditional 2-dimensional (2D) and conformal 3-dimensional (3D) treatment plans were prepared for 10 gliomas representing the subanatomical sites of the supratentorial brain. Isoeffect distributions were generated by the biologically effective dose (BED) formula to analyse the effect of conventionally fractionated (CF) and HOF schedules on both the spatial biological dose distribution and biological dose-volume histograms. A comparison was made between 2D-CF (2.0 Gy/day) and 3D-HOF (2.5 Gy/day) regimens, applying the same 60 Gy total doses. Integral biologically effective dose (IBED) and volumes received biologically equivalent to a dose of 54 Gy or more (V-BED54) were calculated for the lower and upper brain stem as organs of risk. The IBED values were lower with the 3D-HOF than with the 2D-CF schedule in each tumour location, means 22.7±17.1 and 40.4±16.9 in Gy, respectively (p<0.0001). The V-BED54 values were also smaller or equal in 90% of the cases favouring the 3D-HOF scheme. The means were 2.7±4.8 ccm for 3D-HOF and 10.7±12.7 ccm for 2D-CF (p=0.0006). Our results suggest that with conformal RT, fraction size can gradually be increased. HOF radiotherapy regimens without TDR shorten the treatment time and seem to be an alternative way of dose escalation in the treatment of glioblastoma

  20. Expression of Bcl-2, p53, and MDM2 in Localized Prostate Cancer With Respect to the Outcome of Radical Radiotherapy Dose Escalation

    International Nuclear Information System (INIS)

    Vergis, Roy; Corbishley, Catherine M.; Thomas, Karen

    2010-01-01

    Purpose: Established prognostic factors in localized prostate cancer explain only a moderate proportion of variation in outcome. We analyzed tumor expression of apoptotic markers with respect to outcome in men with localized prostate cancer in two randomized controlled trials of radiotherapy dose escalation. Methods and Materials: Between 1995 and 2001, 308 patients with localized prostate cancer received neoadjuvant androgen deprivation and radical radiotherapy at our institution in one of two dose-escalation trials. The biopsy specimens in 201 cases were used to make a biopsy tissue microarray. We evaluated tumor expression of Bcl-2, p53, and MDM2 by immunohistochemistry with respect to outcome. Results: Median follow-up was 7 years, and 5-year freedom from biochemical failure (FFBF) was 70.4% (95% CI, 63.5-76.3%). On univariate analysis, expression of Bcl-2 (p < 0.001) and p53 (p = 0.017), but not MDM2 (p = 0.224), was significantly associated with FFBF. Expression of Bcl-2 remained significantly associated with FFBF (p = 0.001) on multivariate analysis, independently of T stage, Gleason score, initial prostate-specific antigen level, and radiotherapy dose. Seven-year biochemical control was 61% vs. 41% (p = 0.0122) for 74 Gy vs. 64 Gy, respectively, among patients with Bcl-2-positive tumors and 87% vs. 81% (p = 0.423) for 74 Gy vs. 64 Gy, respectively, among patients with Bcl-2-negative tumors. There was no statistically significant interaction between dose and Bcl-2 expression. Conclusions: Bcl-2 expression was a significant, independent determinant of biochemical control after neoadjuvant androgen deprivation and radical radiotherapy for prostate cancer. These data generate the hypothesis that Bcl-2 expression could be used to inform the choice of radiotherapy dose in individual patients.

  1. Hyperfractionated accelerated radiotherapy with concomitant integrated boost of 70-75 Gy in 5 weeks for advanced head and neck cancer. A phase I dose escalation study

    Energy Technology Data Exchange (ETDEWEB)

    Cvek, J.; Skacelikova, E.; Otahal, B.; Halamka, M.; Feltl, D. [University Hospital Ostrava (Czech Republic). Dept. of Oncology; Kubes, J. [University Hospital Bulovka, Prague (Czech Republic). Dept. of Radiation Oncology; Kominek, P. [University Hospital Ostrava (Czech Republic). Dept. of Otolaryngology

    2012-08-15

    Background and purpose: The present study was performed to evaluate the feasibility of a new, 5-week regimen of 70-75 Gy hyperfractionated accelerated radiotherapy with concomitant integrated boost (HARTCIB) for locally advanced, inoperable head and neck cancer. Methods and materials: A total of 39 patients with very advanced, stage IV nonmetastatic head and neck squamous cell carcinoma (median gross tumor volume 72 ml) were included in this phase I dose escalation study. A total of 50 fractions intensity-modulated radiotherapy (IMRT) were administered twice daily over 5 weeks. Prescribed total dose/dose per fraction for planning target volume (PTV{sub tumor}) were 70 Gy in 1.4 Gy fractions, 72.5 Gy in 1.45 Gy fractions, and 75 Gy in 1.5 Gy fractions for 10, 13, and 16 patients, respectively. Uninvolved lymphatic nodes (PTV{sub uninvolved}) were irradiated with 55 Gy in 1.1 Gy fractions using the concomitant integrated boost. Results: Acute toxicity was evaluated according to the RTOG/EORTC scale; the incidence of grade 3 mucositis was 51% in the oral cavity/pharynx and 0% in skin and the recovery time was {<=} 9 weeks for all patients. Late toxicity was evaluated in patients in complete remission according to the RTOG/EORTC scale. No grade 3/4 late toxicity was observed. The 1-year locoregional progression-free survival was 50% and overall survival was 55%. Conclusion: HARTCIB (75 Gy in 5 weeks) is feasible for patients deemed unsuitable for chemoradiation. Acute toxicity was lower than predicted from radiobiological models; duration of dysphagia and confluent mucositis were particularly short. Better conformity of radiotherapy allows the use of more intensive altered fractionation schedules compared with older studies. These results suggest that further dose escalation might be possible when highly conformal techniques (e.g., stereotactic radiotherapy) are used.

  2. Modelling normal tissue isoeffect distribution in conformal radiotherapy of glioblastoma provides an alternative dose escalation pattern through hypofractionation without reducing the total dose

    Energy Technology Data Exchange (ETDEWEB)

    Mangel, L.; Skriba, Z.; Major, T.; Polgar, C.; Fodor, J.; Somogyi, A.; Nemeth, G. [National Research Inst. for Radiobiology and Radiohygiene, Budapest (Hungary)

    2002-04-01

    The purpose of this study was to prove that by using conformal external beam radiotherapy (RT) normal brain structures can be protected even when applying an alternative approach of biological dose escalation: hypofractionation (HOF) without total dose reduction (TDR). Traditional 2-dimensional (2D) and conformal 3-dimensional (3D) treatment plans were prepared for 10 gliomas representing the subanatomical sites of the supratentorial brain. Isoeffect distributions were generated by the biologically effective dose (BED) formula to analyse the effect of conventionally fractionated (CF) and HOF schedules on both the spatial biological dose distribution and biological dose-volume histograms. A comparison was made between 2D-CF (2.0 Gy/day) and 3D-HOF (2.5 Gy/day) regimens, applying the same 60 Gy total doses. Integral biologically effective dose (IBED) and volumes received biologically equivalent to a dose of 54 Gy or more (V-BED54) were calculated for the lower and upper brain stem as organs of risk. The IBED values were lower with the 3D-HOF than with the 2D-CF schedule in each tumour location, means 22.7{+-}17.1 and 40.4{+-}16.9 in Gy, respectively (p<0.0001). The V-BED54 values were also smaller or equal in 90% of the cases favouring the 3D-HOF scheme. The means were 2.7{+-}4.8 ccm for 3D-HOF and 10.7{+-}12.7 ccm for 2D-CF (p=0.0006). Our results suggest that with conformal RT, fraction size can gradually be increased. HOF radiotherapy regimens without TDR shorten the treatment time and seem to be an alternative way of dose escalation in the treatment of glioblastoma.

  3. Double-blind, placebo-controlled food challenge with apple

    DEFF Research Database (Denmark)

    Skamstrup Hansen, K; Vestergaard, H; Stahl Skov, P

    2001-01-01

    The aim of the study was to develop and evaluate different methods of double-blind, placebo-controlled food challenge (DBPCFC) with apple. Three different DBPCFC models were evaluated: fresh apple juice, freshly grated apple, and freeze-dried apple powder. All challenges were performed outside...... frequency of reactions to placebo, probably due to the ingredients used for blinding. The sensitivity of the models with freshly grated apple and freeze-dried apple powder was 0.74/0.60. An increase in sensitivity is desirable. The freeze-dried apple powder proved to be useful for SPT, HR, and oral...

  4. Exploring the Effect of Lactium™ and Zizyphus Complex on Sleep Quality: A Double-Blind, Randomized Placebo-Controlled Trial

    Directory of Open Access Journals (Sweden)

    Andrew Scholey

    2017-02-01

    Full Text Available Acute, non-clinical insomnia is not uncommon. Sufferers commonly turn to short-term use of herbal supplements to alleviate the symptoms. This placebo-controlled, double-blind study investigated the efficacy of LZComplex3 (lactium™, Zizyphus, Humulus lupulus, magnesium and vitamin B6, in otherwise healthy adults with mild insomnia. After a 7-day single-blind placebo run-in, eligible volunteers (n = 171 were randomized (1:1 to receive daily treatment for 2 weeks with LZComplex3 or placebo. Results revealed that sleep quality measured by change in Pittsburgh Sleep Quality Index (PSQI score improved in both the LZComplex3 and placebo groups. There were no significant between group differences between baseline and endpoint on the primary outcome. The majority of secondary outcomes, which included daytime functioning and physical fatigue, mood and anxiety, cognitive performance, and stress reactivity, showed similar improvements in the LZComplex3 and placebo groups. A similar proportion of participants reported adverse events (AEs in both groups, with two of four treatment-related AEs in the LZComplex3 group resulting in permanent discontinuation. It currently cannot be concluded that administration of LZComplex3 for 2 weeks improves sleep quality, however, a marked placebo response (despite placebo run-in and/or short duration of treatment may have masked a potential beneficial effect on sleep quality.

  5. Treating locally advanced lung cancer with a 1.5T MR-Linac - Effects of the magnetic field and irradiation geometry on conventionally fractionated and isotoxic dose-escalated radiotherapy.

    Science.gov (United States)

    Bainbridge, Hannah E; Menten, Martin J; Fast, Martin F; Nill, Simeon; Oelfke, Uwe; McDonald, Fiona

    2017-11-01

    This study investigates the feasibility and potential benefits of radiotherapy with a 1.5T MR-Linac for locally advanced non-small cell lung cancer (LA NSCLC) patients. Ten patients with LA NSCLC were retrospectively re-planned six times: three treatment plans were created according to a protocol for conventionally fractionated radiotherapy and three treatment plans following guidelines for isotoxic target dose escalation. In each case, two plans were designed for the MR-Linac, either with standard (∼7mm) or reduced (∼3mm) planning target volume (PTV) margins, while one conventional linac plan was created with standard margins. Treatment plan quality was evaluated using dose-volume metrics or by quantifying dose escalation potential. All generated treatment plans fulfilled their respective planning constraints. For conventionally fractionated treatments, MR-Linac plans with standard margins had slightly increased skin dose when compared to conventional linac plans. Using reduced margins alleviated this issue and decreased exposure of several other organs-at-risk (OAR). Reduced margins also enabled increased isotoxic target dose escalation. It is feasible to generate treatment plans for LA NSCLC patients on a 1.5T MR-Linac. Margin reduction, facilitated by an envisioned MRI-guided workflow, enables increased OAR sparing and isotoxic target dose escalation for the respective treatment approaches. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  6. Treatment for non-thyroidal illness syndrome in advanced chronic kidney disease: a single-blind controlled study.

    Science.gov (United States)

    Yan, Wenjun; Wang, Lijuan; Huang, Tianlun; Xu, Gaosi

    2017-08-01

    Non-thyroidal illness syndrome (NTIS) is common among patients with advanced chronic kidney disease (CKD) and is strongly associated with poor prognosis. However, it remains unclear in how to correct this disorder and this study aimed to evaluate the effectiveness of sodium bicarbonate (SB) and N-acetyl-cysteine (NAC) for correcting NTIS status. Patients with CKD stage 3-4 were single-blind, placebo-controlled treated with placebo, SB, or NAC for 18 weeks. The primary end points were the correction of NTIS and the occurrence of end-stage renal disease (ESRD). The secondary point was the change in estimated glomerular filtration rate (eGFR) after the follow-up. The Kaplan-Meier survival analysis showed significant lower correcting ratio of NTIS in control group compared with SB group [Hazard ratio (HR) 0.19, 95 % confidence interval (CI) 0.04-0.89, p = 0.035] and NAC group (HR 0.09, 95 % CI 0.02-0.38, p = 0.001), and increased ESRD risk in control group than in SB group (HR 1.97, 95 % CI 1.02-3.84, p = 0.045) and NAC group (HR 5.50, 95 % CI 2.23-13.57, p < 0.001). The Cox regression analysis demonstrated significantly different effectiveness of placebo, SB and NAC on NTIS correction and ESRD risk, p < 0.05, respectively. Variance analysis displayed a greater reduction in eGFR in controls than in SB (p = 0.044) and NAC group (p < 0.001). SB and NAC are effective in promoting the recovery from NTIS status and delaying the deterioration of renal function in advanced CKD patients.

  7. Interim report of image-guided conformal high-dose-rate brachytherapy for patients with unfavorable prostate cancer: the William Beaumont Phase II dose-escalating trial

    International Nuclear Information System (INIS)

    Martinez, Alvaro A.; Kestin, Larry L.; Stromberg, Jannifer S.; Gonzalez, Jose A.; Wallace, Michelle; Gustafson, Gary S.; Edmundson, Gregory K.; Spencer, William; Vicini, Frank A.

    2000-01-01

    Purpose: We analyzed our institution's experience treating patients with unfavorable prostate cancer in a prospective Phase II dose-escalating trial of external beam radiation therapy (EBRT) integrated with conformal high-dose-rate (HDR) brachytherapy boosts. This interim report discusses treatment outcome and prognostic factors using this treatment approach. Methods and Materials: From November 1991 through February 1998, 142 patients with unfavorable prostate cancer were prospectively treated in a dose-escalating trial with pelvic EBRT in combination with outpatient HDR brachytherapy at William Beaumont Hospital. Patients with any of the following characteristics were eligible: pretreatment prostate-specific antigen (PSA) ≥ 10.0 ng/ml, Gleason score ≥ 7, or clinical stage T2b or higher. All patients received pelvic EBRT to a median total dose of 46.0 Gy. Pelvic EBRT was integrated with ultrasound-guided transperineal conformal interstitial iridium-192 HDR implants. From 1991 to 1995, 58 patients underwent three conformal interstitial HDR implants during the first, second, and third weeks of pelvic EBRT. After October 1995, 84 patients received two interstitial implants during the first and third weeks of pelvic EBRT. The dose delivered via interstitial brachytherapy was escalated from 5.50 Gy to 6.50 Gy for each implant in those patients receiving three implants, and subsequently, from 8.25 Gy to 9.50 Gy per fraction in those patients receiving two implants. To improve implant quality and reduce operator dependency, an on-line, image-guided interactive dose optimization program was utilized during each HDR implant. No patient received hormonal therapy unless treatment failure was documented. The median follow-up was 2.1 years (range: 0.2-7.2 years). Biochemical failure was defined according to the American Society for Therapeutic Radiology and Oncology Consensus Panel definition. Results: The pretreatment PSA level was ≥ 10.0 ng/ml in 51% of patients. The

  8. Effect of Standard vs Dose-Escalated Radiation Therapy for Patients With Intermediate-Risk Prostate Cancer: The NRG Oncology RTOG 0126 Randomized Clinical Trial.

    Science.gov (United States)

    Michalski, Jeff M; Moughan, Jennifer; Purdy, James; Bosch, Walter; Bruner, Deborah W; Bahary, Jean-Paul; Lau, Harold; Duclos, Marie; Parliament, Matthew; Morton, Gerard; Hamstra, Daniel; Seider, Michael; Lock, Michael I; Patel, Malti; Gay, Hiram; Vigneault, Eric; Winter, Kathryn; Sandler, Howard

    2018-03-15

    Optimizing radiation therapy techniques for localized prostate cancer can affect patient outcomes. Dose escalation improves biochemical control, but no prior trials were powered to detect overall survival (OS) differences. To determine whether radiation dose escalation to 79.2 Gy compared with 70.2 Gy would improve OS and other outcomes in prostate cancer. The NRG Oncology/RTOG 0126 randomized clinical trial randomized 1532 patients from 104 North American Radiation Therapy Oncology Group institutions March 2002 through August 2008. Men with stage cT1b to T2b, Gleason score 2 to 6, and prostate-specific antigen (PSA) level of 10 or greater and less than 20 or Gleason score of 7 and PSA less than 15 received 3-dimensional conformal radiation therapy or intensity-modulated radiation therapy to 79.2 Gy in 44 fractions or 70.2 Gy in 39 fractions. Time to OS measured from randomization to death due to any cause. American Society for Therapeutic Radiology and Oncology (ASTRO)/Phoenix definitions were used for biochemical failure. Acute (≤90 days of treatment start) and late radiation therapy toxic effects (>90 days) were graded using the National Cancer Institute Common Toxicity Criteria, version 2.0, and the RTOG/European Organisation for the Research and Treatment of Cancer Late Radiation Morbidity Scoring Scheme, respectively. With a median follow-up of 8.4 (range, 0.02-13.0) years in 1499 patients (median [range] age, 71 [33-87] years; 70% had PSA <10 ng/mL, 84% Gleason score of 7, 57% T1 disease), there was no difference in OS between the 751 men in the 79.2-Gy arm and the 748 men in the 70.2-Gy arm. The 8-year rates of OS were 76% with 79.2 Gy and 75% with 70.2 Gy (hazard ratio [HR], 1.00; 95% CI, 0.83-1.20; P = .98). The 8-year cumulative rates of distant metastases were 4% for the 79.2-Gy arm and 6% for the 70.2-Gy arm (HR, 0.65; 95% CI, 0.42-1.01; P = .05). The ASTRO and Phoenix biochemical failure rates at 5 and 8 years were 31% and 20% with 79.2 Gy

  9. SU-E-T-69: A Radiobiological Investigation of Dose Escalation in Lower Oesophageal Tumours with a Focus On Gastric Toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Carrington, R [Cardiff University, Cardiff, Wales (United Kingdom); Staffurth, J; Spezi, E; Crosby, T [Velindre Cancer Centre, Cardiff, Wales (United Kingdom); Warren, S; Partridge, M; Hawkins, M [CRUK/MRC Oxford Institute for Radiation Oncology, Oxford (United Kingdom); Gwynne, S [Singleton Hospital, Swansea, Wales (United Kingdom)

    2015-06-15

    The incidence of lower third oesophageal tumours is increasing in most Western populations. With the role of radiotherapy dose escalation being identified as a research priority in improving outcomes, it is important to quantify the increased toxicity that this may pose to sites such as the lower oesophagus. This study therefore aims to investigate the feasibility of lower oesophageal dose escalation with a focus on stomach tissue toxicity.The original 3D-conformal plans (50Gy3D) from 10 patients in the SCOPE1 trial were reviewed and compared to two RapidArc plans created retrospectively to represent the treatment arms of the forthcoming SCOPE2 trial: 50GyRA and 60GyRA (50Gy to PTV1 with a simultaneously integrated boost of 60Gy to PTV2). The stomach was contoured as stomach wall and dose constraints set according to QUANTEC. Normal tissue complication probability (NTCP) was estimated for the stomach wall for an endpoint of gastric bleeding. There was a mean increase of 5.93% in NTCP from 50Gy3D to 60GyRA and a mean increase of 8.15% in NTCP from the 50GyRA to 60GyRA. With NTCP modelling restricted to volumes outside PTV2, there was a mean decrease of 0.92% in NTCP from the 50Gy3D to 60GyRA, and a mean increase of 2.25% from 50GyRA to 60GyRA. There was a strong correlation between the NTCP and Stomach Wall/PTV1 overlap volume for all plans (R=0.80, 0.77 and 0.77 for 60GyRA, 50GyRA and 50Gy3D respectively). There was also a strong correlation between NTCP and the Stomach Wall/PTV2 overlap volume for 60GyRA (R= 0.82).Radiobiological modelling suggests that increasing the prescribed dose to 60Gy may be associated with a significantly increased risk of toxicity to the stomach within the boost volume. It is recommended that stomach toxicity be closely monitored prospectively when treating patients with lower oesophageal tumours in the forthcoming SCOPE 2 trial. Rhys Carrington received a PhD studentship grant from Cancer Research Wales. Grant number: 2445; Dr Warren and

  10. A Phase 1 Study of Stereotactic Body Radiation Therapy Dose Escalation for Borderline Resectable Pancreatic Cancer After Modified FOLFIRINOX (NCT01446458).

    Science.gov (United States)

    Shaib, Walid L; Hawk, Natalyn; Cassidy, Richard J; Chen, Zhengjia; Zhang, Chao; Brutcher, Edith; Kooby, David; Maithel, Shishir K; Sarmiento, Juan M; Landry, Jerome; El-Rayes, Bassel F

    2016-10-01

    A challenge in borderline resectable pancreatic cancer (BRPC) management is the high rate of positive posterior margins (PM). Stereotactic body radiation therapy (SBRT) allows for higher radiation delivery dose with conformity. This study evaluated the maximal tolerated dose with a dose escalation plan level up to 45 Gy using SBRT in BRPC. A single-institution, 3 + 3 phase 1 clinical trial design was used to evaluate 4 dose levels of SBRT delivered in 3 fractions to the planning target volume (PTV) with a simultaneous in-field boost (SIB) to the PM. Dose level (DL) 1 was 30 Gy to the PTV, and for dose levels 2 through 4 (DL2-DL4) the dose was 36 Gy. The SIB dose to the PM was 6, 6, 7.5, and 9 Gy for DL-1, DL-2, DL-3, and DL-4, respectively. All patients received 4 treatments of modified FOLFIRINOX (fluorouracil, leucovorin, irinotecan, oxaliplatin) before SBRT. Thirteen patients with a median age of 64 years were enrolled. The median follow-up time was 18 months. The locations of the cancer were head (n=12) and uncinate/neck (n=1). One patient did not undergo SBRT. There were no grade 3 or 4 toxicities. Five patients did not undergo resection because of disease progression (1 local, 4 distant); 8 had R0 resection in the PM, and 5 of 8 had vessel reconstruction. Two patients had disease downstaged to T1 and T2 from T3 disease. Four patients are still alive, and 3 are disease free. The median overall survival for resected patients was not reached (9.3: not reached). The SBRT dose of 36 Gy with a 9-Gy SIB to the PM (total 45 Gy) delivered in 3 fractions is safe and well tolerated. The dose-limiting toxicity for a 45-Gy dose was not reached, and further dose escalations are needed in future trials. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Somatostatin-based radiotherapy with [90Y-DOTA]-TOC in neuroendocrine tumors: long-term outcome of a phase I dose escalation study.

    Science.gov (United States)

    Marincek, Nicolas; Jörg, Ann-Catherine; Brunner, Philippe; Schindler, Christian; Koller, Michael T; Rochlitz, Christoph; Müller-Brand, Jan; Maecke, Helmut R; Briel, Matthias; Walter, Martin A

    2013-01-15

    We describe the long-term outcome after clinical introduction and dose escalation of somatostatin receptor targeted therapy with [90Y-DOTA]-TOC in patients with metastasized neuroendocrine tumors. In a clinical phase I dose escalation study we treated patients with increasing [90Y-DOTA]-TOC activities. Multivariable Cox regression and competing risk regression were used to compare efficacy and toxicities of the different dosage protocols. Overall, 359 patients were recruited; 60 patients were enrolled for low dose (median: 2.4 GBq/cycle, range 0.9-7.8 GBq/cycle), 77 patients were enrolled for intermediate dose (median: 3.3 GBq/cycle, range: 2.0-7.4 GBq/cycle) and 222 patients were enrolled for high dose (median: 6.7 GBq/cycle, range: 3.7-8.1 GBq/cycle) [90Y-DOTA]-TOC treatment. The incidences of hematotoxicities grade 1-4 were 65.0%, 64.9% and 74.8%; the incidences of grade 4/5 kidney toxicities were 8.4%, 6.5% and 14.0%, and the median survival was 39 (range: 1-158) months, 34 (range: 1-118) months and 29 (range: 1-113) months. The high dose protocol was associated with an increased risk of kidney toxicity (Hazard Ratio: 3.12 (1.13-8.59) vs. intermediate dose, p = 0.03) and a shorter overall survival (Hazard Ratio: 2.50 (1.08-5.79) vs. low dose, p = 0.03). Increasing [90Y-DOTA]-TOC activities may be associated with increasing hematological toxicities. The dose related hematotoxicity profile of [90Y-DOTA]-TOC could facilitate tailoring [90Y-DOTA]-TOC in patients with preexisting hematotoxicities. The results of the long-term outcome suggest that fractionated [90Y-DOTA]-TOC treatment might allow to reduce renal toxicity and to improve overall survival. (ClinicalTrials.gov number NCT00978211).

  12. Somatostatin-based radiotherapy with [90Y-DOTA]-TOC in neuroendocrine tumors: long-term outcome of a phase I dose escalation study

    Directory of Open Access Journals (Sweden)

    Marincek Nicolas

    2013-01-01

    Full Text Available Abstract Background We describe the long-term outcome after clinical introduction and dose escalation of somatostatin receptor targeted therapy with [90Y-DOTA]-TOC in patients with metastasized neuroendocrine tumors. Methods In a clinical phase I dose escalation study we treated patients with increasing [90Y-DOTA]-TOC activities. Multivariable Cox regression and competing risk regression were used to compare efficacy and toxicities of the different dosage protocols. Results Overall, 359 patients were recruited; 60 patients were enrolled for low dose (median: 2.4 GBq/cycle, range 0.9-7.8 GBq/cycle, 77 patients were enrolled for intermediate dose (median: 3.3 GBq/cycle, range: 2.0-7.4 GBq/cycle and 222 patients were enrolled for high dose (median: 6.7 GBq/cycle, range: 3.7-8.1 GBq/cycle [90Y-DOTA]-TOC treatment. The incidences of hematotoxicities grade 1–4 were 65.0%, 64.9% and 74.8%; the incidences of grade 4/5 kidney toxicities were 8.4%, 6.5% and 14.0%, and the median survival was 39 (range: 1–158 months, 34 (range: 1–118 months and 29 (range: 1–113 months. The high dose protocol was associated with an increased risk of kidney toxicity (Hazard Ratio: 3.12 (1.13-8.59 vs. intermediate dose, p = 0.03 and a shorter overall survival (Hazard Ratio: 2.50 (1.08-5.79 vs. low dose, p = 0.03. Conclusions Increasing [90Y-DOTA]-TOC activities may be associated with increasing hematological toxicities. The dose related hematotoxicity profile of [90Y-DOTA]-TOC could facilitate tailoring [90Y-DOTA]-TOC in patients with preexisting hematotoxicities. The results of the long-term outcome suggest that fractionated [90Y-DOTA]-TOC treatment might allow to reduce renal toxicity and to improve overall survival. (ClinicalTrials.gov number NCT00978211.

  13. Risk of Late Toxicity in Men Receiving Dose-Escalated Hypofractionated Intensity Modulated Prostate Radiation Therapy: Results From a Randomized Trial

    Energy Technology Data Exchange (ETDEWEB)

    Hoffman, Karen E., E-mail: khoffman1@mdanderson.org; Voong, K. Ranh; Pugh, Thomas J.; Skinner, Heath; Levy, Lawrence B.; Takiar, Vinita; Choi, Seungtaek; Du, Weiliang; Frank, Steven J.; Johnson, Jennifer; Kanke, James; Kudchadker, Rajat J.; Lee, Andrew K.; Mahmood, Usama; McGuire, Sean E.; Kuban, Deborah A.

    2014-04-01

    Objective: To report late toxicity outcomes from a randomized trial comparing conventional and hypofractionated prostate radiation therapy and to identify dosimetric and clinical parameters associated with late toxicity after hypofractionated treatment. Methods and Materials: Men with localized prostate cancer were enrolled in a trial that randomized men to either conventionally fractionated intensity modulated radiation therapy (CIMRT, 75.6 Gy in 1.8-Gy fractions) or to dose-escalated hypofractionated IMRT (HIMRT, 72 Gy in 2.4-Gy fractions). Late (≥90 days after completion of radiation therapy) genitourinary (GU) and gastrointestinal (GI) toxicity were prospectively evaluated and scored according to modified Radiation Therapy Oncology Group criteria. Results: 101 men received CIMRT and 102 men received HIMRT. The median age was 68, and the median follow-up time was 6.0 years. Twenty-eight percent had low-risk, 71% had intermediate-risk, and 1% had high-risk disease. There was no difference in late GU toxicity in men treated with CIMRT and HIMRT. The actuarial 5-year grade ≥2 GU toxicity was 16.5% after CIMRT and 15.8% after HIMRT (P=.97). There was a nonsignificant numeric increase in late GI toxicity in men treated with HIMRT compared with men treated with CIMRT. The actuarial 5-year grade ≥2 GI toxicity was 5.1% after CIMRT and 10.0% after HIMRT (P=.11). In men receiving HIMRT, the proportion of rectum receiving 36.9 Gy, 46.2 Gy, 64.6 Gy, and 73.9 Gy was associated with the development of late GI toxicity (P<.05). The 5-year actuarial grade ≥2 GI toxicity was 27.3% in men with R64.6Gy ≥ 20% but only 6.0% in men with R64.6Gy < 20% (P=.016). Conclusions: Dose-escalated IMRT using a moderate hypofractionation regimen (72 Gy in 2.4-Gy fractions) can be delivered safely with limited grade 2 or 3 late toxicity. Minimizing the proportion of rectum that receives moderate and high dose decreases the risk of late rectal toxicity after this

  14. Preliminary Results of a Phase 1 Dose-Escalation Trial for Early-Stage Breast Cancer Using 5-Fraction Stereotactic Body Radiation Therapy for Partial-Breast Irradiation

    International Nuclear Information System (INIS)

    Rahimi, Asal; Thomas, Kimberly; Spangler, Ann; Rao, Roshni; Leitch, Marilyn; Wooldridge, Rachel; Rivers, Aeisha; Seiler, Stephen; Albuquerque, Kevin; Stevenson, Stella; Goudreau, Sally; Garwood, Dan; Haley, Barbara; Euhus, David; Heinzerling, John; Ding, Chuxiong; Gao, Ang; Ahn, Chul; Timmerman, Robert

    2017-01-01

    Purpose: To evaluate the tolerability of a dose-escalated 5-fraction stereotactic body radiation therapy for partial-breast irradiation (S-PBI) in treating early-stage breast cancer after partial mastectomy; the primary objective was to escalate dose utilizing a robotic stereotactic radiation system treating the lumpectomy cavity without exceeding the maximum tolerated dose. Methods and Materials: Eligible patients included those with ductal carcinoma in situ or invasive nonlobular epithelial histologies and stage 0, I, or II, with tumor size <3 cm. Patients and physicians completed baseline and subsequent cosmesis outcome questionnaires. Starting dose was 30 Gy in 5 fractions and was escalated by 2.5 Gy total for each cohort to 40 Gy. Results: In all, 75 patients were enrolled, with a median age of 62 years. Median follow-up for 5 cohorts was 49.9, 42.5, 25.7, 20.3, and 13.5 months, respectively. Only 3 grade 3 toxicities were experienced. There was 1 dose-limiting toxicity in the overall cohort. Ten patients experienced palpable fat necrosis (4 of which were symptomatic). Physicians scored cosmesis as excellent or good in 95.9%, 100%, 96.7%, and 100% at baseline and 6, 12, and 24 months after S-PBI, whereas patients scored the same periods as 86.5%, 97.1%, 95.1%, and 95.3%, respectively. The disagreement rates between MDs and patients during those periods were 9.4%, 2.9%, 1.6%, and 4.7%, respectively. There have been no recurrences or distant metastases. Conclusion: Dose was escalated to the target dose of 40 Gy in 5 fractions, with the occurrence of only 1 dose-limiting toxicity. Patients felt cosmetic results improved within the first year after surgery and stereotactic body radiation therapy. Our results show minimal toxicity with excellent cosmesis; however, further follow-up is warranted in future studies. This study is the first to show the safety, tolerability, feasibility, and cosmesis results of a 5-fraction dose-escalated S-PBI treatment for

  15. Preliminary Results of a Phase 1 Dose-Escalation Trial for Early-Stage Breast Cancer Using 5-Fraction Stereotactic Body Radiation Therapy for Partial-Breast Irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Rahimi, Asal, E-mail: asal.rahimi@utsouthwestern.edu [University of Texas Southwestern Medical Center, Dallas, Texas (United States); Thomas, Kimberly; Spangler, Ann [University of Texas Southwestern Medical Center, Dallas, Texas (United States); Rao, Roshni; Leitch, Marilyn; Wooldridge, Rachel; Rivers, Aeisha [Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Seiler, Stephen [Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Albuquerque, Kevin; Stevenson, Stella [University of Texas Southwestern Medical Center, Dallas, Texas (United States); Goudreau, Sally [Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Garwood, Dan [University of Texas Southwestern Medical Center, Dallas, Texas (United States); Haley, Barbara [Department of Medical Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Euhus, David [Department of Surgery, Johns Hopkins University, Baltimore, Maryland (United States); Heinzerling, John [Department of Radiation Oncology, Levine Cancer Institute, Charlotte, North Carolina (United States); Ding, Chuxiong [University of Texas Southwestern Medical Center, Dallas, Texas (United States); Gao, Ang; Ahn, Chul [Department of Statistics, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Timmerman, Robert [University of Texas Southwestern Medical Center, Dallas, Texas (United States)

    2017-05-01

    Purpose: To evaluate the tolerability of a dose-escalated 5-fraction stereotactic body radiation therapy for partial-breast irradiation (S-PBI) in treating early-stage breast cancer after partial mastectomy; the primary objective was to escalate dose utilizing a robotic stereotactic radiation system treating the lumpectomy cavity without exceeding the maximum tolerated dose. Methods and Materials: Eligible patients included those with ductal carcinoma in situ or invasive nonlobular epithelial histologies and stage 0, I, or II, with tumor size <3 cm. Patients and physicians completed baseline and subsequent cosmesis outcome questionnaires. Starting dose was 30 Gy in 5 fractions and was escalated by 2.5 Gy total for each cohort to 40 Gy. Results: In all, 75 patients were enrolled, with a median age of 62 years. Median follow-up for 5 cohorts was 49.9, 42.5, 25.7, 20.3, and 13.5 months, respectively. Only 3 grade 3 toxicities were experienced. There was 1 dose-limiting toxicity in the overall cohort. Ten patients experienced palpable fat necrosis (4 of which were symptomatic). Physicians scored cosmesis as excellent or good in 95.9%, 100%, 96.7%, and 100% at baseline and 6, 12, and 24 months after S-PBI, whereas patients scored the same periods as 86.5%, 97.1%, 95.1%, and 95.3%, respectively. The disagreement rates between MDs and patients during those periods were 9.4%, 2.9%, 1.6%, and 4.7%, respectively. There have been no recurrences or distant metastases. Conclusion: Dose was escalated to the target dose of 40 Gy in 5 fractions, with the occurrence of only 1 dose-limiting toxicity. Patients felt cosmetic results improved within the first year after surgery and stereotactic body radiation therapy. Our results show minimal toxicity with excellent cosmesis; however, further follow-up is warranted in future studies. This study is the first to show the safety, tolerability, feasibility, and cosmesis results of a 5-fraction dose-escalated S-PBI treatment for

  16. [18F]fluoroethylcholine-PET/CT imaging for radiation treatment planning of recurrent and primary prostate cancer with dose escalation to PET/CT-positive lymph nodes

    Directory of Open Access Journals (Sweden)

    Wahl Andreas

    2011-05-01

    Full Text Available Abstract Background At present there is no consensus on irradiation treatment volumes for intermediate to high-risk primary cancers or recurrent disease. Conventional imaging modalities, such as CT, MRI and transrectal ultrasound, are considered suboptimal for treatment decisions. Choline-PET/CT might be considered as the imaging modality in radiooncology to select and delineate clinical target volumes extending the prostate gland or prostate fossa. In conjunction with intensity modulated radiotherapy (IMRT and imaged guided radiotherapy (IGRT, it might offer the opportunity of dose escalation to selected sites while avoiding unnecessary irradiation of healthy tissues. Methods Twenty-six patients with primary (n = 7 or recurrent (n = 19 prostate cancer received Choline-PET/CT planned 3D conformal or intensity modulated radiotherapy. The median age of the patients was 65 yrs (range 45 to 78 yrs. PET/CT-scans with F18-fluoroethylcholine (FEC were performed on a combined PET/CT-scanner equipped for radiation therapy planning. The majority of patients had intermediate to high risk prostate cancer. All patients received 3D conformal or intensity modulated and imaged guided radiotherapy with megavoltage cone beam CT. The median dose to primary tumours was 75.6 Gy and to FEC-positive recurrent lymph nodal sites 66,6 Gy. The median follow-up time was 28.8 months. Results The mean SUVmax in primary cancer was 5,97 in the prostate gland and 3,2 in pelvic lymph nodes. Patients with recurrent cancer had a mean SUVmax of 4,38. Two patients had negative PET/CT scans. At 28 months the overall survival rate is 94%. Biochemical relapse free survival is 83% for primary cancer and 49% for recurrent tumours. Distant disease free survival is 100% and 75% for primary and recurrent cancer, respectively. Acute normal tissue toxicity was mild in 85% and moderate (grade 2 in 15%. No or mild late side effects were observed in the majority of patients (84%. One patient had

  17. A Phase 1 Study of Stereotactic Body Radiation Therapy Dose Escalation for Borderline Resectable Pancreatic Cancer After Modified FOLFIRINOX (NCT01446458)

    International Nuclear Information System (INIS)

    Shaib, Walid L.; Hawk, Natalyn; Cassidy, Richard J.; Chen, Zhengjia; Zhang, Chao; Brutcher, Edith; Kooby, David; Maithel, Shishir K.; Sarmiento, Juan M.; Landry, Jerome; El-Rayes, Bassel F.

    2016-01-01

    Purpose: A challenge in borderline resectable pancreatic cancer (BRPC) management is the high rate of positive posterior margins (PM). Stereotactic body radiation therapy (SBRT) allows for higher radiation delivery dose with conformity. This study evaluated the maximal tolerated dose with a dose escalation plan level up to 45 Gy using SBRT in BRPC. Methods and Materials: A single-institution, 3 + 3 phase 1 clinical trial design was used to evaluate 4 dose levels of SBRT delivered in 3 fractions to the planning target volume (PTV) with a simultaneous in-field boost (SIB) to the PM. Dose level (DL) 1 was 30 Gy to the PTV, and for dose levels 2 through 4 (DL2-DL4) the dose was 36 Gy. The SIB dose to the PM was 6, 6, 7.5, and 9 Gy for DL-1, DL-2, DL-3, and DL-4, respectively. All patients received 4 treatments of modified FOLFIRINOX (fluorouracil, leucovorin, irinotecan, oxaliplatin) before SBRT. Results: Thirteen patients with a median age of 64 years were enrolled. The median follow-up time was 18 months. The locations of the cancer were head (n=12) and uncinate/neck (n=1). One patient did not undergo SBRT. There were no grade 3 or 4 toxicities. Five patients did not undergo resection because of disease progression (1 local, 4 distant); 8 had R0 resection in the PM, and 5 of 8 had vessel reconstruction. Two patients had disease downstaged to T1 and T2 from T3 disease. Four patients are still alive, and 3 are disease free. The median overall survival for resected patients was not reached (9.3: not reached). Conclusion: The SBRT dose of 36 Gy with a 9-Gy SIB to the PM (total 45 Gy) delivered in 3 fractions is safe and well tolerated. The dose-limiting toxicity for a 45-Gy dose was not reached, and further dose escalations are needed in future trials.

  18. Prostate-Specific Antigen (PSA) Bounce After Dose-Escalated External Beam Radiation Therapy Is an Independent Predictor of PSA Recurrence, Metastasis, and Survival in Prostate Adenocarcinoma Patients.

    Science.gov (United States)

    Romesser, Paul B; Pei, Xin; Shi, Weiji; Zhang, Zhigang; Kollmeier, Marisa; McBride, Sean M; Zelefsky, Michael J

    2018-01-01

    To evaluate the difference in prostate-specific antigen (PSA) recurrence-free, distant metastasis-free, overall, and cancer-specific survival between PSA bounce (PSA-B) and non-bounce patients treated with dose-escalated external beam radiation therapy (DE-EBRT). During 1990-2010, 1898 prostate adenocarcinoma patients were treated with DE-EBRT to ≥75 Gy with ≥5 years follow-up. Patients receiving neoadjuvant/concurrent androgen-deprivation therapy (n=1035) or with fewer than 4 PSA values obtained 6 months or more after post-EBRT completion (n=87) were excluded. The evaluable 776 patients were treated (median, 81.0 Gy). Prostate-specific antigen bounce was defined as a ≥0.2-ng/mL increase above the interval PSA nadir, followed by a decrease to nadir or below. Prostate-specific antigen relapse was defined as post-radiation therapy PSA nadir + 2 ng/mL. Median follow-up was 9.2 years (interquartile range, 6.9-11.3 years). One hundred twenty-three patients (15.9%) experienced PSA-B after DE-EBRT at a median of 24.6 months (interquartile range, 16.1-38.5 months). On multivariate analysis, younger age (P=.001), lower Gleason score (P=.0003), and higher radiation therapy dose (P=.0002) independently predicted PSA-B. Prostate-specific antigen bounce was independently associated with decreased risk for PSA relapse (hazard ratio [HR] 0.53; 95% confidence interval [CI] 0.33-0.85; P=.008), distant metastatic disease (HR 0.34; 95% CI 0.12-0.94; P=.04), and all-cause mortality (HR 0.53; 95% CI 0.29-0.96; P=.04) on multivariate Cox analysis. Because all 50 prostate cancer-specific deaths in patients without PSA-B were in the non-bounce cohort, competing-risks analysis was not applicable. A nonparametric competing-risks test demonstrated that patients with PSA-B had superior cancer-specific survival compared with patients without PSA-B (P=.004). Patients treated with dose-escalated radiation therapy for prostate adenocarcinoma who experience posttreatment PSA-B have

  19. Risk of Late Toxicity in Men Receiving Dose-Escalated Hypofractionated Intensity Modulated Prostate Radiation Therapy: Results From a Randomized Trial

    International Nuclear Information System (INIS)

    Hoffman, Karen E.; Voong, K. Ranh; Pugh, Thomas J.; Skinner, Heath; Levy, Lawrence B.; Takiar, Vinita; Choi, Seungtaek; Du, Weiliang; Frank, Steven J.; Johnson, Jennifer; Kanke, James; Kudchadker, Rajat J.; Lee, Andrew K.; Mahmood, Usama; McGuire, Sean E.; Kuban, Deborah A.

    2014-01-01

    Objective: To report late toxicity outcomes from a randomized trial comparing conventional and hypofractionated prostate radiation therapy and to identify dosimetric and clinical parameters associated with late toxicity after hypofractionated treatment. Methods and Materials: Men with localized prostate cancer were enrolled in a trial that randomized men to either conventionally fractionated intensity modulated radiation therapy (CIMRT, 75.6 Gy in 1.8-Gy fractions) or to dose-escalated hypofractionated IMRT (HIMRT, 72 Gy in 2.4-Gy fractions). Late (≥90 days after completion of radiation therapy) genitourinary (GU) and gastrointestinal (GI) toxicity were prospectively evaluated and scored according to modified Radiation Therapy Oncology Group criteria. Results: 101 men received CIMRT and 102 men received HIMRT. The median age was 68, and the median follow-up time was 6.0 years. Twenty-eight percent had low-risk, 71% had intermediate-risk, and 1% had high-risk disease. There was no difference in late GU toxicity in men treated with CIMRT and HIMRT. The actuarial 5-year grade ≥2 GU toxicity was 16.5% after CIMRT and 15.8% after HIMRT (P=.97). There was a nonsignificant numeric increase in late GI toxicity in men treated with HIMRT compared with men treated with CIMRT. The actuarial 5-year grade ≥2 GI toxicity was 5.1% after CIMRT and 10.0% after HIMRT (P=.11). In men receiving HIMRT, the proportion of rectum receiving 36.9 Gy, 46.2 Gy, 64.6 Gy, and 73.9 Gy was associated with the development of late GI toxicity (P<.05). The 5-year actuarial grade ≥2 GI toxicity was 27.3% in men with R64.6Gy ≥ 20% but only 6.0% in men with R64.6Gy < 20% (P=.016). Conclusions: Dose-escalated IMRT using a moderate hypofractionation regimen (72 Gy in 2.4-Gy fractions) can be delivered safely with limited grade 2 or 3 late toxicity. Minimizing the proportion of rectum that receives moderate and high dose decreases the risk of late rectal toxicity after this

  20. Long term results of a prospective dose escalation phase-II trial: Interstitial pulsed-dose-rate brachytherapy as boost for intermediate- and high-risk prostate cancer

    International Nuclear Information System (INIS)

    Lettmaier, Sebastian; Lotter, Michael; Kreppner, Stephan; Strnad, Annedore; Fietkau, Rainer; Strnad, Vratislav

    2012-01-01

    Purpose: We reviewed our seven year single institution experience with pulsed dose rate brachytherapy dose escalation study in patients with intermediate and high risk prostate cancer. Materials and methods: We treated a total of 130 patients for intermediate and high risk prostate cancer at our institution between 2000 and 2007 using PDR-brachytherapy as a boost after conformal external beam radiation therapy to 50.4 Gy. The majority of patients had T2 disease (T1c 6%, T2 75%, T3 19%). Seventy three patients had intermediate-risk and 53 patients had high-risk disease according to the D’Amico classification. The dose of the brachytherapy boost was escalated from 25 to 35 Gy – 33 pts. received 25 Gy (total dose 75 Gy), 63 pts. 30 Gy (total dose 80 Gy) and 34 pts. 35 Gy, (total dose 85 Gy) given in one session (dose per pulse was 0.60 Gy or 0.70 Gy/h, 24 h per day, night and day, with a time interval of 1 h between two pulses). PSA-recurrence-free survival according to Kaplan–Meier using the Phoenix definition of biochemical failure was calculated and also late toxicities according to Common Toxicity Criteria scale were assessed. Results: At the time of analysis with a median follow-up of 60 months biochemical control was achieved by 88% of patients – only 16/130 patients (12.3%) developed a biochemical relapse. Biochemical relapse free survival calculated according to Kaplan–Meier for all patients at 5 years was 85.6% (83.9% for intermediate-risk patients and 84.2% for high-risk patients) and at 9 years’ follow up it was 79.0%. Analysing biochemical relapse free survival separately for different boost dose levels, at 5 years it was 97% for the 35 Gy boost dose and 82% for the 25 and 30 Gy dose levels. The side effects of therapy were negligible: There were 18 cases (15%) of grade 1/2 rectal proctitis, one case (0.8%) of grade 3 proctitis, 18 cases (15%) of grade 1/2 cystitis, and no cases (0%) with dysuria grade 3. No patient had a bulbourethral

  1. The Percent of Positive Biopsy Cores Improves Prediction of Prostate Cancer-Specific Death in Patients Treated With Dose-Escalated Radiotherapy

    International Nuclear Information System (INIS)

    Qian Yushen; Feng, Felix Y.; Halverson, Schuyler; Blas, Kevin; Sandler, Howard M.; Hamstra, Daniel A.

    2011-01-01

    Purpose: To examine the prognostic utility of the percentage of positive cores (PPC) at the time of prostate biopsy for patients treated with dose-escalated external beam radiation therapy. Methods and Materials: We performed a retrospective analysis of patients treated at University of Michigan Medical Center to at least 75 Gy. Patients were stratified according to PPC by quartile, and freedom from biochemical failure (nadir + 2 ng/mL), freedom from metastasis (FFM), cause-specific survival (CSS), and overall survival (OS) were assessed by log-rank test. Receiver operator characteristic (ROC) curve analysis was used to determine the optimal cut point for PPC stratification. Finally, Cox proportional hazards multivariate regression was used to assess the impact of PPC on clinical outcome when adjusting for National Comprehensive Cancer Network (NCCN) risk group and androgen deprivation therapy. Results: PPC information was available for 651 patients. Increasing-risk features including T stage, prostate-specific antigen, Gleason score, and NCCN risk group were all directly correlated with increasing PPC. On log-rank evaluation, all clinical endpoints, except for OS, were associated with PPC by quartile, with worse clinical outcomes as PPC increased, with the greatest impact seen in the highest quartile (>66.7% of cores positive). ROC curve analysis confirmed that a cut point using two-thirds positive cores was most closely associated with CSS (p = 0.002; area under ROC curve, 0.71). On univariate analysis, stratifying patients according to PPC less than or equal to 66.7% vs. PPC greater than 66.7% was prognostic for freedom from biochemical failure (p = 0.0001), FFM (p = 0.0002), and CSS (p = 0.0003) and marginally prognostic for OS (p = 0.055). On multivariate analysis, after adjustment for NCCN risk group and androgen deprivation therapy use, PPC greater than 66.7% increased the risk for biochemical failure (p = 0.0001; hazard ratio [HR], 2.1 [95% confidence

  2. Cardiac Toxicity After Radiotherapy for Stage III Non–Small-Cell Lung Cancer: Pooled Analysis of Dose-Escalation Trials Delivering 70 to 90 Gy

    Science.gov (United States)

    Eblan, Michael J.; Deal, Allison M.; Lipner, Matthew; Zagar, Timothy M.; Wang, Yue; Mavroidis, Panayiotis; Lee, Carrie B.; Jensen, Brian C.; Rosenman, Julian G.; Socinski, Mark A.; Stinchcombe, Thomas E.; Marks, Lawrence B.

    2017-01-01

    Purpose The significance of radiotherapy (RT) –associated cardiac injury for stage III non–small-cell lung cancer (NSCLC) is unclear, but higher heart doses were associated with worse overall survival in the Radiation Therapy Oncology Group (RTOG) 0617 study. We assessed the impact of heart dose in patients treated at our institution on several prospective dose-escalation trials. Patients and Methods From 1996 to 2009, 127 patients with stage III NSCLC (Eastern Cooperative Oncology Group performance status, 0 to 1) received dose-escalated RT to 70 to 90 Gy (median, 74 Gy) in six trials. RT plans and cardiac doses were reviewed. Records were reviewed for the primary end point: symptomatic cardiac events (symptomatic pericardial effusion, acute coronary syndrome, pericarditis, significant arrhythmia, and heart failure). Cardiac risk was assessed by noting baseline coronary artery disease and calculating the WHO/International Society of Hypertension score. Competing risks analysis was used. Results In all, 112 patients were analyzed. Median follow-up for surviving patients was 8.8 years. Twenty-six patients (23%) had one or more events at a median of 26 months to first event (effusion [n = 7], myocardial infarction [n = 5], unstable angina [n = 3], pericarditis [n = 2], arrhythmia [n = 12], and heart failure [n = 1]). Heart doses (eg, heart mean dose; hazard ratio, 1.03/Gy; P = .002,), coronary artery disease (P < .001), and WHO/International Society of Hypertension score (P = .04) were associated with events on univariable analysis. Heart doses remained significant on multivariable analysis that accounted for baseline risk. Two-year competing risk–adjusted event rates for patients with heart mean dose < 10 Gy, 10 to 20 Gy, or ≥ 20 Gy were 4%, 7%, and 21%, respectively. Heart doses were not associated with overall survival. Conclusion Cardiac events were relatively common after high-dose thoracic RT and were independently associated with both heart dose and

  3. A Phase 1 Study of Stereotactic Body Radiation Therapy Dose Escalation for Borderline Resectable Pancreatic Cancer After Modified FOLFIRINOX (NCT01446458)

    Energy Technology Data Exchange (ETDEWEB)

    Shaib, Walid L.; Hawk, Natalyn [Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Cassidy, Richard J. [Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Chen, Zhengjia; Zhang, Chao [Department of Biostatistics, Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Brutcher, Edith [Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Kooby, David; Maithel, Shishir K.; Sarmiento, Juan M. [Department of Surgery, Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Landry, Jerome [Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); El-Rayes, Bassel F., E-mail: bassel.el-rayes@emoryhealthcare.org [Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia (United States)

    2016-10-01

    Purpose: A challenge in borderline resectable pancreatic cancer (BRPC) management is the high rate of positive posterior margins (PM). Stereotactic body radiation therapy (SBRT) allows for higher radiation delivery dose with conformity. This study evaluated the maximal tolerated dose with a dose escalation plan level up to 45 Gy using SBRT in BRPC. Methods and Materials: A single-institution, 3 + 3 phase 1 clinical trial design was used to evaluate 4 dose levels of SBRT delivered in 3 fractions to the planning target volume (PTV) with a simultaneous in-field boost (SIB) to the PM. Dose level (DL) 1 was 30 Gy to the PTV, and for dose levels 2 through 4 (DL2-DL4) the dose was 36 Gy. The SIB dose to the PM was 6, 6, 7.5, and 9 Gy for DL-1, DL-2, DL-3, and DL-4, respectively. All patients received 4 treatments of modified FOLFIRINOX (fluorouracil, leucovorin, irinotecan, oxaliplatin) before SBRT. Results: Thirteen patients with a median age of 64 years were enrolled. The median follow-up time was 18 months. The locations of the cancer were head (n=12) and uncinate/neck (n=1). One patient did not undergo SBRT. There were no grade 3 or 4 toxicities. Five patients did not undergo resection because of disease progression (1 local, 4 distant); 8 had R0 resection in the PM, and 5 of 8 had vessel reconstruction. Two patients had disease downstaged to T1 and T2 from T3 disease. Four patients are still alive, and 3 are disease free. The median overall survival for resected patients was not reached (9.3: not reached). Conclusion: The SBRT dose of 36 Gy with a 9-Gy SIB to the PM (total 45 Gy) delivered in 3 fractions is safe and well tolerated. The dose-limiting toxicity for a 45-Gy dose was not reached, and further dose escalations are needed in future trials.

  4. Somatostatin-based radiotherapy with [90Y-DOTA]-TOC in neuroendocrine tumors: long-term outcome of a phase I dose escalation study

    Science.gov (United States)

    2013-01-01

    Background We describe the long-term outcome after clinical introduction and dose escalation of somatostatin receptor targeted therapy with [90Y-DOTA]-TOC in patients with metastasized neuroendocrine tumors. Methods In a clinical phase I dose escalation study we treated patients with increasing [90Y-DOTA]-TOC activities. Multivariable Cox regression and competing risk regression were used to compare efficacy and toxicities of the different dosage protocols. Results Overall, 359 patients were recruited; 60 patients were enrolled for low dose (median: 2.4 GBq/cycle, range 0.9-7.8 GBq/cycle), 77 patients were enrolled for intermediate dose (median: 3.3 GBq/cycle, range: 2.0-7.4 GBq/cycle) and 222 patients were enrolled for high dose (median: 6.7 GBq/cycle, range: 3.7-8.1 GBq/cycle) [90Y-DOTA]-TOC treatment. The incidences of hematotoxicities grade 1–4 were 65.0%, 64.9% and 74.8%; the incidences of grade 4/5 kidney toxicities were 8.4%, 6.5% and 14.0%, and the median survival was 39 (range: 1–158) months, 34 (range: 1–118) months and 29 (range: 1–113) months. The high dose protocol was associated with an increased risk of kidney toxicity (Hazard Ratio: 3.12 (1.13-8.59) vs. intermediate dose, p = 0.03) and a shorter overall survival (Hazard Ratio: 2.50 (1.08-5.79) vs. low dose, p = 0.03). Conclusions Increasing [90Y-DOTA]-TOC activities may be associated with increasing hematological toxicities. The dose related hematotoxicity profile of [90Y-DOTA]-TOC could facilitate tailoring [90Y-DOTA]-TOC in patients with preexisting hematotoxicities. The results of the long-term outcome suggest that fractionated [90Y-DOTA]-TOC treatment might allow to reduce renal toxicity and to improve overall survival. Trial registration ClinicalTrials.gov number:NCT00978211 PMID:23320604

  5. Safety of polyethylene glycol 3350 solution in chronic constipation: randomized, placebo-controlled trial

    Directory of Open Access Journals (Sweden)

    McGraw T

    2016-07-01

    Full Text Available Thomas McGraw Global Medical Affairs, Merck & Co., Inc., Kenilworth, NJ, USA Purpose: To evaluate the safety and tolerability of aqueous solution concentrate (ASC of polyethylene glycol (PEG 3350 in patients with functional constipation.Patients and methods: The patients who met Rome III diagnostic criteria for functional constipation were randomized in this multicenter, randomized, placebo-controlled, single-blind study to receive once daily dose of PEG 3350 (17 g ASC or placebo solution for 14 days. The study comprised a screening period (visit 1, endoscopy procedure (visits 2 and 3, and follow-up telephone calls 30 days post-treatment. Safety end points included adverse events (AEs, clinical laboratory evaluations, vital signs, and others. The primary end points were the proportion of patients with abnormalities of the oral and esophageal mucosa, detected by visual and endoscopic examination of the oral cavity and esophagus, respectively, compared with placebo. A secondary objective was to compare the safety and tolerability of ASC by evaluating AEs or adverse drug reactions.Results: A total of 65 patients were enrolled in this study, 31 were randomized to PEG 3350 ASC and 34 were randomized to placebo, of which 62 patients completed the study. No patients in either group showed abnormalities in inflammation of the oral mucosa during visit 2 (before treatment or visit 3 (after treatment. Fewer abnormalities of the esophageal mucosa were observed in the PEG 3350 ASC group than in the placebo group on visit 3, with no significant difference in the proportion of abnormalities between the treatment groups. Overall, 40 treatment-emergent AEs were observed in 48.4% of patients treated with PEG 3350 ASC, and 41 treatment-emergent AEs were observed in 55.9% of patients treated with placebo – nonsignificant difference of -7.5% (95% CI: -21.3, 6.3 between treatment groups. No serious AEs or deaths were reported, and no patient discontinued because

  6. Double-blind, placebo controlled food challenge with apple

    DEFF Research Database (Denmark)

    Hansen, K.S.; Vestergaard, H.S.; Skov, P.S.

    2001-01-01

    The aim of the study was to develop and evaluate different methods of double-blind, placebo-controlled food challenge (DBPCFC) with apple. Three different DBPCFC models were evaluated: fresh apple juice, freshly grated apple, and freeze-dried apple powder. All challenges were performed outside...... the pollen season and took place from 1997 to 1999. The freeze-dried apple material was characterized by means of leukocyte histamine release (HR), skin prick test (SPT), and immunoblotting experiments. The study population consisted of birch pollen-allergic patients with a history of rhinitis in the birch......-pollen season and positive specific IgE to birch. For comparison of the DBPCFC models, 65 patients with a positive open oral challenge with apple were selected. In the characterization of the freeze-dried apple material, 46 birch pollen-allergic patients were included. The IgE reactivity to apple was evaluated...

  7. Deep inspiration breath-hold technique for lung tumors: the potential value of target immobilization and reduced lung density in dose escalation

    International Nuclear Information System (INIS)

    Hanley, J.; Debois, M.M.; Raben, A.; Mageras, G.S.; Lutz, W.R.; Mychalczak, B.; Schwartz, L.H.; Gloeggler, P.J.; Leibel, S.A.; Fuks, Z.; Kutcher, G.J.

    1996-01-01

    Purpose/Objective: Lung tumors are subject to movement due to respiratory motion. Conventionally, a margin is applied to the clinical target volume (CTV) to account for this and other treatment uncertainties. The purpose of this study is to evaluate the dosimetric benefits of a deep inspiration breath-hold (DIBH) technique which has two distinct features - deep inspiration which reduces lung density and breath-hold which immobilizes lung tumors. Both properties can potentially reduce the mass of normal lung tissue in the high dose region, thus improving the possibility of dose escalation. Methods and Materials: To study the efficacy of the DIBH technique, CT scans are acquired for each patient under 4 respiration conditions: free-breathing; DIBH; shallow inspiration breath-hold; shallow expiration breath-hold. The free-breathing and DIBH scans are used to generate treatment plans for comparison of standard and DIBH techniques, while the shallow inspiration and expiration scans provide information on the maximum extent of tumor motion under free-breathing conditions. To acquire the breath-hold scans, the patients are brought to reproducible respiration levels using spirometry and slow vital capacity maneuvers. For the treatment plan comparison free-breathing and DIBH planning target volumes (PTVs) are constructed consisting of the CTV plus a margin for setup error and lung tumor motion. For both plans the margin for setup error is the same while the margin for lung tumor motion differs. The margin for organ motion in free-breathing is determined by the maximum tumor excursions in the shallow inspiration and expiration CT scans. For the DIBH, tumor motion is reduced to the extent to which DIBH can be maintained and the margin for any residual tumor motion is determined from repeat fluoroscopic movies, acquired with the patient monitored using spirometry. Three-dimensional treatment plans, generated using apertures based on the free-breathing and DIBH PTVs, are

  8. Radiotherapy boost dose-escalation for invasive breast cancer after breast-conserving surgery: 2093 Patients treated with a prospective margin-directed policy

    International Nuclear Information System (INIS)

    Livi, Lorenzo; Meattini, Icro; Franceschini, Davide; Saieva, Calogero; Meacci, Fiammetta; Marrazzo, Livia; Gerlain, Elena; Desideri, Isacco; Scotti, Vieri; Nori, Jacopo; Sanchez, Luis Jose; Orzalesi, Lorenzo; Bonomo, Pierluigi; Greto, Daniela; Bianchi, Simonetta; Biti, Giampaolo

    2013-01-01

    Purpose: To investigate the outcome of invasive early breast cancer patients that underwent breast-conserving surgery and adjuvant radiotherapy (RT), treated with a prospective margin-directed institutional policy for RT boost dose, based on final margins status (FMS). Methods and materials: A total of 2093 patients were treated between 2000 and 2008. 10 Gy boost was prescribed in case of FMS > 5 mm; 16 Gy boost with FMS between 2 and 5 mm; 20 Gy boost in case of FMS 5 mm. At multivariate analysis, higher nuclear grade (p = 0.045), triple negative subtype (p = 0.036) and higher T-stage (p = 0.02) resulted as the independent predictors of LR occurrence. Conclusions: Our experience showed that a margin-directed policy of RT boost dose-escalation seems to reduce the negative impact of FMS on LR, but it is not able to overcome the unfavorable effect of higher nuclear grade, higher T stage and triple negative subtype

  9. Safety of dose escalation by simultaneous integrated boosting radiation dose within the primary tumor guided by 18FDG-PET/CT for esophageal cancer

    International Nuclear Information System (INIS)

    Yu, Wen; Cai, Xu-Wei; Liu, Qi; Zhu, Zheng-Fei; Feng, Wen; Zhang, Qin; Zhang, Ying-Jian; Yao, Zhi-Feng; Fu, Xiao-Long

    2015-01-01

    Purpose: To observe the safety of selective dose boost to the pre-treatment high 18 F-deoxyglucose (FDG) uptake areas of the esophageal GTV. Methods: Patients with esophageal squamous cell carcinoma were treated with escalating radiation dose of 4 levels, with a simultaneous integrated boost (SIB) to the pre-treatment 50% SUVmax area of the primary tumor. Patients received 4 monthly cycles of cisplatin and fluorouracil. Dose-limiting toxicity (DLT) was defined as any Grade 3 or higher acute toxicities causing continuous interruption of radiation for over 1 week. Results: From April 2012 to February 2014, dose has been escalated up to LEVEL 4 (70 Gy). All of the 25 patients finished the prescribed dose without DLT, and 10 of them developed Grade 3 acute esophagitis. One patient of LEVEL 2 died of esophageal hemorrhage within 1 month after completion of radiotherapy, which was not definitely correlated with treatment yet. Late toxicities remained under observation. With median follow up of 8.9 months, one-year overall survival and local control was 69.2% and 77.4%, respectively. Conclusions: Dose escalation in esophageal cancer based on 18 FDG-PET/CT has been safely achieved up to 70 Gy using the SIB technique. Acute toxicities were well tolerated, whereas late toxicities and long-term outcomes deserved further observation

  10. A Phase I-II dose escalation study of fixed-dose rate gemcitabine, oxaliplatin and capecitabine every two weeks in advanced cholangiocarcinomas

    DEFF Research Database (Denmark)

    Lassen, Ulrik V; Jensen, Lars Henrik; Sorensen, Morten

    2011-01-01

    (O) and capecitabine (C), and evaluate the safety and efficacy of this regimen in patients with advanced cholangiocarcinoma (CC). Methods. In the Phase I part of the study a dose-escalation schedule of FDR G, O and C, administered every two weeks, was performed in patients with solid tumours...... and no other treatments or advanced CC. In the Phase II part response rate, toxicity, progression-free survival (PFS) and overall survival was evaluated in patients with newly diagnosed advanced CC. Results. Thirty-six patients entered the Phase I part and G 1 000 mg/m(2) day 1 and 15, O 60 mg/m(2) day 1...... and 15, and C 1 000 mg/m(2) BID day 1-7 and day 15-21 were established as MTD. In the Phase II part, 41 patients with advanced CC were included. Overall response rate was 34% and 51% had stable disease, resulting in a clinical benefit rate of 85%. Grade III and IV adverse events were rare. Median...

  11. A multicenter dose-escalation study of the analgesic and adverse effects of an oral cannabis extract (Cannador) for postoperative pain management.

    Science.gov (United States)

    Holdcroft, Anita; Maze, Mervyn; Doré, Caroline; Tebbs, Susan; Thompson, Simon

    2006-05-01

    Cannabinoids have dose-related antinociceptive effects in animals. This clinical study aimed to investigate whether a single oral dose of cannabis plant extract (Cannador; Institute for Clinical Research, IKF, Berlin, Germany) could provide pain relief with minimal side effects for postoperative pain. Patients (aged 18-75 yr) were recruited and consented before surgery if patient-controlled analgesia was planned for provision of postoperative pain relief. Each patient received a single dose of 5, 10, or 15 mg Cannador if he or she had at least moderate pain after stopping patient-controlled analgesia. Starting with 5 mg, dose escalation was based on the number of patients requesting rescue analgesia and adverse effects. Pain relief, pain intensity, and side effects were recorded over 6 h and analyzed using tests for trend with dose. Rescue analgesia was requested by all 11 patients (100%) receiving 5 mg, 15 of 30 patient (50%) receiving 10 mg, and 6 of 24 patients (25%) receiving 15 mg Cannador (log rank test for trend in time to rescue analgesia with dose P analgesics without frequent adverse effects.

  12. Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial.

    Science.gov (United States)

    Heery, Christopher R; O'Sullivan-Coyne, Geraldine; Madan, Ravi A; Cordes, Lisa; Rajan, Arun; Rauckhorst, Myrna; Lamping, Elizabeth; Oyelakin, Israel; Marté, Jennifer L; Lepone, Lauren M; Donahue, Renee N; Grenga, Italia; Cuillerot, Jean-Marie; Neuteboom, Berend; Heydebreck, Anja von; Chin, Kevin; Schlom, Jeffrey; Gulley, James L

    2017-05-01

    Avelumab (MSB0010718C) is a human IgG1 monoclonal antibody that binds to PD-L1, inhibiting its binding to PD-1, which inactivates T cells. We aimed to establish the safety and pharmacokinetics of avelumab in patients with solid tumours while assessing biological correlatives for future development. This open-label, single-centre, phase 1a, dose-escalation trial (part of the JAVELIN Solid Tumor trial) assessed four doses of avelumab (1 mg/kg, 3 mg/kg, 10 mg/kg, and 20 mg/kg), with dose-level cohort expansions to provide additional safety, pharmacokinetics, and target occupancy data. This study used a standard 3 + 3 cohort design and assigned patients sequentially at trial entry according to the 3 + 3 dose-escalation algorithm and depending on the number of dose-limiting toxicities during the first 3-week assessment period (the primary endpoint). Patient eligibility criteria included age 18 years or older, Eastern Cooperative Oncology Group performance status 0-1, metastatic or locally advanced previously treated solid tumours, and adequate end-organ function. Avelumab was given as a 1-h intravenous infusion every 2 weeks. Patients in the dose-limiting toxicity analysis set were assessed for the primary endpoint of dose-limiting toxicity, and all patients enrolled in the dose-escalation part were assessed for the secondary endpoints of safety (treatment-emergent and treatment-related adverse events according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0), pharmacokinetic and pharmacodynamic profiles (immunological effects), best overall response by Response Evaluation Criteria, and antidrug antibody formation. The population for the pharmacokinetic analysis included a subset of patients with rich pharmacokinetic samples from two selected disease-specific expansion cohorts at the same study site who had serum samples obtained at multiple early timepoints. This trial is registered with ClinicalTrials.gov, number NCT

  13. Predictors of Rectal Tolerance Observed in a Dose-Escalated Phase 1-2 Trial of Stereotactic Body Radiation Therapy for Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Kim, D.W. Nathan [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Cho, L. Chinsoo [Department of Radiation Oncology, University of Minnesota, Minneapolis, Minnesota (United States); Straka, Christopher [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Christie, Alana [Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Lotan, Yair [Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Pistenmaa, David [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Kavanagh, Brian D. [Department of Radiation Oncology, University of Colorado, Denver, Colorado (United States); Nanda, Akash [Department of Radiation Oncology, University of Florida Health Cancer Center at Orlando Health, Orlando, Florida (United States); Kueplian, Patrick [Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, California (United States); Brindle, Jeffrey [Prairie Lakes Hospital, Watertown, South Dakota (United States); Cooley, Susan; Perkins, Alida [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Raben, David [Department of Radiation Oncology, University of Colorado, Denver, Colorado (United States); Xie, Xian-Jin [Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Timmerman, Robert D., E-mail: robert.timmerman@utsouthwestern.edu [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States)

    2014-07-01

    Purpose: To convey the occurrence of isolated cases of severe rectal toxicity at the highest dose level tested in 5-fraction stereotactic body radiation therapy (SBRT) for localized prostate cancer; and to rationally test potential causal mechanisms to guide future studies and experiments to aid in mitigating or altogether avoiding such severe bowel injury. Methods and Materials: Clinical and treatment planning data were analyzed from 91 patients enrolled from 2006 to 2011 on a dose-escalation (45, 47.5, and 50 Gy in 5 fractions) phase 1/2 clinical study of SBRT for localized prostate cancer. Results: At the highest dose level, 6.6% of patients treated (6 of 91) developed high-grade rectal toxicity, 5 of whom required colostomy. Grade 3+ delayed rectal toxicity was strongly correlated with volume of rectal wall receiving 50 Gy >3 cm{sup 3} (P<.0001), and treatment of >35% circumference of rectal wall to 39 Gy (P=.003). Grade 2+ acute rectal toxicity was significantly correlated with treatment of >50% circumference of rectal wall to 24 Gy (P=.010). Conclusion: Caution is advised when considering high-dose SBRT for treatment of tumors near bowel structures, including prostate cancer. Threshold dose constraints developed from physiologic principles are defined, and if respected can minimize risk of severe rectal toxicity.

  14. Stereotactic Body Radiotherapy for Recurrent Squamous Cell Carcinoma of the Head and Neck: Results of a Phase I Dose-Escalation Trial

    International Nuclear Information System (INIS)

    Heron, Dwight E.; Ferris, Robert L.; Karamouzis, Michalis; Andrade, Regiane S.; Deeb, Erin L.; Burton, Steven; Gooding, William E.; Branstetter, Barton F.; Mountz, James M.; Johnson, Jonas T.; Argiris, Athanassios; Grandis, Jennifer R.; Lai, Stephen Y.

    2009-01-01

    Purpose: To evaluate the safety and efficacy of stereotactic body radiotherapy (SBRT) in previously irradiated patients with squamous cell carcinoma of the head and neck (SCCHN). Patients and Methods: In this Phase I dose-escalation clinical trial, 25 patients were treated in five dose tiers up to 44 Gy, administered in 5 fractions over a 2-week course. Response was assessed according to the Response Evaluation Criteria in Solid Tumors and [ 18 F]-fluorodeoxyglucose standardized uptake value change on positron emission tomography-computed tomography (PET-CT). Results: No Grade 3/4 or dose-limiting toxicities occurred. Four patients had Grade 1/2 acute toxicities. Four objective responses were observed, for a response rate of 17% (95% confidence interval 2%-33%). The maximum duration of response was 4 months. Twelve patients had stable disease. Median time to disease progression was 4 months, and median overall survival was 6 months. Self-reported quality of life was not significantly affected by treatment. Fluorodeoxyglucose PET was a more sensitive early-measure response to treatment than CT volume changes. Conclusion: Reirradiation up to 44 Gy using SBRT is well tolerated in the acute setting and warrants further evaluation in combination with conventional and targeted therapies.

  15. WE-G-BRB-02: The Role of Program Project Grants in Study of 3D Conformal Therapy, Dose Escalation and Motion Management

    International Nuclear Information System (INIS)

    Fraass, B.

    2015-01-01

    Over the past 20 years the NIH has funded individual grants, program projects grants, and clinical trials which have been instrumental in advancing patient care. The ways that each grant mechanism lends itself to the different phases of translating research into clinical practice will be described. Major technological innovations, such as IMRT and proton therapy, have been advanced with R01-type and P01-type funding and will be discussed. Similarly, the role of program project grants in identifying and addressing key hypotheses on the potential of 3D conformal therapy, normal tissue-guided dose escalation and motion management will be described. An overview will be provided regarding how these technological innovations have been applied to multi-institutional NIH-sponsored trials. Finally, the panel will discuss regarding which research questions should be funded by the NIH to inspire the next advances in radiation therapy. Learning Objectives: Understand the different funding mechanisms of the NIH Learn about research advances that have led to innovation in delivery Review achievements due to NIH-funded program project grants in radiotherapy over the past 20 years Understand example advances achieved with multi-institutional clinical trials NIH

  16. Phase I dose-escalation and pharmacokinetic study (TED 11576) of cabazitaxel in Japanese patients with castration-resistant prostate cancer.

    Science.gov (United States)

    Mukai, Hirofumi; Takahashi, Shunji; Nozawa, Masahiro; Onozawa, Yusuke; Miyazaki, Jun; Ohno, Keiji; Suzuki, Kazuhiro

    2014-04-01

    The purpose of the study is to analyze the pharmacokinetic (PK) profile of cabazitaxel and evaluate its safety and tolerability as a 1-h IV infusion every 3 weeks in Japanese patients with castration-resistant prostate cancer (CRPC). Seventeen patients were treated with cabazitaxel at doses of 20 and 25 mg/m(2) for PK analyses. Dose escalation was performed only in the absence of dose-limiting toxicity (DLT). The maximum tolerated dose (MTD) was the highest dose at which less than 33 % of the patients developed DLT. Cabazitaxel exhibited a triphasic elimination profile with a long terminal half-life of 116 ± 29.0 or 113 ± 28.0 h after IV infusion of 20 or 25 mg/m(2) cabazitaxel, respectively. The major differences in the PK parameters of cabazitaxel and docetaxel were cabazitaxel's fairly high clearance rate, representing approximately half the hepatic flow, and its large volume of distribution at steady-state conditions. No DLT was observed during Cycle 1. Mild-to-moderate hematological adverse events (AEs), including neutropenia, and other AEs typically associated with taxanes were observed; all AEs were manageable. Cabazitaxel at 25 mg/m(2) every 3 weeks was selected as the MTD in Japanese patients. The PK parameters of cabazitaxel in Japanese CRPC patients were comparable with those previously determined in Caucasian subjects. The safety and tolerability of cabazitaxel were also comparable in both ethnic populations.

  17. Radiation dose escalation or longer androgen suppression for locally advanced prostate cancer? Data from the TROG 03.04 RADAR trial

    International Nuclear Information System (INIS)

    Denham, James W.; Steigler, Allison; Joseph, David; Lamb, David S.; Spry, Nigel A.; Duchesne, Gillian; Atkinson, Chris; Matthews, John; Turner, Sandra; Kenny, Lizbeth; Tai, Keen-Hun; Gogna, Nirdosh Kumar; Gill, Suki; Tan, Hendrick; Kearvell, Rachel; Murray, Judy; Ebert, Martin; Haworth, Annette; Kennedy, Angel; Delahunt, Brett

    2015-01-01

    Background: The relative effects of radiation dose escalation (RDE) and androgen suppression (AS) duration on local prostatic progression (LP) remain unclear. Methods: We addressed this in the TROG 03.04 RADAR trial by incorporating a RDE programme by stratification at randomisation. Men were allocated 6 or 18 months AS ± 18 months zoledronate (Z). The main endpoint was a composite of clinically diagnosed LP or PSA progression with a PSA doubling time ⩾6 months. Fine and Gray competing risk modelling with adjustment for site clustering produced cumulative incidence estimates at 6.5 years for each RDE group. Results: Composite LP declined coherently in the 66, 70 and 74 Gy external beam dosing groups and was lowest in the high dose rate brachytherapy boost (HDRB) group. At 6.5 years, adjusted cumulative incidences were 22%, 15%, 13% and 7% respectively. Compared to 6 months AS, 18 months AS also significantly reduced LP (p < 0.001). Post-radiation urethral strictures were documented in 45 subjects and increased incrementally in the dosing groups. Crude incidences were 0.8%, 0.9%, 3.8% and 12.7% respectively. Conclusion: RDE and increasing AS independently reduce LP and increase urethral strictures. The risks and benefits to the individual must be balanced when selecting radiation dose and AS duration

  18. Radiation dose escalation or longer androgen suppression for locally advanced prostate cancer? Data from the TROG 03.04 RADAR trial.

    Science.gov (United States)

    Denham, James W; Steigler, Allison; Joseph, David; Lamb, David S; Spry, Nigel A; Duchesne, Gillian; Atkinson, Chris; Matthews, John; Turner, Sandra; Kenny, Lizbeth; Tai, Keen-Hun; Gogna, Nirdosh Kumar; Gill, Suki; Tan, Hendrick; Kearvell, Rachel; Murray, Judy; Ebert, Martin; Haworth, Annette; Kennedy, Angel; Delahunt, Brett; Oldmeadow, Christopher; Holliday, Elizabeth G; Attia, John

    2015-06-01

    The relative effects of radiation dose escalation (RDE) and androgen suppression (AS) duration on local prostatic progression (LP) remain unclear. We addressed this in the TROG 03.04 RADAR trial by incorporating a RDE programme by stratification at randomisation. Men were allocated 6 or 18 months AS±18 months zoledronate (Z). The main endpoint was a composite of clinically diagnosed LP or PSA progression with a PSA doubling time ⩾6 months. Fine and Gray competing risk modelling with adjustment for site clustering produced cumulative incidence estimates at 6.5 years for each RDE group. Composite LP declined coherently in the 66, 70 and 74 Gy external beam dosing groups and was lowest in the high dose rate brachytherapy boost (HDRB) group. At 6.5 years, adjusted cumulative incidences were 22%, 15%, 13% and 7% respectively. Compared to 6 months AS, 18 months AS also significantly reduced LP (pRDE and increasing AS independently reduce LP and increase urethral strictures. The risks and benefits to the individual must be balanced when selecting radiation dose and AS duration. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  19. Dose-escalated intensity-modulated radiotherapy and irradiation of subventricular zones in relation to tumor control outcomes of patients with glioblastoma multiforme

    Directory of Open Access Journals (Sweden)

    Kusumawidjaja G

    2016-03-01

    Full Text Available Grace Kusumawidjaja,1 Patricia Zhun Hong Gan,1 Whee Sze Ong,2 Achiraya Teyateeti,3 Pittaya Dankulchai,3 Daniel Yat Harn Tan,1 Eu Tiong Chua,1 Kevin Lee Min Chua,1 Chee Kian Tham,4 Fuh Yong Wong,1 Melvin Lee Kiang Chua1,5 1Division of Radiation Oncology, National Cancer Centre, Singapore; 2Division of Clinical Trials and Epidemiological Sciences, National Cancer Centre, Singapore; 3Department of Radiology, Division of Radiation Oncology, Faculty of Medicine Siriraj Hospital, Mahidol University, Thailand; 4Division of Medical Oncology, National Cancer Centre, Singapore; 5Duke-NUS Graduate Medical School, Singapore Background: Glioblastoma multiforme (GBM is the most aggressive primary brain tumor with high relapse rate. In this study, we aimed to determine if dose-escalated (DE radiotherapy improved tumor control and survival in GBM patients. Methods: We conducted a retrospective analysis of 49 and 23 newly-diagnosed histology-proven GBM patients, treated with DE radiotherapy delivered in 70 Gy (2.33 Gy per fraction and conventional doses (60 Gy, respectively, between 2007 and 2013. Clinical target volumes for 70 and 60 Gy were defined by 0.5 and 2.0 cm expansion of magnetic resonance imaging T1-gadolinium-enhanced tumor/surgical cavity, respectively. Bilateral subventricular zones (SVZ were contoured on a co-registered pre-treatment magnetic resonance imaging and planning computed tomography dataset as a 5 mm wide structure along the lateral margins of the lateral ventricles. Survival outcomes of both cohorts were compared using log-rank test. Radiation dose to SVZ in the DE cohort was evaluated. Results: Median follow-up was 13.6 and 15.1 months for the DE- and conventionally-treated cohorts, respectively. Median overall survival (OS of patients who received DE radiotherapy was 15.2 months (95% confidence interval [CI] =11.0–18.6, while median OS of the latter cohort was 18.4 months (95% CI =12.5–31.4, P=0.253. Univariate analyses of

  20. Long-term outcomes from dose-escalated image-guided intensity-modulated radiotherapy with androgen deprivation: encouraging results for intermediate- and high-risk prostate cancer

    Directory of Open Access Journals (Sweden)

    Wilcox SW

    2014-08-01

    Full Text Available Shea W Wilcox,1,4 Noel J Aherne,2,4 Linus C Benjamin,1 Bosco Wu,1 Thomaz de Campos Silva,3 Craig S McLachlan,4 Michael J McKay,3,5 Andrew J Last,1 Thomas P Shakespeare1–4 1North Coast Cancer Institute, Port Macquarie, NSW, Australia; 2North Coast Cancer Institute, Coffs Harbour, NSW, Australia; 3North Coast Cancer Institute, Lismore, NSW, Australia; 4The University of New South Wales, Rural Clinical School, Sydney, NSW, Australia; 5The University of Sydney, Sydney, NSW, Australia Purpose: Dose-escalated (DE radiotherapy in the setting of localized prostate cancer has been shown to improve biochemical disease-free survival (bDFS in several studies. In the same group of patients, androgen deprivation therapy (ADT has been shown to confer a survival benefit when combined with radiotherapy doses of up to 70 Gy; however, there is currently little long-term data on patients who have received high-dose intensity-modulated radiotherapy (IMRT with ADT. We report the long-term outcomes in a large cohort of patients treated with the combination of DE image-guided IMRT (IG-IMRT and ADT. Methods and materials: Patients with localized prostate cancer were identified from a centralized database across an integrated cancer center. All patients received DE IG-IMRT, combined with ADT, and had a minimum follow up of 12 months post-radiotherapy. All relapse and toxicity data were collected prospectively. Actuarial bDFS, metastasis-free survival, prostate cancer-specific survival, and multivariate analyses were calculated using the SPSS v20.0 statistical package. Results: Seven hundred and eighty-two eligible patients were identified with a median follow up of 46 months. Overall, 4.3% of patients relapsed, 2.0% developed distant metastases, and 0.6% died from metastatic prostate cancer. At 5-years, bDFS was 88%, metastasis-free survival was 95%, and prostate cancer-specific survival was 98%. Five-year grade 2 genitourinary and gastrointestinal toxicity was 2

  1. An open-label dose escalation study to evaluate the safety of administration of nonviral stromal cell-derived factor-1 plasmid to treat symptomatic ischemic heart failure.

    Science.gov (United States)

    Penn, Marc S; Mendelsohn, Farrell O; Schaer, Gary L; Sherman, Warren; Farr, Maryjane; Pastore, Joseph; Rouy, Didier; Clemens, Ruth; Aras, Rahul; Losordo, Douglas W

    2013-03-01

    Preclinical studies indicate that adult stem cells induce tissue repair by activating endogenous stem cells through the stromal cell-derived factor-1:chemokine receptor type 4 axis. JVS-100 is a DNA plasmid encoding human stromal cell-derived factor-1. We tested in a phase 1, open-label, dose-escalation study with 12 months of follow-up in subjects with ischemic cardiomyopathy to see if JVS-100 improves clinical parameters. Seventeen subjects with ischemic cardiomyopathy, New York Heart Association class III heart failure, with an ejection fraction ≤40% on stable medical therapy, were enrolled to receive 5, 15, or 30 mg of JVS-100 via endomyocardial injection. The primary end points for safety and efficacy were at 1 and 4 months, respectively. The primary safety end point was a major adverse cardiac event. Efficacy end points were change in quality of life, New York Heart Association class, 6-minute walk distance, single photon emission computed tomography, N-terminal pro-brain natruretic peptide, and echocardiography at 4 and 12 months. The primary safety end point was met. At 4 months, all of the cohorts demonstrated improvements in 6-minute walk distance, quality of life, and New York Heart Association class. Subjects in the 15- and 30-mg dose groups exhibited improvements in 6-minute walk distance (15 mg: median [range]: 41 minutes [3-61 minutes]; 30 mg: 31 minutes [22-74 minutes]) and quality of life (15 mg: -16 points [+1 to -32 points]; 30 mg: -24 points [+17 to -38 points]) over baseline. At 12 months, improvements in symptoms were maintained. These data highlight the importance of defining the molecular mechanisms of stem cell-based tissue repair and suggest that overexpression of stromal cell-derived factor-1 via gene therapy is a strategy for improving heart failure symptoms in patients with ischemic cardiomyopathy.

  2. Safety, efficacy and pharmacokinetics of neratinib (HKI-272) in Japanese patients with advanced solid tumors: a Phase 1 dose-escalation study.

    Science.gov (United States)

    Ito, Yoshinori; Suenaga, Mitsukuni; Hatake, Kiyohiko; Takahashi, Shunji; Yokoyama, Masahiro; Onozawa, Yusuke; Yamazaki, Kentaro; Hironaka, Shuichi; Hashigami, Kiyoshi; Hasegawa, Hirotaka; Takenaka, Nobuko; Boku, Narikazu

    2012-04-01

    Neratinib (HKI-272), a potent, irreversible, small-molecule, orally administered, pan-ErbB inhibitor that blocks signal transduction via inhibition of three epidermal growth factor receptors [ErbB1, ErbB2 (Her2) and ErbB4], is being developed for the treatment of solid tumors, including breast cancer. This Phase 1 dose-escalation study assessed the safety, tolerability, maximum-tolerated dose, antitumor activity and pharmacokinetics of neratinib in Japanese patients with advanced solid tumors. Patients received neratinib 80, 160, 240 or 320 mg orally; each patient enrolled in only one dose cohort. Patients received a single dose in week 1, followed by daily continuous doses. Blood samples collected were on days 1 and 21 for pharmacokinetic analyses. Twenty-one patients were enrolled (3 breast cancer; 17 colorectal cancer; 1 gastric cancer). Neratinib-related adverse events (all grades) included diarrhea (20 patients), fatigue (14 patients), nausea and abdominal pain (9 patients each) and anorexia (8 patients). Grade ≥3 neratinib-related adverse events in two or more patients were diarrhea and anorexia (two patients each). Dose-limiting toxicities were diarrhea and anorexia (two patients, 320 mg dose). The maximum-tolerated dose and recommended dose was neratinib 240 mg once daily. Of 21 evaluable patients, 2 with breast cancer had partial response, 3 had stable disease ≥24 weeks, 7 had stable disease ≥16 weeks and 9 had progressive disease. Pharmacokinetic analyses indicated that neratinib exposures increased with dose. The safety, efficacy and pharmacokinetic profiles of neratinib are consistent with those reported for non-Japanese patients and warrant further investigation of neratinib in Japanese patients with solid tumors.

  3. Disulfonated tetraphenyl chlorin (TPCS2a)-induced photochemical internalisation of bleomycin in patients with solid malignancies: a phase 1, dose-escalation, first-in-man trial.

    Science.gov (United States)

    Sultan, Ahmed A; Jerjes, Waseem; Berg, Kristian; Høgset, Anders; Mosse, Charles A; Hamoudi, Rifat; Hamdoon, Zaid; Simeon, Celia; Carnell, Dawn; Forster, Martin; Hopper, Colin

    2016-09-01

    Photochemical internalisation, a novel minimally invasive treatment, has shown promising preclinical results in enhancing and site-directing the effect of anticancer drugs by illumination, which initiates localised chemotherapy release. We assessed the safety and tolerability of a newly developed photosensitiser, disulfonated tetraphenyl chlorin (TPCS2a), in mediating photochemical internalisation of bleomycin in patients with advanced and recurrent solid malignancies. In this phase 1, dose-escalation, first-in-man trial, we recruited patients (aged ≥18 to internalisation were either local, resulting from the local inflammatory process, or systemic, mostly as a result of the skin-photosensitising effect of TPCS2a. The most common grade 3 or worse adverse events were unexpected higher transient pain response (grade 3) localised to the treatment site recorded in nine patients, and respiratory failure (grade 4) noted in two patients. One dose-limiting toxicity was reported in the 1·0 mg/kg cohort (skin photosensitivity [grade 2]). Dose-limiting toxicities were reported in two of three patients at a TPCS2a dose of 1·5 mg/kg (skin photosensitivity [grade 3] and wound infection [grade 3]); thus, the maximum tolerated dose of TPCS2a was 1·0 mg/kg. Administration of TPCS2a was found to be safe and tolerable by all patients. No deaths related to photochemical internalisation treatment occurred. TPCS2a-mediated photochemical internalisation of bleomycin is safe and tolerable. We identified TPCS2a 0·25 mg/kg as the recommended treatment dose for future trials. PCI Biotech. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Increase in tumor control and normal tissue complication probabilities in advanced head-and-neck cancer for dose-escalated intensity-modulated photon and proton therapy

    Directory of Open Access Journals (Sweden)

    Annika eJakobi

    2015-11-01

    Full Text Available Introduction:Presently used radio-chemotherapy regimens result in moderate local control rates for patients with advanced head and neck squamous cell carcinoma (HNSCC. Dose escalation (DE may be an option to improve patient outcome, but may also increase the risk of toxicities in healthy tissue. The presented treatment planning study evaluated the feasibility of two DE levels for advanced HNSCC patients, planned with either intensity-modulated photon therapy (IMXT or proton therapy (IMPT.Materials and Methods:For 45 HNSCC patients, IMXT and IMPT treatment plans were created including DE via a simultaneous integrated boost (SIB in the high-risk volume, while maintaining standard fractionation with 2 Gy per fraction in the remaining target volume. Two DE levels for the SIB were compared: 2.3 Gy and 2.6 Gy. Treatment plan evaluation included assessment of tumor control probabilities (TCP and normal tissue complication probabilities (NTCP.Results:An increase of approximately 10% in TCP was estimated between the DE levels. A pronounced high-dose rim surrounding the SIB volume was identified in IMXT treatment. Compared to IMPT, this extra dose slightly increased the TCP values and to a larger extent the NTCP values. For both modalities, the higher DE level led only to a small increase in NTCP values (mean differences < 2% in all models, except for the risk of aspiration, which increased on average by 8% and 6% with IMXT and IMPT, respectively, but showed a considerable patient dependence. Conclusions:Both DE levels appear applicable to patients with IMXT and IMPT since all calculated NTCP values, except for one, increased only little for the higher DE level. The estimated TCP increase is of relevant magnitude. The higher DE schedule needs to be investigated carefully in the setting of a prospective clinical trial, especially regarding toxicities caused by high local doses that lack a sound dose response description, e.g., ulcers.

  5. The role of androgen deprivation therapy on biochemical failure and distant metastasis in intermediate-risk prostate cancer: effects of radiation dose escalation

    International Nuclear Information System (INIS)

    Ludwig, Michelle S; Kuban, Deborah A; Du, Xianglin L; Lopez, David S; Yamal, Jose-Miguel; Strom, Sara S

    2015-01-01

    To determine whether the effect of androgen deprivation therapy (ADT) on the risk of biochemical failure varies at different doses of radiation in patients treated with definitive external beam radiation for intermediate risk prostate cancer (IRPC). This study included 1218 IRPC patients treated with definitive external beam radiation therapy to the prostate and seminal vesicles from June 1987 to January 2009 at our institution. Patient, treatment, and tumor information was collected, including age, race, Gleason score, radiation dose, PSA, T-stage, and months on ADT. The median follow-up was 6 years. A total of 421(34.6%) patients received ADT, 211 (17.3%) patients experienced a biochemical failure, and 38 (3.1%) developed distant metastasis. On univariable analyses, higher PSA, earlier year of diagnosis, higher T-stage, lower doses of radiation, and the lack of ADT were associated with an increased risk of biochemical failure. No difference in biochemical failure was seen among different racial groups or with the use of greater than 6 months of ADT compared with less than 6 months. On multivariate analysis, the use of ADT was associated with a lower risk of biochemical failure than no ADT (HR, 0.599; 95% CI, 0.367-0.978; P < 0.04) and lower risk of distant metastasis (HR, 0.114; 95% CI, 0.014-0.905; P = 0.04). ADT reduced the risk of biochemical failure and distant metastasis in both low- and high dose radiation groups among men with intermediate-risk PCa. Increasing the duration of ADT beyond 6 months did not reduce the risk of biochemical failures. Better understanding the benefit of ADT in the era of dose escalation will require a randomized clinical trial

  6. Dose-Volume Parameters of the Corpora Cavernosa Do Not Correlate With Erectile Dysfunction After External Beam Radiotherapy for Prostate Cancer: Results From a Dose-Escalation Trial

    International Nuclear Information System (INIS)

    Wielen, Gerard J. van der; Hoogeman, Mischa S.; Dohle, Gert R.; Putten, Wim L.J. van; Incrocci, Luca

    2008-01-01

    Purpose: To analyze the correlation between dose-volume parameters of the corpora cavernosa and erectile dysfunction (ED) after external beam radiotherapy (EBRT) for prostate cancer. Methods and Materials: Between June 1997 and February 2003, a randomized dose-escalation trial comparing 68 Gy and 78 Gy was conducted. Patients at our institute were asked to participate in an additional part of the trial evaluating sexual function. After exclusion of patients with less than 2 years of follow-up, ED at baseline, or treatment with hormonal therapy, 96 patients were eligible. The proximal corpora cavernosa (crura), the superiormost 1-cm segment of the crura, and the penile bulb were contoured on the planning computed tomography scan and dose-volume parameters were calculated. Results: Two years after EBRT, 35 of the 96 patients had developed ED. No statistically significant correlations between ED 2 years after EBRT and dose-volume parameters of the crura, the superiormost 1-cm segment of the crura, or the penile bulb were found. The few patients using potency aids typically indicated to have ED. Conclusion: No correlation was found between ED after EBRT for prostate cancer and radiation dose to the crura or penile bulb. The present study is the largest study evaluating the correlation between ED and radiation dose to the corpora cavernosa after EBRT for prostate cancer. Until there is clear evidence that sparing the penile bulb or crura will reduce ED after EBRT, we advise to be careful in sparing these structures, especially when this involves reducing treatment margins

  7. Phase I, Dose-Escalation, Two-Part Trial of the PARP Inhibitor Talazoparib in Patients with Advanced Germline BRCA1/2 Mutations and Selected Sporadic Cancers.

    Science.gov (United States)

    de Bono, Johann; Ramanathan, Ramesh K; Mina, Lida; Chugh, Rashmi; Glaspy, John; Rafii, Saeed; Kaye, Stan; Sachdev, Jasgit; Heymach, John; Smith, David C; Henshaw, Joshua W; Herriott, Ashleigh; Patterson, Miranda; Curtin, Nicola J; Byers, Lauren Averett; Wainberg, Zev A

    2017-06-01

    Talazoparib inhibits PARP catalytic activity, trapping PARP1 on damaged DNA and causing cell death in BRCA1/2 -mutated cells. We evaluated talazoparib therapy in this two-part, phase I, first-in-human trial. Antitumor activity, MTD, pharmacokinetics, and pharmacodynamics of once-daily talazoparib were determined in an open-label, multicenter, dose-escalation study (NCT01286987). The MTD was 1.0 mg/day, with an elimination half-life of 50 hours. Treatment-related adverse events included fatigue (26/71 patients; 37%) and anemia (25/71 patients; 35%). Grade 3 to 4 adverse events included anemia (17/71 patients; 24%) and thrombocytopenia (13/71 patients; 18%). Sustained PARP inhibition was observed at doses ≥0.60 mg/day. At 1.0 mg/day, confirmed responses were observed in 7 of 14 (50%) and 5 of 12 (42%) patients with BRCA mutation-associated breast and ovarian cancers, respectively, and in patients with pancreatic and small cell lung cancer. Talazoparib demonstrated single-agent antitumor activity and was well tolerated in patients at the recommended dose of 1.0 mg/day. Significance: In this clinical trial, we show that talazoparib has single-agent antitumor activity and a tolerable safety profile. At its recommended phase II dose of 1.0 mg/day, confirmed responses were observed in patients with BRCA mutation-associated breast and ovarian cancers and in patients with pancreatic and small cell lung cancer. Cancer Discov; 7(6); 620-9. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 539 . ©2017 American Association for Cancer Research.

  8. Three-Dimensional Conformal Radiation Therapy and Intensity-Modulated Radiation Therapy Combined With Transcatheter Arterial Chemoembolization for Locally Advanced Hepatocellular Carcinoma: An Irradiation Dose Escalation Study

    International Nuclear Information System (INIS)

    Ren Zhigang; Zhao Jiandong; Gu Ke; Chen Zhen; Lin Junhua; Xu Zhiyong; Hu Weigang; Zhou Zhenhua; Liu Luming; Jiang Guoliang

    2011-01-01

    Purpose: To determine the maximum tolerated dose (MTD) of three-dimensional conformal radiation therapy (3DCRT)/intensity-modulated radiation therapy (IMRT) combined with transcatheter arterial chemoembolization for locally advanced hepatocellular carcinoma. Methods and Materials: Patients were assigned to two subgroups based on tumor diameter: Group 1 had tumors <10 cm; Group II had tumors ≥10 cm. Escalation was achieved by increments of 4.0 Gy for each cohort in both groups. Dose-limiting toxicity (DLT) was defined as a grade of ≥3 acute liver or gastrointestinal toxicity or any grade 5 acute toxicity in other organs at risk or radiation-induced liver disease. The dose escalation would be terminated when ≥2 of 8 patients in a cohort experienced DLT. Results: From April 2005 to May 2008, 40 patients were enrolled. In Group I, 11 patients had grade ≤2 acute treatment-related toxicities, and no patient experienced DLT; and in Group II, 10 patients had grade ≤2 acute toxicity, and 1 patient in the group receiving 52 Gy developed radiation-induced liver disease. MTD was 62 Gy for Group I and 52 Gy for Group II. In-field progression-free and local progression-free rates were 100% and 69% at 1 year, and 93% and 44% at 2 years, respectively. Distant metastasis rates were 6% at 1 year and 15% at 2 years. Overall survival rates for 1-year and 2-years were 72% and 62%, respectively. Conclusions: The irradiation dose was safely escalated in hepatocellular carcinoma patients by using 3DCRT/IMRT with an active breathing coordinator. MTD was 62 Gy and 52 Gy for patients with tumor diameters of <10 cm and ≥10 cm, respectively.

  9. Retrospective Evaluation Reveals That Long-term Androgen Deprivation Therapy Improves Cause-Specific and Overall Survival in the Setting of Dose-Escalated Radiation for High-Risk Prostate Cancer

    International Nuclear Information System (INIS)

    Feng, Felix Y.; Blas, Kevin; Olson, Karin; Stenmark, Matthew; Sandler, Howard; Hamstra, Daniel A.

    2013-01-01

    Purpose: To evaluate the role of androgen deprivation therapy (ADT) and duration for high-risk prostate cancer patients treated with dose-escalated radiation therapy (RT). Methods and Materials: A retrospective analysis of high-risk prostate cancer patients treated with dose-escalated RT (minimum 75 Gy) with or without ADT was performed. The relationship between ADT use and duration with biochemical failure (BF), metastatic failure (MF), prostate cancer-specific mortality (PCSM), non-prostate cancer death (NPCD), and overall survival (OS) was assessed as a function of pretreatment characteristics, comorbid medical illness, and treatment using Fine and Gray's cumulative incidence methodology. Results: The median follow-up time was 64 months. In men with National Comprehensive Cancer Network defined high-risk prostate cancer treated with dose-escalated RT, on univariate analysis, both metastasis (P<.0001; hazard ratio 0.34; 95% confidence interval 0.18-0.67; cumulative incidence at 60 months 13% vs 35%) and PCSM (P=.015; hazard ratio 0.41; 95% confidence interval 0.2-1.0; cumulative incidence at 60 months 6% vs 11%) were improved with the use of ADT. On multivariate analysis for all high-risk patients, Gleason score was the strongest negative prognostic factor, and long-term ADT (LTAD) improved MF (P=.002), PCSM (P=.034), and OS (P=.001). In men with prostate cancer and Gleason scores 8 to 10, on multivariate analysis after adjustment for other risk features, there was a duration-dependent improvement in BF, metastasis, PCSM, and OS, all favoring LTAD in comparison with STAD or RT alone. Conclusion: For men with high-risk prostate cancer treated with dose-escalated EBRT, this retrospective study suggests that the combination of LTAD and RT provided a significant improvement in clinical outcome, which was especially true for those with Gleason scores of 8 to 10

  10. Efficacy and safety of milnacipran 100 mg/day in patients with fibromyalgia: results of a randomized, double-blind, placebo-controlled trial.

    Science.gov (United States)

    Arnold, Lesley M; Gendreau, R Michael; Palmer, Robert H; Gendreau, Judy F; Wang, Yong

    2010-09-01

    To assess the efficacy and safety of milnacipran at a dosage of 100 mg/day (50 mg twice daily) for monotherapy treatment of fibromyalgia. A double-blind, placebo-controlled trial was performed to assess 1,025 patients with fibromyalgia who were randomized to receive milnacipran 100 mg/day (n = 516) or placebo (n = 509). Patients underwent 4-6 weeks of flexible dose escalation followed by 12 weeks of stable-dose treatment. Two composite responder definitions were used as primary end points to classify the response to treatment. The 2-measure composite response required achievement of ≥30% improvement from baseline in the pain score and a rating of "very much improved" or "much improved" on the Patient's Global Impression of Change (PGIC) scale. The 3-measure composite response required satisfaction of these same 2 improvement criteria for pain and global status as well as improvement in physical function on the Short Form 36 (SF-36) physical component summary (PCS) score. After 12 weeks of stable-dose treatment, a significantly greater proportion of milnacipran-treated patients compared with placebo-treated patients showed clinically meaningful improvements, as evidenced by the proportion of patients meeting the 2-measure composite responder criteria (P recall pain score, PGIC score, SF-36 PCS and mental component summary scores, average pain severity score on the Brief Pain Inventory, Fibromyalgia Impact Questionnaire total score (all P total score (P = 0.036 versus placebo). Milnacipran was well tolerated by most patients, with nausea being the most commonly reported adverse event (placebo-adjusted rate of 15.8%). Milnacipran administered at a dosage of 100 mg/day improved pain, global status, fatigue, and physical and mental function in patients with fibromyalgia.

  11. A Clinical phase I/II trial to investigate preoperative dose-escalated intensity-modulated radiation therapy (IMRT and intraoperative radiation therapy (IORT in patients with retroperitoneal soft tissue sarcoma

    Directory of Open Access Journals (Sweden)

    Roeder Falk

    2012-07-01

    Full Text Available Abstract Background Local control rates in patients with retroperitoneal soft tissue sarcoma (RSTS remain disappointing even after gross total resection, mainly because wide margins are not achievable in the majority of patients. In contrast to extremity sarcoma, postoperative radiation therapy (RT has shown limited efficacy due to its limitations in achievable dose and coverage. Although Intraoperative Radiation Therapy (IORT has been introduced in some centers to overcome the dose limitations and resulted in increased outcome, local failure rates are still high even if considerable treatment related toxicity is accepted. As postoperative administration of RT has some general disadvantages, neoadjuvant approaches could offer benefits in terms of dose escalation, target coverage and reduction of toxicity, especially if highly conformal techniques like intensity-modulated radiation therapy (IMRT are considered. Methods/design The trial is a prospective, one armed, single center phase I/II study investigating a combination of neoadjuvant dose-escalated IMRT (50–56 Gy followed by surgery and IORT (10–12 Gy in patients with at least marginally resectable RSTS. The primary objective is the local control rate after five years. Secondary endpoints are progression-free and overall survival, acute and late toxicity, surgical resectability and patterns of failure. The aim of accrual is 37 patients in the per-protocol population. Discussion The present study evaluates combined neoadjuvant dose-escalated IMRT followed by surgery and IORT concerning its value for improved local control without markedly increased toxicity. Trial registration NCT01566123

  12. A Clinical phase I/II trial to investigate preoperative dose-escalated intensity-modulated radiation therapy (IMRT) and intraoperative radiation therapy (IORT) in patients with retroperitoneal soft tissue sarcoma

    International Nuclear Information System (INIS)

    Roeder, Falk; Hensley, Frank W; Buechler, Markus W; Debus, Juergen; Koch, Moritz; Weitz, Juergen; Bischof, Marc; Schulz-Ertner, Daniela; Nikoghosyan, Anna V; Huber, Peter E; Edler, Lutz; Habl, Gregor; Krempien, Robert; Oertel, Susanne; Saleh-Ebrahimi, Ladan

    2012-01-01

    Local control rates in patients with retroperitoneal soft tissue sarcoma (RSTS) remain disappointing even after gross total resection, mainly because wide margins are not achievable in the majority of patients. In contrast to extremity sarcoma, postoperative radiation therapy (RT) has shown limited efficacy due to its limitations in achievable dose and coverage. Although Intraoperative Radiation Therapy (IORT) has been introduced in some centers to overcome the dose limitations and resulted in increased outcome, local failure rates are still high even if considerable treatment related toxicity is accepted. As postoperative administration of RT has some general disadvantages, neoadjuvant approaches could offer benefits in terms of dose escalation, target coverage and reduction of toxicity, especially if highly conformal techniques like intensity-modulated radiation therapy (IMRT) are considered. The trial is a prospective, one armed, single center phase I/II study investigating a combination of neoadjuvant dose-escalated IMRT (50–56 Gy) followed by surgery and IORT (10–12 Gy) in patients with at least marginally resectable RSTS. The primary objective is the local control rate after five years. Secondary endpoints are progression-free and overall survival, acute and late toxicity, surgical resectability and patterns of failure. The aim of accrual is 37 patients in the per-protocol population. The present study evaluates combined neoadjuvant dose-escalated IMRT followed by surgery and IORT concerning its value for improved local control without markedly increased toxicity. NCT01566123

  13. Sucralfate versus cimetidine in reflux esophagitis. A single-blind multicenter study

    NARCIS (Netherlands)

    Hameeteman, W.; v d Boomgaard, D. M.; Dekker, W.; Schrijver, M.; Wesdorp, I. C.; Tytgat, G. N.

    1987-01-01

    A single-blind randomized multicenter study was performed in 42 patients with endoscopically documented reflux esophagitis. Patients were randomly given 400 mg cimetidine q.i.d. or a suspension of 1 g sucralfate q.i.d. for a period of 8 weeks. Forty patients were evaluated after 8 weeks. Symptomatic

  14. Botulinum toxin in the treatment of orofacial tardive dyskinesia : A single blind study

    NARCIS (Netherlands)

    Slotema, Christina W.; van Harten, Peter N.; Bruggeman, Richard; Hoek, Hans W.

    2008-01-01

    Objective: Orofacial tardive dyskinesia (OTD) is difficult to treat and Botulinium Toxin A (BTA) may be an option. Methods: In a single blind (raters were blind) study (N= 12, duration 33 weeks) OTD was treated with Botulinum Toxin A in three consecutive sessions with increasing dosages. The

  15. Unilateral pallidotomy in Parkinson's disease : a randomised, single-blind, multicentre trial

    NARCIS (Netherlands)

    de Bie, RMA; de Haan, RJ; Nijssen, PCG; Rutgers, AWF; Beute, GN; Haaxma, R; Schmand, B; Staal, MJ; Speelman, J.D.

    1999-01-01

    Background The results of several cohort studies suggest that patients with advanced Parkinson's disease would benefit from unilateral pallidotomy. We have assessed the efficacy of unilateral pallidotomy in a randomised, single-blind, multicentre trial. Methods We enrolled 37 patients with advanced

  16. Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy (the ASCENDE-RT Trial): An Analysis of Survival Endpoints for a Randomized Trial Comparing a Low-Dose-Rate Brachytherapy Boost to a Dose-Escalated External Beam Boost for High- and Intermediate-risk Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Morris, W. James, E-mail: jmorris@bccancer.bc.ca [Department of Surgery, University of British Columbia, Vancouver, British Columbia (Canada); BC Cancer Agency–Vancouver Centre, Vancouver, British Columbia (Canada); Tyldesley, Scott [Department of Surgery, University of British Columbia, Vancouver, British Columbia (Canada); BC Cancer Agency–Vancouver Centre, Vancouver, British Columbia (Canada); Rodda, Sree [Department of Surgery, University of British Columbia, Vancouver, British Columbia (Canada); Halperin, Ross [Department of Surgery, University of British Columbia, Vancouver, British Columbia (Canada); BC Cancer Agency–Centre for the Southern Interior, Vancouver, British Columbia (Canada); Pai, Howard [Department of Surgery, University of British Columbia, Vancouver, British Columbia (Canada); BC Cancer Agency–Vancouver Island Centre, Vancouver, British Columbia (Canada); McKenzie, Michael; Duncan, Graeme [Department of Surgery, University of British Columbia, Vancouver, British Columbia (Canada); BC Cancer Agency–Vancouver Centre, Vancouver, British Columbia (Canada); Morton, Gerard [Department of Radiation Oncology, University of Toronto, Sunnybrook Health Sciences Centre, Toronto, Ontario (Canada); Hamm, Jeremy [Department of Population Oncology, BC Cancer Agency, Vancouver, British Columbia (Canada); Murray, Nevin [BC Cancer Agency–Vancouver Centre, Vancouver, British Columbia (Canada); Department of Medicine, University of British Columbia, Vancouver, British Columbia (Canada)

    2017-06-01

    Purpose: To report the primary endpoint of biochemical progression-free survival (b-PFS) and secondary survival endpoints from ASCENDE-RT, a randomized trial comparing 2 methods of dose escalation for intermediate- and high-risk prostate cancer. Methods and Materials: ASCENDE-RT enrolled 398 men, with a median age of 68 years; 69% (n=276) had high-risk disease. After stratification by risk group, the subjects were randomized to a standard arm with 12 months of androgen deprivation therapy, pelvic irradiation to 46 Gy, followed by a dose-escalated external beam radiation therapy (DE-EBRT) boost to 78 Gy, or an experimental arm that substituted a low-dose-rate prostate brachytherapy (LDR-PB) boost. Of the 398 trial subjects, 200 were assigned to DE-EBRT boost and 198 to LDR-PB boost. The median follow-up was 6.5 years. Results: In an intent-to-treat analysis, men randomized to DE-EBRT were twice as likely to experience biochemical failure (multivariable analysis [MVA] hazard ratio [HR] 2.04; P=.004). The 5-, 7-, and 9-year Kaplan-Meier b-PFS estimates were 89%, 86%, and 83% for the LDR-PB boost versus 84%, 75%, and 62% for the DE-EBRT boost (log-rank P<.001). The LDR-PB boost benefited both intermediate- and high-risk patients. Because the b-PFS curves for the treatment arms diverge sharply after 4 years, the relative advantage of the LDR-PB should increase with longer follow-up. On MVA, the only variables correlated with reduced overall survival were age (MVA HR 1.06/y; P=.004) and biochemical failure (MVA HR 6.30; P<.001). Although biochemical failure was associated with increased mortality and randomization to DE-EBRT doubled the rate of biochemical failure, no significant overall survival difference was observed between the treatment arms (MVA HR 1.13; P=.62). Conclusions: Compared with 78 Gy EBRT, men randomized to the LDR-PB boost were twice as likely to be free of biochemical failure at a median follow-up of 6.5 years.

  17. Stereotactic Body Radiation Therapy Boost After Concurrent Chemoradiation for Locally Advanced Non-Small Cell Lung Cancer: A Phase 1 Dose Escalation Study

    Energy Technology Data Exchange (ETDEWEB)

    Hepel, Jaroslaw T., E-mail: jhepel@lifespan.org [Department of Radiation Oncology, Rhode Island Hospital, Brown University, Providence, Rhode Island (United States); Department of Radiation Oncology, Tufts Medical Center, Tufts University, Boston, Massachusetts (United States); Leonard, Kara Lynne [Department of Radiation Oncology, Rhode Island Hospital, Brown University, Providence, Rhode Island (United States); Department of Radiation Oncology, Tufts Medical Center, Tufts University, Boston, Massachusetts (United States); Safran, Howard [Division of Medical Oncology, Rhode Island Hospital, Brown University, Providence, Rhode Island (United States); Division of Medical Oncology, Miriam Hospital, Brown University, Providence, Rhode Island (United States); Ng, Thomas [Division of Thoracic Surgery, Rhode Island Hospital, Brown University, Providence, Rhode Island (United States); Taber, Angela [Division of Medical Oncology, Miriam Hospital, Brown University, Providence, Rhode Island (United States); Khurshid, Humera; Birnbaum, Ariel [Division of Medical Oncology, Rhode Island Hospital, Brown University, Providence, Rhode Island (United States); Wazer, David E.; DiPetrillo, Thomas [Department of Radiation Oncology, Rhode Island Hospital, Brown University, Providence, Rhode Island (United States); Department of Radiation Oncology, Tufts Medical Center, Tufts University, Boston, Massachusetts (United States)

    2016-12-01

    Purpose: Stereotactic body radiation therapy (SBRT) boost to primary and nodal disease after chemoradiation has potential to improve outcomes for advanced non-small cell lung cancer (NSCLC). A dose escalation study was initiated to evaluate the maximum tolerated dose (MTD). Methods and Materials: Eligible patients received chemoradiation to a dose of 50.4 Gy in 28 fractions and had primary and nodal volumes appropriate for SBRT boost (<120 cc and <60 cc, respectively). SBRT was delivered in 2 fractions after chemoradiation. Dose was escalated from 16 to 28 Gy in 2 Gy/fraction increments, resulting in 4 dose cohorts. MTD was defined when ≥2 of 6 patients per cohort experienced any treatment-related grade 3 to 5 toxicity within 4 weeks of treatment or the maximum dose was reached. Late toxicity, disease control, and survival were also evaluated. Results: Twelve patients (3 per dose level) underwent treatment. All treatment plans met predetermined dose-volume constraints. The mean age was 64 years. Most patients had stage III disease (92%) and were medically inoperable (92%). The maximum dose level was reached with no grade 3 to 5 acute toxicities. At a median follow-up time of 16 months, 1-year local-regional control (LRC) was 78%. LRC was 50% at <24 Gy and 100% at ≥24 Gy (P=.02). Overall survival at 1 year was 67%. Late toxicity (grade 3-5) was seen in only 1 patient who experienced fatal bronchopulmonary hemorrhage (grade 5). There were no predetermined dose constraints for the proximal bronchial-vascular tree (PBV) in this study. This patient's 4-cc PBV dose was substantially higher than that received by other patients in all 4 cohorts and was associated with the toxicity observed: 20.3 Gy (P<.05) and 73.5 Gy (P=.07) for SBRT boost and total treatment, respectively. Conclusions: SBRT boost to both primary and nodal disease after chemoradiation is feasible and well tolerated. Local control rates are encouraging, especially at doses ≥24

  18. Using generalized equivalent uniform dose atlases to combine and analyze prospective dosimetric and radiation pneumonitis data from 2 non-small cell lung cancer dose escalation protocols.

    Science.gov (United States)

    Liu, Fan; Yorke, Ellen D; Belderbos, José S A; Borst, Gerben R; Rosenzweig, Kenneth E; Lebesque, Joos V; Jackson, Andrew

    2013-01-01

    To demonstrate the use of generalized equivalent uniform dose (gEUD) atlas for data pooling in radiation pneumonitis (RP) modeling, to determine the dependence of RP on gEUD, to study the consistency between data sets, and to verify the increased statistical power of the combination. Patients enrolled in prospective phase I/II dose escalation studies of radiation therapy of non-small cell lung cancer at Memorial Sloan-Kettering Cancer Center (MSKCC) (78 pts) and the Netherlands Cancer Institute (NKI) (86 pts) were included; 10 (13%) and 14 (17%) experienced RP requiring steroids (RPS) within 6 months after treatment. gEUD was calculated from dose-volume histograms. Atlases for each data set were created using 1-Gy steps from exact gEUDs and RPS data. The Lyman-Kutcher-Burman model was fit to the atlas and exact gEUD data. Heterogeneity and inconsistency statistics for the fitted parameters were computed. gEUD maps of the probability of RPS rate≥20% were plotted. The 2 data sets were homogeneous and consistent. The best fit values of the volume effect parameter a were small, with upper 95% confidence limit around 1.0 in the joint data. The likelihood profiles around the best fit a values were flat in all cases, making determination of the best fit a weak. All confidence intervals (CIs) were narrower in the joint than in the individual data sets. The minimum P value for correlations of gEUD with RPS in the joint data was .002, compared with P=.01 and .05 for MSKCC and NKI data sets, respectively. gEUD maps showed that at small a, RPS risk increases with gEUD. The atlas can be used to combine gEUD and RPS information from different institutions and model gEUD dependence of RPS. RPS has a large volume effect with the mean dose model barely included in the 95% CI. Data pooling increased statistical power. Copyright © 2013 Elsevier Inc. All rights reserved.

  19. SU-C-BRA-01: 18F-NaF PET/CT-Directed Dose Escalation in Stereotactic Body Radiotherapy for Spine Oligometastases From Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Wu, L [Cancer Hospital of Shantou University Medical College, Shantou, Guangdong (China); University of Nevada, Las Vegas, Las Vegas, NV (United States); Zhang, W; Li, M; Peng, X; Xie, L; Lin, Z [Cancer Hospital of Shantou University Medical College, Shantou, Guangdong (China); Kwee, S [The Queen’s Medical Center, Honolulu, HI (United States); Wang, H; Kuang, Y [University of Nevada, Las Vegas, Las Vegas, NV (United States)

    2015-06-15

    Purpose: To investigate the technical feasibility of SBRT dose painting using {sup 18}F-NaF positron emission tomography (PET) scans guidance in patients with spine oligometastases from prostate cancer. Methods: As a proof of concept, six patients with 14 spine oligometastatic lesions from prostate cancer who had {sup 18}F-NaF PET/CT scan prior to treatment were retrospectively included. GTV{sub reg} was delineated according to the regular tumor boundary shown on PET and/or CT images; and GTV{sub MATV} was contoured based on a net metabolically active tumor volume (MATV) defined by 60% of the SUV{sub max} values on {sup 18}F-NaF PET images. The PTVs (PTV{sub reg} and PTV{sub MATV}) were defined as respective GTVs (plus involved entire vertebral body for PTV{sub reg}) with a 3-mm isotropic expansion margin. Three 1-fraction SBRT plans using VMAT technique along with 10 MV FFF beams (Plan{sub 24Gy}, Plan{sub 24–27Gy}, and Plan{sub 24–30Gy}) were generated for each patient. All plans included a dose of 24 Gy prescribed to PTV{sub reg}. The Plan{sub 24–27Gy} and Plan{sub 24–30Gy} also included a simultaneous boost dose of 27 Gy or 30 Gy prescribed to the PTV{sub MATV}, respectively. The feasibility of 18F-NaF PET-guided SBRT dose escalation was evaluated by its ability to achieve the prescription dose objectives while adhering to organ-at-risk (OAR) dose constraints. The normal tissue complication probabilities (NTCP) calculated by radiological models were also compared between the plans. Results: In all 33 SBRT plans generated, the planning objectives and dose constraints were met without exception. Plan{sub 24–27Gy} and Plan{sub 24–30Gy} had a significantly higher dose in PTV{sub MATV} than Plan{sub 24Gy} (p < 0.05), respectively, while maintaining a similar OAR sparing profile and NTCP values. Conclusion: Using VMAT with FFF beams to incorporate a simultaneous {sup 18}F-NaF PET-guided radiation boost dose up to 30 Gy into a SBRT plan is technically

  20. Gleason Pattern 5 Is the Greatest Risk Factor for Clinical Failure and Death From Prostate Cancer After Dose-Escalated Radiation Therapy and Hormonal Ablation

    Energy Technology Data Exchange (ETDEWEB)

    Sabolch, Aaron [University of Michigan Medical School, Ann Arbor, MI (United States); Feng, Felix Y. [University of Michigan Medical School, Ann Arbor, MI (United States); Department of Radiation Oncology, Ann Arbor, MI (United States); Veterans Administration Medical Center, Ann Arbor, MI (United States); Daignault-Newton, Stephanie [University of Michigan Medical School, Ann Arbor, MI (United States); Division of Biostatistics, Ann Arbor, MI (United States); Halverson, Schuyler; Blas, Kevin; Phelps, Laura [University of Michigan Medical School, Ann Arbor, MI (United States); Olson, Karin B. [University of Michigan Medical School, Ann Arbor, MI (United States); Department of Radiation Oncology, Ann Arbor, MI (United States); Sandler, Howard M. [Department of Radiation Oncology, Cedars Sinai Medical Center, Los Angeles, CA (United States); Hamstra, Daniel A., E-mail: dhamm@med.umich.edu [Department of Radiation Oncology, Ann Arbor, MI (United States)

    2011-11-15

    Purpose: The division of Gleason score (GS) into three categories (2-6, 7, 8-10) may not fully use its prognostic power, as revealed by recent reports demonstrating the presence of Gleason Pattern 5 (GP5) as a strong predictor for biochemical recurrence. Therefore, we analyzed the clinical outcomes in patients treated with dose-escalated radiation therapy (RT) based on the presence or absence of GP5. Methods and Materials: Outcomes were analyzed for 718 men treated for localized prostate cancer with external-beam RT to a minimum planning target volume dose of at least 75 Gy. We assessed the impact of GP5 and that of pretreatment- and treatment-related factors on freedom from biochemical failure, freedom from metastasis (FFM), cause-specific survival (CSS), and overall survival (OS). Results: At biopsy, 89% of patients had no GP5, and 11% (76/718) had GP5. There were no differences in age, comorbid illness, T stage, prostate-specific antigen, or the use or duration of androgen deprivation therapy between GS8 without GP5 and GS8-10 with GP5. The presence of GP5 predicted lower FFM (p < 0.002; hazard ratio [HR] 3.4 [1.7-7.1]); CSS (p < 0.0001; HR 12.9 [5.4-31]); and OS (p < 0.0001; HR 3.6 [2.0-6.5]) in comparison with GS8 (without GP5). The 8-year FFM, CSS, and OS were 89%, 98%, and 57%, respectively, for those with Gleason 8 prostate cancer without GP5 in comparison with 61%, 55%, and 31%, respectively, for those with GP5. In addition, both FFM and CSS were strongly influenced by androgen deprivation therapy given concurrently with RT. On multivariate analysis, GP5 was the strongest prognostic factor for all clinical endpoints, including OS. Conclusion: The presence of GP5 predicts for worse clinical behavior, which therefore needs to be accounted for by risk stratification schemes. Further intensification of local and/or systemic therapy may be appropriate for such patients.

  1. Long-term outcomes from dose-escalated image-guided intensity-modulated radiotherapy with androgen deprivation: encouraging results for intermediate- and high-risk prostate cancer.

    Science.gov (United States)

    Wilcox, Shea W; Aherne, Noel J; Benjamin, Linus C; Wu, Bosco; de Campos Silva, Thomaz; McLachlan, Craig S; McKay, Michael J; Last, Andrew J; Shakespeare, Thomas P

    2014-01-01

    Dose-escalated (DE) radiotherapy in the setting of localized prostate cancer has been shown to improve biochemical disease-free survival (bDFS) in several studies. In the same group of patients, androgen deprivation therapy (ADT) has been shown to confer a survival benefit when combined with radiotherapy doses of up to 70 Gy; however, there is currently little long-term data on patients who have received high-dose intensity-modulated radiotherapy (IMRT) with ADT. We report the long-term outcomes in a large cohort of patients treated with the combination of DE image-guided IMRT (IG-IMRT) and ADT. Patients with localized prostate cancer were identified from a centralized database across an integrated cancer center. All patients received DE IG-IMRT, combined with ADT, and had a minimum follow up of 12 months post-radiotherapy. All relapse and toxicity data were collected prospectively. Actuarial bDFS, metastasis-free survival, prostate cancer-specific survival, and multivariate analyses were calculated using the SPSS v20.0 statistical package. Seven hundred and eighty-two eligible patients were identified with a median follow up of 46 months. Overall, 4.3% of patients relapsed, 2.0% developed distant metastases, and 0.6% died from metastatic prostate cancer. At 5-years, bDFS was 88%, metastasis-free survival was 95%, and prostate cancer-specific survival was 98%. Five-year grade 2 genitourinary and gastrointestinal toxicity was 2.1% and 3.4%, respectively. No grade 3 or 4 late toxicities were reported. Pretreatment prostate specific antigen (P=0.001) and Gleason score (P=0.03) were significant in predicting biochemical failure on multivariate analysis. There is a high probability of tumor control with DE IG-IMRT combined with androgen deprivation, and this is a technique with a low probability of significant late toxicity. Our long term results corroborate the safety and efficacy of treating with IG-IMRT to high doses and compares favorably with published series for

  2. Gleason Pattern 5 Is the Greatest Risk Factor for Clinical Failure and Death From Prostate Cancer After Dose-Escalated Radiation Therapy and Hormonal Ablation

    International Nuclear Information System (INIS)

    Sabolch, Aaron; Feng, Felix Y.; Daignault-Newton, Stephanie; Halverson, Schuyler; Blas, Kevin; Phelps, Laura; Olson, Karin B.; Sandler, Howard M.; Hamstra, Daniel A.

    2011-01-01

    Purpose: The division of Gleason score (GS) into three categories (2–6, 7, 8–10) may not fully use its prognostic power, as revealed by recent reports demonstrating the presence of Gleason Pattern 5 (GP5) as a strong predictor for biochemical recurrence. Therefore, we analyzed the clinical outcomes in patients treated with dose-escalated radiation therapy (RT) based on the presence or absence of GP5. Methods and Materials: Outcomes were analyzed for 718 men treated for localized prostate cancer with external-beam RT to a minimum planning target volume dose of at least 75 Gy. We assessed the impact of GP5 and that of pretreatment- and treatment-related factors on freedom from biochemical failure, freedom from metastasis (FFM), cause-specific survival (CSS), and overall survival (OS). Results: At biopsy, 89% of patients had no GP5, and 11% (76/718) had GP5. There were no differences in age, comorbid illness, T stage, prostate-specific antigen, or the use or duration of androgen deprivation therapy between GS8 without GP5 and GS8–10 with GP5. The presence of GP5 predicted lower FFM (p < 0.002; hazard ratio [HR] 3.4 [1.7–7.1]); CSS (p < 0.0001; HR 12.9 [5.4-31]); and OS (p < 0.0001; HR 3.6 [2.0-6.5]) in comparison with GS8 (without GP5). The 8-year FFM, CSS, and OS were 89%, 98%, and 57%, respectively, for those with Gleason 8 prostate cancer without GP5 in comparison with 61%, 55%, and 31%, respectively, for those with GP5. In addition, both FFM and CSS were strongly influenced by androgen deprivation therapy given concurrently with RT. On multivariate analysis, GP5 was the strongest prognostic factor for all clinical endpoints, including OS. Conclusion: The presence of GP5 predicts for worse clinical behavior, which therefore needs to be accounted for by risk stratification schemes. Further intensification of local and/or systemic therapy may be appropriate for such patients.

  3. A phase 1/2, dose-escalation trial of deferasirox for the treatment of iron overload in HFE-related hereditary hemochromatosis.

    Science.gov (United States)

    Phatak, Pradyumna; Brissot, Pierre; Wurster, Mark; Adams, Paul C; Bonkovsky, Herbert L; Gross, John; Malfertheiner, Peter; McLaren, Gordon D; Niederau, Claus; Piperno, Alberto; Powell, Lawrie W; Russo, Mark W; Stoelzel, Ulrich; Stremmel, Wolfgang; Griffel, Louis; Lynch, Nicola; Zhang, Yiyun; Pietrangelo, Antonello

    2010-11-01

    Hereditary hemochromatosis (HH) is characterized by increased intestinal iron absorption that may result in iron overload. Although phlebotomy is widely practiced, it is poorly tolerated or contraindicated in patients with anemias, severe heart disease, or poor venous access, and compliance can vary. The once-daily, oral iron chelator, deferasirox (Exjade) may provide an alternative treatment option. Patients with HH carrying the HFE gene who were homozygous for the Cys282Tyr mutation, serum ferritin levels of 300-2000 ng/mL, transferrin saturation ≥ 45%, and no known history of cirrhosis were enrolled in this dose-escalation study to characterize the safety and efficacy of deferasirox, comprising a core and an extension phase (each 24 weeks). Forty-nine patients were enrolled and received starting deferasirox doses of 5 (n = 11), 10 (n = 15), or 15 (n = 23) mg/kg/day. Adverse events were generally dose-dependent, the most common being diarrhea, headache, and nausea (n = 18, n = 10, and n = 8 in the core and n = 1, n = 1, and n = 0 in the extension, respectively). More patients in the 15 mg/kg/day than in the 5 or 10 mg/kg/day cohorts experienced increases in alanine aminotransferase and serum creatinine levels during the 48-week treatment period; six patients had alanine aminotransferase > 3 × baseline and greater than the upper limit of normal range, and eight patients had serum creatinine > 33% above baseline and greater than upper limit of normal on two consecutive occasions. After receiving deferasirox for 48 weeks, median serum ferritin levels decreased by 63.5%, 74.8%, and 74.1% in the 5, 10, and 15 mg/kg/day cohorts, respectively. In all cohorts, median serum ferritin decreased to < 250 ng/mL. Deferasirox doses of 5, 10, and 15 mg/kg/day can reduce iron burden in patients with HH. Based on the safety and efficacy results, starting deferasirox at 10 mg/kg/day appears to be most appropriate for further study in this patient population.

  4. HER2-Specific Chimeric Antigen Receptor-Modified Virus-Specific T Cells for Progressive Glioblastoma: A Phase 1 Dose-Escalation Trial.

    Science.gov (United States)

    Ahmed, Nabil; Brawley, Vita; Hegde, Meenakshi; Bielamowicz, Kevin; Kalra, Mamta; Landi, Daniel; Robertson, Catherine; Gray, Tara L; Diouf, Oumar; Wakefield, Amanda; Ghazi, Alexia; Gerken, Claudia; Yi, Zhongzhen; Ashoori, Aidin; Wu, Meng-Fen; Liu, Hao; Rooney, Cliona; Dotti, Gianpietro; Gee, Adrian; Su, Jack; Kew, Yvonne; Baskin, David; Zhang, Yi Jonathan; New, Pamela; Grilley, Bambi; Stojakovic, Milica; Hicks, John; Powell, Suzanne Z; Brenner, Malcolm K; Heslop, Helen E; Grossman, Robert; Wels, Winfried S; Gottschalk, Stephen

    2017-08-01

    Glioblastoma is an incurable tumor, and the therapeutic options for patients are limited. To determine whether the systemic administration of HER2-specific chimeric antigen receptor (CAR)-modified virus-specific T cells (VSTs) is safe and whether these cells have antiglioblastoma activity. In this open-label phase 1 dose-escalation study conducted at Baylor College of Medicine, Houston Methodist Hospital, and Texas Children's Hospital, patients with progressive HER2-positive glioblastoma were enrolled between July 25, 2011, and April 21, 2014. The duration of follow-up was 10 weeks to 29 months (median, 8 months). Monotherapy with autologous VSTs specific for cytomegalovirus, Epstein-Barr virus, or adenovirus and genetically modified to express HER2-CARs with a CD28.ζ-signaling endodomain (HER2-CAR VSTs). Primary end points were feasibility and safety. The key secondary end points were T-cell persistence and their antiglioblastoma activity. A total of 17 patients (8 females and 9 males; 10 patients ≥18 years [median age, 60 years; range, 30-69 years] and 7 patients VSTs (1 × 106/m2 to 1 × 108/m2) without prior lymphodepletion. Infusions were well tolerated, with no dose-limiting toxic effects. HER2-CAR VSTs were detected in the peripheral blood for up to 12 months after the infusion by quantitative real-time polymerase chain reaction. Of 16 evaluable patients (9 adults and 7 children), 1 had a partial response for more than 9 months, 7 had stable disease for 8 weeks to 29 months, and 8 progressed after T-cell infusion. Three patients with stable disease are alive without any evidence of progression during 24 to 29 months of follow-up. For the entire study cohort, median overall survival was 11.1 months (95% CI, 4.1-27.2 months) from the first T-cell infusion and 24.5 months (95% CI, 17.2-34.6 months) from diagnosis. Infusion of autologous HER2-CAR VSTs is safe and can be associated with clinical benefit for patients with progressive glioblastoma

  5. The impact of eszopiclone on sleep and cognition in patients with schizophrenia and insomnia: a double-blind, randomized, placebo-controlled trial.

    Science.gov (United States)

    Tek, Cenk; Palmese, Laura B; Krystal, Andrew D; Srihari, Vinod H; DeGeorge, Pamela C; Reutenauer, Erin L; Guloksuz, Sinan

    2014-12-01

    Insomnia is frequent in schizophrenia and may contribute to cognitive impairment as well as overuse of weight inducing sedative antipsychotics. We investigated the effects of eszopiclone on sleep and cognition for patients with schizophrenia-related insomnia in a double-blind placebo controlled study, followed by a two-week, single-blind placebo phase. Thirty-nine clinically stable outpatients with schizophrenia or schizoaffective disorder and insomnia were randomized to either 3mg eszopiclone (n=20) or placebo (n=19). Primary outcome measure was change in Insomnia Severity Index (ISI) over 8 weeks. Secondary outcome measure was change in MATRICS Consensus Cognitive Battery (MATRICS). Sleep diaries, psychiatric symptoms, and quality of life were also monitored. ISI significantly improved more in eszopiclone (mean=-10.7, 95% CI=-13.2; -8.2) than in placebo (mean=-6.9, 95% CI=-9.5; -4.3) with a between-group difference of -3.8 (95% CI=-7.5; -0.2). MATRICS score change did not differ between groups. On further analysis there was a significant improvement in the working memory test, letter-number span component of MATRICS (mean=9.8±9.2, z=-2.00, p=0.045) only for subjects with schizophrenia on eszopiclone. There were improvements in sleep diary items in both groups with no between-group differences. Psychiatric symptoms remained stable. Discontinuation rates were similar. Sleep remained improved during single-blind placebo phase after eszopiclone was stopped, but the working memory improvement in patients with schizophrenia was not durable. Eszopiclone stands as a safe and effective alternative for the treatment of insomnia in patients with schizophrenia. Its effects on cognition require further study. Copyright © 2014 Elsevier B.V. All rights reserved.

  6. Ursodeoxycholic acid for treatment of primary sclerosing cholangitis: a placebo-controlled trial

    NARCIS (Netherlands)

    Beuers, U.; Spengler, U.; Kruis, W.; AYDEMIR, U.; WIEBECKE, B.; HELDWEIN, W.; WEINZIERL, M.; Pape, G. R.; Sauerbruch, T.; Paumgartner, G.

    1992-01-01

    The efficacy and safety of ursodeoxycholic acid for the treatment of primary sclerosing cholangitis were evaluated in a prospective, randomized, double-blind, placebo-controlled trial. Fourteen patients with primary sclerosing cholangitis documented by cholestatic serum enzyme pattern, liver

  7. An alternative approach to treating lateral epicondylitis. A randomized, placebo-controlled, double-blinded study

    NARCIS (Netherlands)

    Nourbakhsh, Mohammad Reza; Fearon, Frank J.

    Objective: To investigate the effect of noxious level electrical stimulation on pain, grip strength and functional abilities in subjects with chronic lateral epicondylitis. Design: Randomized, placebo-control, double-blinded study. Setting: Physical Therapy Department, North Georgia College and

  8. Lack of effect of intravenous immunoglobulins on tics : A double-blind placebo-controlled study

    NARCIS (Netherlands)

    Hoekstra, PJ; Minderaa, RB; Kallenberg, CGM

    Background: Case studies and a placebo-controlled study previously suggested the effectiveness of immunomodulatory therapy in patients with tic or related disorders whose symptoms show a relationship with streptococcal infections. No data are available on the effectiveness of intravenous

  9. The use of placebo control in clinical trials: An overview of the ...

    African Journals Online (AJOL)

    The use of placebo control in clinical trials: An overview of the ethical issues involved for the protection of human research participants. ... A placebo looks exactly like the experimental drugs in every respect both in appearance and wrappings ...

  10. Attitudes toward Placebo-Controlled Clinical Trials of Patients with Schizophrenia in Japan.

    Directory of Open Access Journals (Sweden)

    Norio Sugawara

    Full Text Available Although the use of placebo in clinical trials of schizophrenia patients is controversial because of medical and ethical concerns, placebo-controlled clinical trials are commonly used in the licensing of new drugs.The objective of this study was to assess the attitudes toward placebo-controlled clinical trials among patients with schizophrenia in Japan.Using a cross-sectional design, we recruited patients (n = 251 aged 47.7±13.2 (mean±SD with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder who were admitted to six psychiatric hospitals from December 2013 to March 2014. We employed a 14-item questionnaire specifically developed to survey patients' attitudes toward placebo-controlled clinical trials.The results indicated that 33% of the patients would be willing to participate in a placebo-controlled clinical trial. Expectations for improvement of disease, a guarantee of hospital treatment continuation, and encouragement by family or friends were associated with the willingness to participate in such trials, whereas a belief of additional time required for medical examinations was associated with non-participation.Fewer than half of the respondents stated that they would be willing to participate in placebo-controlled clinical trials. Therefore, interpreting the results from placebo-controlled clinical trials could be negatively affected by selection bias.

  11. Is Intermediate Radiation Dose Escalation With Concurrent Chemotherapy for Stage III Non–Small-Cell Lung Cancer Beneficial? A Multi-Institutional Propensity Score Matched Analysis

    Energy Technology Data Exchange (ETDEWEB)

    Rodrigues, George, E-mail: george.rodrigues@lhsc.on.ca [London Health Sciences Centre, London, Ontario (Canada); Oberije, Cary [MAASTRO Clinic, Maastricht (Netherlands); Senan, Suresh [VU University Medical Center, Amsterdam (Netherlands); Tsujino, Kayoko [Hyogo Cancer Center, Akashi (Japan); Wiersma, Terry [MAASTRO Clinic, Maastricht (Netherlands); Moreno-Jimenez, Marta [Universidad de Navarra, Pamplona (Spain); Kim, Tae Hyun [National Cancer Center, Goyang-si, Gy eonggi (Korea, Republic of); Marks, Lawrence B. [University of North Carolina, Chapel Hill, North Carolina (United States); Rengan, Ramesh [University of Washington, Seattle, Washington (United States); De Petris, Luigi [Karolinska University Hospital, Stockholm (Sweden); Ramella, Sara [Campus Bio-Medico University, Rome (Italy); DeRuyck, Kim [Ghent University, Ghent (Belgium); De Dios, Núria Rodriguez [Universidad Pompeu Fabra, Barcelona (Spain); Warner, Andrew [London Health Sciences Centre, London, Ontario (Canada); Bradley, Jeffrey D. [Washington University School of Medicine, St. Louis, Missouri (United States); Palma, David A. [London Health Sciences Centre, London, Ontario (Canada)

    2015-01-01

    Purpose: The clinical benefits and risks of dose escalation (DE) for stage III non–small-cell lung cancer (NSCLC) remain uncertain despite the results from Radiation Therapy Oncology Group (RTOG) protocol 0617. There is significant heterogeneity of practice, with many clinicians prescribing intermediate dose levels between the 0617 study arms of 60 and 74 Gy. This study investigated whether this strategy is associated with any survival benefits/risks by analyzing a large multi-institutional database. Methods and Materials: An individual patient database of stage III NSCLC patients treated with radical intent concurrent chemoradiation therapy was created (13 institutions, n=1274 patients). Patients were divided into 2 groups based on tumor Biological Effective Dose at 10 Gy (BED 10): those receiving standard dose (SD; n=552), consisting of 72Gy ≤ BED 10 ≤ 76.8 Gy (eg 60-64 Gy/30-32 fractions [fr]), and those receiving intermediate dose (ID; n=497), consisting of 76.8Gy < BED 10 < 100.8 Gy (eg >64 Gy/32 fr and <74 Gy/37 fr), with lower-dose patients (n=225) excluded from consideration. Patients were then matched using propensity scores, leading to 2 matched groups of 196 patients. Outcomes were compared using various statistics including interquartile range (IQR), Kaplan-Meier curves, and adjusted Cox regression analysis. Results: Matched groups were found to be balanced except for N stage (more N3 disease in SD), median treatment year (SD in 2003; ID in 2007), platinum and taxane chemotherapy (SD in 28%; ID in 39%), and median follow-up (SD were 89 months; ID were 40 months). Median dose fractionation was 60 Gy/30 fr in SD (BED 10 IQR: 72.0-75.5 Gy) and 66 Gy/33 fr (BED 10 IQR: 78.6-79.2 Gy) in ID. Survival curves for SD and ID matched cohorts were statistically similar (P=.27); however, a nonstatistically significant trend toward better survival for ID was observed after 15 months (median survival SD: 19.3 months; ID: 21.0

  12. Heterogeneous FDG-guided dose-escalation for locally advanced NSCLC (the NARLAL2 trial): Design and early dosimetric results of a randomized, multi-centre phase-III study

    DEFF Research Database (Denmark)

    Møller, Ditte Sloth; Nielsen, Tine Bjørn; Brink, Carsten

    2017-01-01

    Background and purpose: Local recurrence is frequent in locally advanced NSCLC and is primarily located in FDG-avid parts of tumour and lymph nodes. Aiming at improving local control without increasing toxicity, we designed a multi-centre phase-III trial delivering inhomogeneous dose-escalation d......Background and purpose: Local recurrence is frequent in locally advanced NSCLC and is primarily located in FDG-avid parts of tumour and lymph nodes. Aiming at improving local control without increasing toxicity, we designed a multi-centre phase-III trial delivering inhomogeneous dose...

  13. Phase I dose-escalation study of the c-Met tyrosine kinase inhibitor SAR125844 in Asian patients with advanced solid tumors, including patients with MET-amplified gastric cancer

    OpenAIRE

    Shitara, Kohei; Kim, Tae Min; Yokota, Tomoya; Goto, Masahiro; Satoh, Taroh; Ahn, Jin-Hee; Kim, Hyo Song; Assadourian, Sylvie; Gomez, Corinne; Harnois, Marzia; Hamauchi, Satoshi; Kudo, Toshihiro; Doi, Toshihido; Bang, Yung-Jue

    2017-01-01

    SAR125844 is a potent and selective inhibitor of the c-Met kinase receptor. This was an open-label, phase I, multicenter, dose-escalation, and dose-expansion trial of SAR125844 in Asian patients with solid tumors, a subgroup of whom had gastric cancer and MET amplification (NCT01657214). SAR125844 was administered by intravenous infusion (260–570 mg/m2) on days 1, 8, 15, and 22 of each 28-day cycle. Objectives were to determine the maximum tolerated dose (MTD) and to evaluate SAR125844 safety...

  14. Potential Use of 18F-fluorodeoxyglucose Positron Emission Tomography–Based Quantitative Imaging Features for Guiding Dose Escalation in Stage III Non-Small Cell Lung Cancer

    International Nuclear Information System (INIS)

    Fried, David V.; Mawlawi, Osama; Zhang, Lifei; Fave, Xenia; Zhou, Shouhao; Ibbott, Geoffrey; Liao, Zhongxing; Court, Laurence E.

    2016-01-01

    Purpose: To determine whether previously identified quantitative image features (QIFs) based on 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) (co-occurrence matrix energy and solidity) are able to isolate subgroups of patients who would receive a benefit or detriment from dose escalation in terms of overall survival (OS) or progression-free survival (PFS). Methods and Materials: Subgroups of a previously analyzed 225 patient cohort were generated with the use of 5-percentile increment cutoff values of disease solidity and primary tumor co-occurrence matrix energy. The subgroups were analyzed with a log-rank test to determine whether there was a difference in OS and PFS between patients treated with 60 to 70 Gy and those receiving 74 Gy. Results: In the entire patient cohort, there was no statistical difference in terms of OS or PFS between patients receiving 74 Gy and those receiving 60 to 70 Gy. It was qualitatively observed that as disease solidity and primary co-occurrence matrix energy increased, patients receiving 74 Gy had an improved OS and PFS compared with those receiving 60 to 70 Gy. The opposite trend (detriment of receiving 74 Gy) was also observed regarding low values of disease solidity and primary co-occurrence matrix energy. Conclusions: FDG-PET–based QIFs were found to be capable of isolating subgroups of patients who received a benefit or detriment from dose escalation.

  15. A phase II, randomized, single-blinded, placebo-controlled clinical trial on the efficacy of Curcumina and Calendula suppositories for the treatment of patients with chronic prostatitis/chronic pelvic pain syndrome type III.

    Science.gov (United States)

    Morgia, Giuseppe; Russo, Giorgio Ivan; Urzì, Daniele; Privitera, Salvatore; Castelli, Tommaso; Favilla, Vincenzo; Cimino, Sebastiano

    2017-06-30

    The management of chronic prostatitis/ chronic pelvic pain syndrome type III (CP/CPPS) has been always considered complex due to several biopsychological factors underling the disease. In this clinical study, we aimed to evaluate the efficacy of the treatment with Curcumin and Calendula extract in patients with CP/CPPS III. From June 2015 to January 2016 we enrolled 60 consecutive patients affected by CP/CPPS III in our institution. Patients between 20 and 50 year of age with symptoms of pelvic pain for 3 months or more before study, a total National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) score ≥ 15 point and diagnosed with NIH category III. Patients were then allocated to receive placebo (Group A) or treatment (Group B). Treatment consisted of rectal suppositories of Curcumin extract 350 mg (95%) and Calendula extract 80 mg (1 suppository/die for 1 month). Patients of Group B received 1 suppository/die for 1 month of placebo. The primary endpoint of the study was the reduction of NIH-CPSI. The secondary outcomes were the change of peak flow, IIEF-5, VAS score and of premature ejaculation diagnostic tool (PEDT). A total of 48 patients concluded the study protocol. The median age of the all cohort was 32.0 years, the median NIH-CPSI was 20.5, the median IIEF-5 was 18.5, the median PEDT was 11.0, the median VAS score was 7.5 and the median peak flow was 14.0. After 3 months of therapy in group A we observed a significant improvement of NIH-CPSI (-5.5; p < 0.01), IIEF-5 (+ 3.5; p < 0.01), PEDT (-6.5; p < 0.01), peak flow (+2.8; p < 0.01) and VAS (-6.5; p < 0.01) with significant differences over placebo group (all p-value significant). In this phase II clinical trial we showed the clinical efficacy of the treatment with Curcumin and Calendula in patients with CP/CPPS III. The benefits of this treatment could be related to the reduction of inflammatory cytokines and of inflammatory cells. These results should be confirmed in further studies with greater sample size.

  16. A phase II, randomized, single-blinded, placebo-controlled clinical trial on the efficacy of Curcumina and Calendula suppositories for the treatment of patients with chronic prostatitis/chronic pelvic pain syndrome type III

    Directory of Open Access Journals (Sweden)

    Giuseppe Morgia

    2017-06-01

    Full Text Available Objective: The management of chronic prostatitis/ chronic pelvic pain syndrome type III (CP/CPPS has been always considered complex due to several biopsychological factors underling the disease. In this clinical study, we aimed to evaluate the efficacy of the treatment with Curcumin and Calendula extract in patients with CP/CPPS III. Material and methods: From June 2015 to January 2016 we enrolled 60 consecutive patients affected by CP/CPPS III in our institution. Patients between 20 and 50 year of age with symptoms of pelvic pain for 3 months or more before study, a total National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI score ≥ 15 point and diagnosed with NIH category III. Patients were then allocated to receive placebo (Group A or treatment (Group B. Treatment consisted of rectal suppositories of Curcumin extract 350 mg (95% and Calendula extract 80 mg (1 suppository/die for 1 month. Patients of Group B received 1 suppository/die for 1 month of placebo. The primary endpoint of the study was the reduction of NIH-CPSI. The secondary outcomes were the change of peak flow, IIEF-5, VAS score and of premature ejaculation diagnostic tool (PEDT. Results: A total of 48 patients concluded the study protocol. The median age of the all cohort was 32.0 years, the median NIH-CPSI was 20.5, the median IIEF-5 was 18.5, the median PEDT was 11.0, the median VAS score was 7.5 and the median peak flow was 14.0. After 3 months of therapy in group A we observed a significant improvement of NIH-CPSI (-5.5; p < 0.01, IIEF-5 (+ 3.5; p < 0.01, PEDT (-6.5; p < 0.01, peak flow (+2.8; p < 0.01 and VAS (-6.5; p < 0.01 with significant differences over placebo group (all p-value significant. Conclusions: In this phase II clinical trial we showed the clinical efficacy of the treatment with Curcumin and Calendula in patients with CP/CPPS III. The benefits of this treatment could be related to the reduction of inflammatory cytokines and of inflammatory cells. These results should be confirmed in further studies with greater sample size.

  17. Controlled single-blind clinical evaluation of low-dose mammographic screen: film systems

    International Nuclear Information System (INIS)

    Sickles, E.A.; Genant, H.K.

    1979-01-01

    The ability of five low-dose mammographic screen-film systems to portray normal and abnormal breast structures was evaluated in parallel with a study of physical image properties. Single-blind evaluations of the visibility of normal breast architecture, mass lesions, and calcifications were made on the mammograms of 100 patients radiographed with each of the systems. There was increased noise and slightly poorer resolution of the faster recording systems, but there was no difference in final diagnostic impressions among the five systems. These results suggest that the faster systems will result in substantial dose reduction without sacrificing diagnostic accuracy

  18. A randomized, double-blind, placebo-controlled, dose-escalation first-in-man study (phase 0) to assess the safety and efficacy of topical cytosolic phospholipase A2 inhibitor, AVX001, in patients with mild to moderate plaque psoriasis

    DEFF Research Database (Denmark)

    Omland, S H; Habicht, A; Damsbo, P

    2017-01-01

    . RESULTS: AVX001 was safe with no grades 3-4 LSRAE. A 29% reduction in mPASI was seen at the 5% dose level at week four. Post hoc analysis of combined doses of 3% and 5% showed a clinical relevant effect with 31% reduction in mPASI (P = 0.058) and statically significant reduction of the infiltration (P = 0.......036). The actively treated side showed improvement in mPASI score after one week of treatment, and the observed improvement continued throughout the four weeks of treatment. CONCLUSIONS: Treatment with AVX001 is well tolerated in doses up to 5%, and showed placebo-adjusted, clinical effects at a level of statistical...

  19. A double-blind, placebo-controlled, randomised, parallel-group, dose-escalating, repeat dose study in healthy volunteers to evaluate the safety, tolerability, pharmacodynamic effects and pharmacokinetics of the once daily rectal application of NRL001 suppositories for 14 days.

    Science.gov (United States)

    Bell, D; Duffin, A; Jacobs, A; Pediconi, C; Gruss, H J

    2014-03-01

    The 1R,2S stereoisomer of methoxamine hydrochloride, NRL001, is a highly selective α1-adrenoceptor agonist being developed for the local treatment of non-structural faecal incontinence caused by weak internal anal sphincter tone. This study investigated the steady state pharmacokinetics (PK) and safety of 2 g rectal suppositories containing NRL001 in different strengths (7.5, 10, 12.5 or 15 mg). Healthy volunteers aged 18-45 years received 14 daily doses of NRL001 2 g suppositories or matching placebo. In each dose group nine participants received NRL001 and three received placebo. Blood samples to determine NRL001 concentrations were taken on Days 1, 7 and 14. Cardiovascular parameters were collected via electrocardiograms, Holter monitoring (three lead Holter monitor) and vital signs. Forty-eight volunteers were enrolled; 43 completed the study and were included in the PK analysis population. AUC and Cmax broadly increased with increasing dose, Tmax generally occurred between 4.0 and 5.0 h. Although the data did not appear strongly dose proportional, dose proportionality analysis did not provide evidence against dose proportionality as the log(dose) coefficients were not significantly < 1. NRL001 did not accumulate over time for any dose. Increasing NRL001 concentrations were related to changes in vital sign variables, most notably decreased heart rate. The most commonly reported adverse events (AEs) in the active treatment groups were paraesthesia and piloerection. Treatment with NRL001 was generally well tolerated over 14 days once daily dosing and plasma NRL001 did not accumulate over time. Treatment was associated with changes in vital sign variables, most notably decreased heart rate. AEs commonly reported with NRL001 treatment were events indicative of a systemic α-adrenergic effect. Colorectal Disease © 2014 The Association of Coloproctology of Great Britain and Ireland.

  20. Safety and immunogenicity in man of a cell culture derived trivalent live attenuated seasonal influenza vaccine: a Phase I dose escalating study in healthy volunteers.

    Science.gov (United States)

    Heldens, Jacco; Hulskotte, Ellen; Voeten, Theo; Breedveld, Belinda; Verweij, Pierre; van Duijnhoven, Wilbert; Rudenko, Larissa; van Damme, Pierre; van den Bosch, Han

    2014-09-03

    Live attenuated influenza vaccine (LAIV) offers the promise of inducing a variety of immune responses thereby conferring protection to circulating field strains. LAIVs are based on cold adapted and temperature sensitive phenotypes of master donor viruses (MDVs) containing the surface glycoprotein genes of seasonal influenza strains. Two types of MDV lineages have been described, the Ann Arbor lineages and the A/Leningrad/17 and B/USSR/60 lineages. Here the safety and immunogenicity of a Madin Darby Canine Kidney - cell culture based, intranasal LAIV derived from A/Leningrad/17 and B/USSR, was evaluated in healthy influenza non-naive volunteers 18-50 years of age. In a double-blind, randomized, placebo-controlled design, single escalating doses of 1×10(5), 1×10(6), or 1×10(7) tissue culture infectious dose 50% (TCID50) of vaccine containing each of the three influenza virus re-assortants recommended by the World Health Organization for the 2008-2009 season were administered intranasally. A statistically significant geometric mean increase in hemagglutination inhibition titer was reached for influenza strain A/H3N2 after immunization with all doses of LAIV. For the A/H1N1 and B strains, the GMI in HI titer did not increase for any of the doses. Virus neutralization antibody titers showed a similar response pattern. A dose-response effect could not be demonstrated for any of the strains, neither for the HI antibody nor for the VN antibody responses. No influenza like symptoms, no nasal congestions, no rhinorrhea, or other influenza related upper respiratory tract symptoms were observed. In addition, no difference in the incidence or nature of adverse events was found between vaccine and placebo treated subjects. Overall, the results indicated that the LAIV for nasal administration is immunogenic (i.e. able to provoke an immune response) and safe both from the perspective of the attenuated virus and the MDCK cell line from which it was derived, and it warrants

  1. Does different information disclosure on placebo control affect blinding and trial outcomes? A case study of participant information leaflets of randomized placebo-controlled trials of acupuncture

    Directory of Open Access Journals (Sweden)

    Soyeon Cheon

    2018-01-01

    Full Text Available Abstract Background While full disclosure of information on placebo control in participant information leaflets (PILs in a clinical trial is ethically required during informed consent, there have been concerning voices such complete disclosures may increase unnecessary nocebo responses, breach double-blind designs, and/or affect direction of trial outcomes. Taking an example of acupuncture studies, we aimed to examine what participants are told about placebo controls in randomized, placebo-controlled trials, and how it may affect blinding and trial outcomes. Methods Authors of published randomized, placebo-controlled trials of acupuncture were identified from PubMed search and invited to provide PILs for their trials. The collected PILs were subjected to content analysis and categorized based on degree of information disclosure on placebo. Blinding index (BI as a chance-corrected measurement of blinding was calculated and its association with different information disclosure was examined. The impact of different information disclosure from PILs on primary outcomes was estimated using a random effects model. Results In 65 collected PILs, approximately 57% of trials fully informed the participants of placebo control, i.e. full disclosure, while the rest gave deceitful or no information on placebo, i.e. no disclosure. Placebo groups in the studies with no disclosure tended to make more opposite guesses on the type of received intervention than those with disclosure, which may reflect wishful thinking (BI −0.21 vs. −0.16; p = 0.38. In outcome analysis, studies with no disclosure significantly favored acupuncture than those with full disclosure (standardized mean difference − 0.43 vs. −0.12; p = 0.03, probably due to enhanced expectations. Conclusions How participants are told about placebos can be another potential factor that may influence participant blinding and study outcomes by possibly modulating patient expectation. As we

  2. Active placebo control groups of pharmacological interventions were rarely used but merited serious consideration

    DEFF Research Database (Denmark)

    Jensen, Jakob Solgaard; Bielefeldt, Andreas Ørsted; Hróbjartsson, Asbjørn

    2017-01-01

    groups based on a random sample of 200 PubMed indexed placebo-controlled randomized drug trials published in October 2013. In a systematic review, we identified and characterized trials with active placebo control groups irrespective of publication time. In a third substudy, we reviewed publications...... with substantial methodological comments on active placebo groups (searches in PubMed, The Cochrane Library, Google Scholar, and HighWirePress). Results The prevalence of trials with active placebo groups published in 2013 was 1 out of 200 (95% confidence interval: 0–2), 0.5% (0–1%). We identified...

  3. Upper limb robot-assisted therapy in cerebral palsy: a single-blind randomized controlled trial.

    Science.gov (United States)

    Gilliaux, Maxime; Renders, Anne; Dispa, Delphine; Holvoet, Dominique; Sapin, Julien; Dehez, Bruno; Detrembleur, Christine; Lejeune, Thierry M; Stoquart, Gaëtan

    2015-02-01

    Several pilot studies have evoked interest in robot-assisted therapy (RAT) in children with cerebral palsy (CP). To assess the effectiveness of RAT in children with CP through a single-blind randomized controlled trial. Sixteen children with CP were randomized into 2 groups. Eight children performed 5 conventional therapy sessions per week over 8 weeks (control group). Eight children completed 3 conventional therapy sessions and 2 robot-assisted sessions per week over 8 weeks (robotic group). For both groups, each therapy session lasted 45 minutes. Throughout each RAT session, the patient attempted to reach several targets consecutively with the REAPlan. The REAPlan is a distal effector robot that allows for displacements of the upper limb in the horizontal plane. A blinded assessment was performed before and after the intervention with respect to the International Classification of Functioning framework: body structure and function (upper limb kinematics, Box and Block test, Quality of Upper Extremity Skills Test, strength, and spasticity), activities (Abilhand-Kids, Pediatric Evaluation of Disability Inventory), and participation (Life Habits). During each RAT session, patients performed 744 movements on average with the REAPlan. Among the variables assessed, the smoothness of movement (P robotic group than in the control group. This single-blind randomized controlled trial provides the first evidence that RAT is effective in children with CP. Future studies should investigate the long-term effects of this therapy. © The Author(s) 2014.

  4. ASCENDE-RT: An Analysis of Treatment-Related Morbidity for a Randomized Trial Comparing a Low-Dose-Rate Brachytherapy Boost with a Dose-Escalated External Beam Boost for High- and Intermediate-Risk Prostate Cancer

    International Nuclear Information System (INIS)

    Rodda, Sree; Tyldesley, Scott; Morris, W. James; Keyes, Mira; Halperin, Ross; Pai, Howard; McKenzie, Michael; Duncan, Graeme; Morton, Gerard; Hamm, Jeremy; Murray, Nevin

    2017-01-01

    Purpose: To report the genitourinary (GU) and gastrointestinal (GI) morbidity and erectile dysfunction in a randomized trial comparing 2 methods of dose escalation for high- and intermediate-risk prostate cancer. Methods and Materials: ASCENDE-RT (Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy) enrolled 398 men, median age 68 years, who were then randomized to either a standard arm that included 12 months of androgen deprivation therapy and pelvic irradiation to 46 Gy followed by a dose-escalated external beam radiation therapy (DE-EBRT) boost to 78 Gy, or an experimental arm that substituted a low-dose-rate prostate brachytherapy (LDR-PB) boost. At clinic visits, investigators recorded GU and GI morbidity and information on urinary continence, catheter use, and erectile function. Exclusion of 15 who received nonprotocol treatment and correction of 14 crossover events left 195 men who actually received a DE-EBRT boost and 188, an LDR-PB boost. Median follow-up was 6.5 years. Results: The LDR-PB boost increased the risk of needing temporary catheterization and/or requiring incontinence pads. At 5 years the cumulative incidence of grade 3 GU events was 18.4% for LDR-PB, versus 5.2% for DE-EBRT (P<.001). Compared with the cumulative incidence, the 5-year prevalence of grade 3 GU morbidity was substantially lower for both arms (8.6% vs 2.2%, P=.058). The 5-year cumulative incidence of grade 3 GI events was 8.1% for LDR-PB, versus 3.2% for DE-EBRT (P=.124). The 5-year prevalence of grade 3 GI toxicity was lower than the cumulative incidence for both arms (1.0% vs 2.2%, respectively). Among men reporting adequate baseline erections, 45% of LDR-PB patients reported similar erectile function at 5 years, versus 37% after DE-EBRT (P=.30). Conclusions: The incidence of acute and late GU morbidity was higher after LDR-PB boost, and there was a nonsignificant trend for worse GI morbidity. No differences in the frequency of

  5. Impact of whole brain radiation therapy on CSF penetration ability of Icotinib in EGFR-mutated non-small cell lung cancer patients with brain metastases: Results of phase I dose-escalation study.

    Science.gov (United States)

    Zhou, Lin; He, Jiazhuo; Xiong, Weijie; Liu, Yongmei; Xiang, Jing; Yu, Qin; Liang, Maozhi; Zhou, Xiaojuan; Ding, Zhenyu; Huang, Meijuan; Ren, Li; Zhu, Jiang; Li, Lu; Hou, Mei; Ding, Lieming; Tan, Fenlai; Lu, You

    2016-06-01

    Whole-brain radiation therapy (WBRT) and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are both treatment options for EGFR-mutated non-small cell lung cancer (NSCLC) patients with brain metastases. However, the dose-escalation toxicity and efficacy of combination therapy, and the effect of WBRT on cerebrospinal fluid (CSF) penetration of EGFR-TKIs are still unclear. EGFR-mutated NSCLC patients with brain metastases were enrolled in this study, and the cohorts were constructed with a 3+3 design. The patients received icotinib with escalating doses (125-625mg, tid), and the concurrent WBRT (37.5Gy/15f/3weeks) started a week later. The CSF penetration rates of icotinib were tested before, immediately after, and 4 weeks after WBRT, respectively. Potential toxicities and benefits from dose-escalation treatment were analyzed. Fifteen patients were included in this study, 3 at each dose level from 125mg-375mg and 6 at 500mg with 3 occurred dose-limiting toxicities. The maximal tolerated dose of icotinib was 375mg tid in this combination therapy. There was a significant correlation between icotinib concentration in the CSF and plasma (R(2)=0.599, Picotinib, from 1.2% to 9.7%, reached a maximum at 375mg (median, 6.1%). There was no significant difference for CSF penetration rates among the three test points (median, 4.1% vs. 2.8% vs. 2.8%, P=0.16). The intracranial objective response rate and median intracranial progression free survival are 80% and 18.9 months. WBRT plus concurrent icotinib is well tolerated in EGFR-mutated NSCLC patients with brain metastases, up to an icotinib dose of 375mg tid. The icotinib CSF concentration seemed to have a potential ceiling effect with the dose escalation, and WBRT seemed to have no significant impact on CSF penetration of icotinib till 4 weeks after the treatment. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  6. Phase I study of continuous MKC-1 in patients with advanced or metastatic solid malignancies using the modified Time-to-Event Continual Reassessment Method (TITE-CRM) dose escalation design.

    Science.gov (United States)

    Tevaarwerk, Amye; Wilding, George; Eickhoff, Jens; Chappell, Rick; Sidor, Carolyn; Arnott, Jamie; Bailey, Howard; Schelman, William; Liu, Glenn

    2012-06-01

    MKC-1 is an oral cell-cycle inhibitor with broad antitumor activity in preclinical models. Clinical studies demonstrated modest antitumor activity using intermittent dosing schedule, however additional preclinical data suggested continuous dosing could be efficacious with additional effects against the mTor/AKT pathway. The primary objectives were to determine the maximum tolerated dose (MTD) and response of continuous MKC-1. Secondary objectives included characterizing the dose limiting toxicities (DLTs) and pharmacokinetics (PK). Patients with solid malignancies were eligible, if they had measurable disease, ECOG PS ≤1, and adequate organ function. Exclusions included brain metastases and inability to receive oral drug. MKC-1 was dosed twice daily, continuously in 28-day cycles. Other medications were eliminated if there were possible drug interactions. Doses were assigned using a TITE-CRM algorithm following enrollment of the first 3 pts. Disease response was assessed every 8 weeks. Between 5/08-9/09, 24 patients enrolled (15 M/9 F, median 58 years, range 44-77). Patients 1-3 received 120 mg/d of MKC-1; patients 4-24 were dosed per the TITE-CRM algorithm: 150 mg [n = 1], 180 [2], 200 [1], 230 [1], 260 [5], 290 [6], 320 [5]. The median time on drug was 8 weeks (range 4-28). The only DLT occurred at 320 mg (grade 3 fatigue). Stable disease occurred at 150 mg/d (28 weeks; RCC) and 320 mg/d (16 weeks; breast, parotid). Escalation halted at 320 mg/d. Day 28 pharmacokinetics indicated absorption and active metabolites. Continuous MKC-1 was well-tolerated; there were no RECIST responses, although clinical benefit occurred in 3/24 pts. Dose escalation stopped at 320 mg/d, and this is the MTD as defined by the CRM dose escalation algorithm; this cumulative dose/cycle exceeds that determined from intermittent dosing studies. A TITE-CRM allowed for rapid dose escalation and was able to account for late toxicities with continuous dosing via a modified algorithm.

  7. ASCENDE-RT: An Analysis of Treatment-Related Morbidity for a Randomized Trial Comparing a Low-Dose-Rate Brachytherapy Boost with a Dose-Escalated External Beam Boost for High- and Intermediate-Risk Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Rodda, Sree [British Columbia (BC) Cancer Agency, Vancouver Centre, Vancouver, British Columbia (Canada); Tyldesley, Scott [British Columbia (BC) Cancer Agency, Vancouver Centre, Vancouver, British Columbia (Canada); Department of Surgery, University of British Columbia, Vancouver, British Columbia (Canada); Morris, W. James, E-mail: jmorris@bccancer.bc.ca [British Columbia (BC) Cancer Agency, Vancouver Centre, Vancouver, British Columbia (Canada); Department of Surgery, University of British Columbia, Vancouver, British Columbia (Canada); Keyes, Mira [British Columbia (BC) Cancer Agency, Vancouver Centre, Vancouver, British Columbia (Canada); Department of Surgery, University of British Columbia, Vancouver, British Columbia (Canada); Halperin, Ross [Department of Surgery, University of British Columbia, Vancouver, British Columbia (Canada); BC Cancer Agency, Centre for the Southern Interior, Kelowna, British Columbia (Canada); Pai, Howard [Department of Surgery, University of British Columbia, Vancouver, British Columbia (Canada); BC Cancer Agency, Vancouver Island Centre, Victoria, British Columbia (Canada); McKenzie, Michael; Duncan, Graeme [British Columbia (BC) Cancer Agency, Vancouver Centre, Vancouver, British Columbia (Canada); Department of Surgery, University of British Columbia, Vancouver, British Columbia (Canada); Morton, Gerard [Sunnybrook Health Sciences Centre, Toronto, Ontario (Canada); Department of Radiation Oncology, University of Toronto, Toronto, Ontario (Canada); Hamm, Jeremy [Department of Population Oncology, BC Cancer Agency, Vancouver, British Columbia (Canada); Murray, Nevin [British Columbia (BC) Cancer Agency, Vancouver Centre, Vancouver, British Columbia (Canada); Department of Medicine, University of British Columbia, Vancouver, British Columbia (Canada)

    2017-06-01

    Purpose: To report the genitourinary (GU) and gastrointestinal (GI) morbidity and erectile dysfunction in a randomized trial comparing 2 methods of dose escalation for high- and intermediate-risk prostate cancer. Methods and Materials: ASCENDE-RT (Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy) enrolled 398 men, median age 68 years, who were then randomized to either a standard arm that included 12 months of androgen deprivation therapy and pelvic irradiation to 46 Gy followed by a dose-escalated external beam radiation therapy (DE-EBRT) boost to 78 Gy, or an experimental arm that substituted a low-dose-rate prostate brachytherapy (LDR-PB) boost. At clinic visits, investigators recorded GU and GI morbidity and information on urinary continence, catheter use, and erectile function. Exclusion of 15 who received nonprotocol treatment and correction of 14 crossover events left 195 men who actually received a DE-EBRT boost and 188, an LDR-PB boost. Median follow-up was 6.5 years. Results: The LDR-PB boost increased the risk of needing temporary catheterization and/or requiring incontinence pads. At 5 years the cumulative incidence of grade 3 GU events was 18.4% for LDR-PB, versus 5.2% for DE-EBRT (P<.001). Compared with the cumulative incidence, the 5-year prevalence of grade 3 GU morbidity was substantially lower for both arms (8.6% vs 2.2%, P=.058). The 5-year cumulative incidence of grade 3 GI events was 8.1% for LDR-PB, versus 3.2% for DE-EBRT (P=.124). The 5-year prevalence of grade 3 GI toxicity was lower than the cumulative incidence for both arms (1.0% vs 2.2%, respectively). Among men reporting adequate baseline erections, 45% of LDR-PB patients reported similar erectile function at 5 years, versus 37% after DE-EBRT (P=.30). Conclusions: The incidence of acute and late GU morbidity was higher after LDR-PB boost, and there was a nonsignificant trend for worse GI morbidity. No differences in the frequency of

  8. Post treatment PSA nadirs support continuing dose escalation study in patients with pretreatment PSA levels >10 ng/ml, but not in those with PSA <10 NG/ML

    International Nuclear Information System (INIS)

    Herold, D.H.; Hanlon, A.L.; Movsas, B.; Hanks, G.E.

    1996-01-01

    Purpose: We have recently shown that ICRU reporting point radiation doses above 71 Gy are not associated with improved bNED survival in prostate cancer patients with pretreatment PSA level 20 ng/ml we found a strong correlation between dose and nadir values < 1.0 ng/ml (p=.003) as well as for nadir's < 0.5 ng/ml (p=.04). This dose/nadir effect held at several dose levels, but 74 Gy for nadir values < 1.0 ng/ml and 72 Gy for nadir's < 0.5 ng/ml remained the most significant. 32% of these patients achieved a nadir < 1.0ng/ml and 15% < 0.5ng/ml. Conclusions: This analysis provides strong additional support that patients with pretreatment PSA values of < 10 ng/ml do not benefit from dose escalation beyond an ICRU reporting point dose of 71 Gy. For patients with pretreatment PSA's of 10-19.9 ng/ml there is no dose/nadir response evaluated at a nadir of 1.0 ng/ml; however, there is a borderline effect observed at a nadir of 0.5 ng/ml. Patients with pretreatment PSA's of 20 ng/ml or greater clearly benefit from higher doses as evaluated by PSA nadirs of 1.0 ng/ml, and 0.5 ng/ml. These studies support the continued investigation of dose escalation in treating patients with PSA levels over 10 ng/ml, they do not support continued investigation of dose escalation beyond 71 Gy in patients with pretreatment PSA levels < 10 ng/ml. The failure to demonstrate any dose response for the low PSA group and the finding of only a borderline effect for the intermediate PSA group may be influenced by the relatively small number of patients in our series treated to doses < 70 Gy and the fact that none of our patients were treated to doses below 65.98 Gy. The lower limit of acceptible dose has yet to be defined

  9. Phase I dose-escalation study of the c-Met tyrosine kinase inhibitor SAR125844 in Asian patients with advanced solid tumors, including patients with MET-amplified gastric cancer.

    Science.gov (United States)

    Shitara, Kohei; Kim, Tae Min; Yokota, Tomoya; Goto, Masahiro; Satoh, Taroh; Ahn, Jin-Hee; Kim, Hyo Song; Assadourian, Sylvie; Gomez, Corinne; Harnois, Marzia; Hamauchi, Satoshi; Kudo, Toshihiro; Doi, Toshihido; Bang, Yung-Jue

    2017-10-03

    SAR125844 is a potent and selective inhibitor of the c-Met kinase receptor. This was an open-label, phase I, multicenter, dose-escalation, and dose-expansion trial of SAR125844 in Asian patients with solid tumors, a subgroup of whom had gastric cancer and MET amplification (NCT01657214). SAR125844 was administered by intravenous infusion (260-570 mg/m 2 ) on days 1, 8, 15, and 22 of each 28-day cycle. Objectives were to determine the maximum tolerated dose (MTD) and to evaluate SAR125844 safety and pharmacokinetic profile. Antitumor activity was also assessed. Of 38 patients enrolled (median age 64.0 years), 22 had gastric cancer, including 14 with MET amplification. In the dose-escalation cohort ( N = 19; unselected population, including three patients with MET -amplification [two with gastric cancer and one with lung cancer]), the MTD was not reached, and the recommended dose was established at 570 mg/m 2 . Most frequent treatment-emergent adverse events (AEs) were nausea (36.8%), vomiting (34.2%), decreased appetite (28.9%), and fatigue or asthenia, constipation, and abdominal pains (each 21.1%); none appeared to be dose-dependent. Grade ≥ 3 AEs were observed in 39.5% of patients and considered drug-related in 7.9%. SAR125844 exposure increased slightly more than expected by dose proportionality; dose had no significant effect on clearance. No objective responses were observed in the dose-escalation cohort, with seven patients (three gastric cancer, two colorectal cancer, one breast cancer, and one with cancer of unknown primary origin) having stable disease. Modest antitumor activity was observed at 570 mg/m 2 in the dose-expansion cohort, comprising patients with MET -amplified tumors ( N = 19). Two gastric cancer patients had partial responses, seven patients had stable disease (six gastric cancer and one kidney cancer), and 10 patients had progressive disease. Single-agent SAR125844 administered up to 570 mg/m 2 has acceptable tolerability and modest

  10. An algorithm for evaluating the ethics of a placebo-controlled trial.

    Science.gov (United States)

    Amdur, R J; Biddle, C J

    2001-10-20

    The purpose of this article is to clarify the decision points that are important to consider when evaluating the ethics of a placebo-controlled trial. The ethical requirements for research involving human subjects are reviewed, and the rationale for and potential problems with concomitant placebo control are explained. A series of case discussions are used to illustrate each decision point. The critical decision points in the evaluation of the ethics of a placebo-controlled trial are as follows: (i) Is placebo being used in place of standard therapy? (ii) Is standard therapy likely to be effective? (iii) Is the toxicity of standard therapy such that patients routinely refuse this treatment? (iv) Could the use of placebo result in severe suffering or irreversible harm? (v) Is the variability in the placebo response such that it is reasonable to consider other options for the control group? (vi) Would a reasonable person with an average degree of altruism and risk aversiveness agree to participate in this study? The algorithm presented in this article gives researchers and research monitors (such as Institutional Review Board members) the tools they need to evaluate the ethics of a study that uses concomitant placebo control. Copyright 2001 Wiley-Liss, Inc.

  11. No matrix effect in double-blind, placebo-controlled egg challenges in egg allergic children

    NARCIS (Netherlands)

    Libbers, L.; Flokstra-de Blok, B. M. J.; Vlieg-Boerstra, B. J.; van der Heide, S.; van der Meulen, G. N.; Kukler, J.; Kerkhof, M.; Dubois, A. E. J.

    Background Diagnostic and accidental food allergic reactions may be modified by the matrix containing the allergenic food. Previous studies of double-blind, placebo-controlled food challenges (DBPCFCs) with peanut found an effect of the fat content of the challenge matrix on the severity of the

  12. A double-blind placebo controlled trial of paroxetine in the ...

    African Journals Online (AJOL)

    A double-blind placebo controlled trial of paroxetine in the management of social phobia (social anxiety disorder) in South Africa. Dan J. Stein, Michael Berk, Charl Els, Robin A. Emsley, Leon Gittelson, Don Wilson, Rosemary Oakes, Brian Hunter ...

  13. Male hormonal contraception: a double-blind, placebo-controlled study.

    NARCIS (Netherlands)

    Mommers, E.; Kersemaekers, W.M.; Elliesen, J.; Kepers, M.; Apter, D.; Behre, H.M.; Beynon, J.; Bouloux, P.M.; Costantino, A.; Gerbershagen, H.P.; Gronlund, L.; Heger-Mahn, D.; Huhtaniemi, I.; Koldewijn, E.L.; Lange, C.; Lindenberg, S.; Meriggiola, M.C.; Meuleman, E.J.H.; Mulders, P.F.A.; Nieschlag, E.; Perheentupa, A.; Solomon, A.; Vaisala, L.; Wu, F.C.; Zitzmann, M.

    2008-01-01

    BACKGROUND: This study was performed to assess spermatogenesis suppression and safety of a new combination of an etonogestrel (ENG) implant combined with testosterone undecanoate (TU) injections for male contraception. This is the first large placebo-controlled study for male hormonal contraception.

  14. Exclusively breastfed infants at risk for false negative double blind placebo controlled milk challenge

    NARCIS (Netherlands)

    Petrus, N. C. M.; Kole, E. A.; Schoemaker, A. A.; van Aalderen, W. M. C.; Sprikkelman, A. B.

    2014-01-01

    The double blind placebo controlled food challenge (DBPCFC) is the gold standard for diagnosing cow's milk allergy (CMA). However, false-negative DBPCFC have been reported. We present 2 cases with a false negative DBPCFC in exclusively breastfed infants suspected of CMA. These cases highlight the

  15. The challenge of recruiting patients into a placebo-controlled surgical trial

    DEFF Research Database (Denmark)

    Hare, Kristoffer B; Lohmander, L Stefan; Roos, Ewa M.

    2014-01-01

    BACKGROUND: Randomized placebo-controlled trials represent the gold standard in evaluating healthcare interventions but are rarely performed within orthopedics. Ethical concerns or well-known challenges in recruiting patients for surgical trials in general have been expressed and adding a placebo...

  16. Escitalopram in the Treatment of Adolescent Depression: A Randomized Placebo-Controlled Multisite Trial

    Science.gov (United States)

    Emslie, Graham J.; Ventura, Daniel; Korotzer, Andrew; Tourkodimitris, Stavros

    2009-01-01

    A randomized, double-blind, placebo-controlled trial that involves 312 male and female patients aged 12-17 reveal the effectiveness of escitalopram in the treatment of depressed adolescents. Eighty-three percent of the participants or 259 participants completed the 8 weeks therapy period.

  17. A double-blind, placebo-controlled study of sertraline with naltrexone for alcohol dependence.

    LENUS (Irish Health Repository)

    Farren, Conor K

    2009-01-01

    Significant preclinical evidence exists for a synergistic interaction between the opioid and the serotonin systems in determining alcohol consumption. Naltrexone, an opiate receptor antagonist, is approved for the treatment of alcohol dependence. This double-blind placebo-controlled study examined whether the efficacy of naltrexone would be augmented by concurrent treatment with sertraline, a selective serotonin receptor uptake inhibitor (SSRI).

  18. Melatonin for chronic whiplash syndrome with delayed melatonin onset randomised, placebo-controlled trial

    NARCIS (Netherlands)

    Wieringen, S. van; Jansen, T.; Smits, M.G.; Nagtegaal, J.E.; Coenen, A.M.L.

    2001-01-01

    Objective: To assess the influence of melatonin in patients with chronic whiplash syndrome and delayed melatonin onset. Design: Randomised, double-blind, placebo-controlled, parallel-group trial. One-week baseline was followed by a 4-week treatment period with either melatonin or placebo. In the

  19. Clinical effects of buspirone in social phobia : A double-blind placebo-controlled study

    NARCIS (Netherlands)

    denBoer, JA; Westenberg, HGM; Pian, KLH

    Background: The results of open pilot studies suggest that the serotonin-1A (5-HT1A) receptor agonist buspirone might be effective in social phobia. Method: In the present study, the efficacy of buspirone was investigated in patients with social phobia using a 12-week double-blind placebo-controlled

  20. Mefloquine prophylaxis prevents malaria during pregnancy: a double-blind, placebo-controlled study

    NARCIS (Netherlands)

    Nosten, F.; ter Kuile, F.; Maelankiri, L.; Chongsuphajaisiddhi, T.; Nopdonrattakoon, L.; Tangkitchot, S.; Boudreau, E.; Bunnag, D.; White, N. J.

    1994-01-01

    A double-blind, placebo-controlled study of mefloquine antimalarial prophylaxis in pregnancy (> 20 weeks of gestation) was conducted in 339 Karen women living in an area of multidrug-resistant malaria transmission on the Thai-Burmese border. Mefloquine gave > or = 86% (95% confidence interval [CI],

  1. Melatonin for chronic sleep onset insomnia in children: A Randomized placebo-controlled study

    NARCIS (Netherlands)

    Smits, M.G.; Nagtegaal, J.E.; Heijden, J.A.M. van der; Coenen, A.M.L.; Kerkhof, G.A.

    2001-01-01

    To establish the efficacy of melatonin treatment in childhood sleep onset insomnia, 40 elementary school children, 6 to 12 years of age, who suffered more than 1 year from chronic sleep onset insomnia, were studied in a double-blind, placebo-controlled study. The children were randomly assigned to

  2. Validation and acceptability of double-blind, placebo-controlled food challenges in children

    NARCIS (Netherlands)

    Venter, Carina; Maslin, Kate; Patil, Veeresh; Grundy, Jane; Glasbey, Gillian; Raza, Abid; Vlieg-Boerstra, Berber; Dean, Taraneh

    2016-01-01

    The Double Blind Placebo Controlled Food Challenge (DBPCFC) is considered the gold standard for food allergy diagnosis (1, 2). It is recommended that active and placebo challenge foods for DBPCFCs are sufficiently blinded in terms of smell, flavour and texture. Difficulties arise with children

  3. Treatment of post-myocardial infarction depressive disorder : A randomized, placebo-controlled trial with mirtazapine

    NARCIS (Netherlands)

    Honig, Adriaan; Kuyper, Astrid M. G.; Schene, Aart H.; van Melle, Joost P.; De Jonge, Peter; Tulner, Dorien M.; Schins, Annique; Crijns, Harry J. G. M.; Kuijpers, Petra M. J. C.; Vossen, Helen; Lousberg, Richel; Ormel, Johan

    Objective: To examine the antidepressant efficacy of a dual-acting antidepressant (mirtazapine) in patients with post-myocardial infarction (MI) depressive disorder. Antidepressants used in post MI trials with a randomized, double-blind, placebo-controlled design have been restricted to selective

  4. Working Memory Training in Young Children with ADHD: A Randomized Placebo-Controlled Trial

    Science.gov (United States)

    Dongen-Boomsma, Martine; Vollebregt, Madelon A.; Buitelaar, Jan K.; Slaats-Willemse, Dorine

    2014-01-01

    Background: Until now, working memory training has not reached sufficient evidence as effective treatment for ADHD core symptoms in children with ADHD; for young children with ADHD, no studies are available. To this end, a triple-blind, randomized, placebo-controlled study was designed to assess the efficacy of Cogmed Working Memory Training…

  5. Ewing sarcoma localized on spine: a dose escalation study in child; Sarcome d'Ewing localise au rachis: une etude d'escalade de dose chez l'enfant

    Energy Technology Data Exchange (ETDEWEB)

    Vogin, G.; Marchesi, V. [Centre Alexis-Vautrin, Nancy (France); Biston, M.C.; Gassa, F. [Centre Leon-Berard, Lyon (France); Amessis, M.; Zefkili, S.; Helfre, S. [Institut Curie, Paris (France); De Marzi, L.; Lacroix, F.; Leroy, A. [Institut Curie, Orsay (France)

    2011-10-15

    The authors report the study of dose escalation for the treatment of spinal in two types of Ewing tumours. They used 5 dose levels at the rate of five 1,6 Gy per week. They compare different radiotherapy techniques: three-dimensional conformation radiotherapy, static intensity-modulated conformational radiotherapy, helical tomo-therapy, volume-modulated arc-therapy (VMAT), stereotactic radiotherapy, and proton-therapy (in passive diffusion). It appears that it is possible to safely and efficiently deliver until 70,4 Gy in some Ewing tumours. In child, exclusive radiotherapy might become a local treatment option and would require a clinic trial and comparison with exclusive surgery or post-operative radiotherapy. Short communication

  6. A European multicenter randomized double-blind placebo-controlled monotherapy clinical trial of milnacipran in treatment of fibromyalgia

    DEFF Research Database (Denmark)

    Branco, Jaime C; Zachrisson, Olof; Perrot, Serge

    2010-01-01

    This randomized, double-blind, placebo-controlled, multicenter study investigated the efficacy and safety of milnacipran in the treatment of fibromyalgia (FM) in a European population.......This randomized, double-blind, placebo-controlled, multicenter study investigated the efficacy and safety of milnacipran in the treatment of fibromyalgia (FM) in a European population....

  7. Single-Blinded Prospective Implementation of a Preoperative Imaging Checklist for Endoscopic Sinus Surgery.

    Science.gov (United States)

    Error, Marc; Ashby, Shaelene; Orlandi, Richard R; Alt, Jeremiah A

    2018-01-01

    Objective To determine if the introduction of a systematic preoperative sinus computed tomography (CT) checklist improves identification of critical anatomic variations in sinus anatomy among patients undergoing endoscopic sinus surgery. Study Design Single-blinded prospective cohort study. Setting Tertiary care hospital. Subjects and Methods Otolaryngology residents were asked to identify critical surgical sinus anatomy on preoperative CT scans before and after introduction of a systematic approach to reviewing sinus CT scans. The percentage of correctly identified structures was documented and compared with a 2-sample t test. Results A total of 57 scans were reviewed: 28 preimplementation and 29 postimplementation. Implementation of the sinus CT checklist improved identification of critical sinus anatomy from 24% to 84% correct ( P identification of sinus anatomic variants, including those not directly included in the systematic review implemented. Conclusion The implementation of a preoperative endoscopic sinus surgery radiographic checklist improves identification of critical anatomic sinus variations in a training population.

  8. Familiar trespassers in histopathology: An obstacle in diagnosis? A single-blind study

    Directory of Open Access Journals (Sweden)

    P Shashikala

    2017-01-01

    Full Text Available Background: Histopathologists encounter strange structures in tissue sections that appear unrelated to tissues, and these artifacts may be misinterpreted and misdiagnosed as pathological lesions. These substances may either be present within the tissues or can get implanted into tissue during biopsy procedure or laboratory handling or processing. Aims: The aim of this study is to observe the microscopic appearance of different abnormal structures like commonly implanted food particles or easily incorporated substances during tissue processing with their probable histological misdiagnosis. Materials and Methods: Certain food particles, suture materials, wood pieces, insects, and filter paper were intentionally introduced in the tissue specimens of uterus and lung. Following routine processing and hematoxylin and eosin staining, the slides were subjected to single-blind study and viewed under light and polarizing microscope. Results: The vivid appearances of these structures lead to histological misdiagnosis. Conclusion: Knowledge and familiarity of these commonly encountered extraneous substances will help to prevent misinterpretation.

  9. Safety and Immunogenicity of EBA-175 RII-NG Malaria Vaccine Administered Intramuscularly in Semi-Immune Adults: A Phase 1, Double-Blinded Placebo Controlled Dosage Escalation Study.

    Directory of Open Access Journals (Sweden)

    Kwadwo A Koram

    Full Text Available The erythrocyte binding antigen region II (EBA-175 RII is a Plasmodium falciparum ligand that mediates erythrocyte invasion and is considered an important malaria vaccine candidate. A phase Ia trial in malaria naïve adults living in the United States found the recombinant non-glycosylated vaccine antigen, EBA-175 RII-NG adjuvanted with aluminium phosphate to be safe, immunogenic and capable of inducing biologically active antibodies that can inhibit parasite growth in vitro. The aim of the current study was to assess the safety and immunogenicity of this vaccine in malaria exposed semi-immune healthy adults living in a malaria endemic country, Ghana. In this double-blinded, placebo controlled, dose escalation phase I trial, eighteen subjects per group received ascending dose concentrations (5 μg, 20 μg or 80 μg of the vaccine intramuscularly at 0, 1 and 6 months, while 6 subjects received placebo (normal saline. The primary end point was the number of subjects experiencing Grade 3 systemic or local adverse events within 14 days post-vaccination. Serious adverse events were assessed throughout the study period. Blood samples for immunological analyses were collected at days 0, 14, 28, 42, 180 and 194. A total of 52 subjects received three doses of the vaccine in the respective groups. No serious adverse events were reported. The majority of all adverse events reported were mild to moderate in severity, with local pain and tenderness being the most common. All adverse events, irrespective of severity, resolved without any sequelae. Subjects who received any of the EBA-175 RII-NG doses had high immunoglobulin G levels which moderately inhibited P. falciparum growth in vitro, compared to those in the placebo group. In conclusion, the EBA-175 RII-NG vaccine was safe, well tolerated and immunogenic in malaria semi-immune Ghanaian adults. Its further development is recommended.ClinicalTrials.gov. Identifier: NCT01026246.

  10. Safety and Immunogenicity of EBA-175 RII-NG Malaria Vaccine Administered Intramuscularly in Semi-Immune Adults: A Phase 1, Double-Blinded Placebo Controlled Dosage Escalation Study.

    Science.gov (United States)

    Koram, Kwadwo A; Adu, Bright; Ocran, Josephine; Karikari, Yaa S; Adu-Amankwah, Susan; Ntiri, Michael; Abuaku, Benjamin; Dodoo, Daniel; Gyan, Ben; Kronmann, Karl C; Nkrumah, Francis

    2016-01-01

    The erythrocyte binding antigen region II (EBA-175 RII) is a Plasmodium falciparum ligand that mediates erythrocyte invasion and is considered an important malaria vaccine candidate. A phase Ia trial in malaria naïve adults living in the United States found the recombinant non-glycosylated vaccine antigen, EBA-175 RII-NG adjuvanted with aluminium phosphate to be safe, immunogenic and capable of inducing biologically active antibodies that can inhibit parasite growth in vitro. The aim of the current study was to assess the safety and immunogenicity of this vaccine in malaria exposed semi-immune healthy adults living in a malaria endemic country, Ghana. In this double-blinded, placebo controlled, dose escalation phase I trial, eighteen subjects per group received ascending dose concentrations (5 μg, 20 μg or 80 μg) of the vaccine intramuscularly at 0, 1 and 6 months, while 6 subjects received placebo (normal saline). The primary end point was the number of subjects experiencing Grade 3 systemic or local adverse events within 14 days post-vaccination. Serious adverse events were assessed throughout the study period. Blood samples for immunological analyses were collected at days 0, 14, 28, 42, 180 and 194. A total of 52 subjects received three doses of the vaccine in the respective groups. No serious adverse events were reported. The majority of all adverse events reported were mild to moderate in severity, with local pain and tenderness being the most common. All adverse events, irrespective of severity, resolved without any sequelae. Subjects who received any of the EBA-175 RII-NG doses had high immunoglobulin G levels which moderately inhibited P. falciparum growth in vitro, compared to those in the placebo group. In conclusion, the EBA-175 RII-NG vaccine was safe, well tolerated and immunogenic in malaria semi-immune Ghanaian adults. Its further development is recommended. ClinicalTrials.gov. Identifier: NCT01026246.

  11. Exposure of eyes to perfume: a double-blind, placebo-controlled experiment.

    Science.gov (United States)

    Elberling, J; Duus Johansen, J; Dirksen, A; Mosbech, H

    2006-08-01

    Environmental perfume exposure can elicit bothersome respiratory symptoms. Symptoms are induced at exposure levels which most people find tolerable, and the mechanisms are unclear. The aim of the study was to investigate patients with eye and respiratory symptoms related to environmental perfume, by exposing the eyes to perfume in a double-blind, placebo-controlled study.Twenty-one eczema patients with respiratory symptoms elicited by perfume were compared with 21 healthy volunteers in a sex- and age-matched case-control study. The participants completed a symptom questionnaire, and underwent a double-blind, placebo-controlled exposure to perfume. Of the 42 individuals tested, 10 had more eye symptoms (irritation, itching, and tears) during perfume exposure than during placebo exposures, and eight of these individuals (P = 0.07, Fisher's exact test) belonged to the patient group. A true positive eye reaction to perfume was significantly associated with identification of perfume as an active exposure (P perfume elicited irritation in the eyes independently of olfaction, but the relative importance of ocular chemoperception in relation to elicitation of respiratory symptoms from common environmental exposures to perfume remains unclear. We investigated the hypothesis of an association between respiratory symptoms related to perfume and ocular perfume sensitivity by exposing the eyes to perfume in a double blind, placebo-controlled experiment. Vapors of perfume provoked symptoms in the relevant eye in some patients and healthy control persons, but under our exposure conditions, ocular chemesthesis failed to elicit respiratory symptoms.

  12. Ethical Overview of Placebo Control in Psychiatric Research - Concepts and Challenges.

    Science.gov (United States)

    Ćurković, Marko; Živković, Maja; Radić, Krešimir; Vilibić, Maja; Ćelić, Ivan; Bagarić, Dario

    2015-06-01

    Permissibility of placebo controls in psychiatric research is raising everlasting controversies. The main ethical issue remains: whether, when, under what conditions, and to what extent is it justifiable to disregard subject's present (best) interest for the presumably "greater" ones. In relation to this main ethical concern, two distinct arguments arose: proponents of placebo controls trials (placebo ortxodoxy) and proponents of active controls trials (active-control orthodoxy). More recently, in new ethical guidelines, Declaration of Helsinki and International Ethical Guidelines for Biomedical Research Involving Human Subjects, a "middle way" approach was formulated, acceptable to both sides of the argument, saying placebo controls can be justified under certain conditions: when and only when, they firstly present undisputed methodological reasoning, and secondly, fulfill certain ethical considerations - mainly regarding the permissibility of accompanied risks. These ethical evaluations are inevitably contextual and evoke the need for the principle of proportionality. In scope of recent findings of substantial and progressively increasing placebo response in psychiatric research, contextual factors are identified and both theoretical and practical challenges are discussed.

  13. Should we reconsider the routine use of placebo controls in clinical research?

    Directory of Open Access Journals (Sweden)

    Avins Andrew L

    2012-04-01

    Full Text Available Abstract Background Modern clinical-research practice favors placebo controls over usual-care controls whenever a credible placebo exists. An unrecognized consequence of this preference is that clinicians are more limited in their ability to provide the benefits of the non-specific healing effects of placebos in clinical practice. Methods We examined the issues in choosing between placebo and usual-care controls. We considered why placebo controls place constraints on clinicians and the trade-offs involved in the choice of control groups. Results We find that, for certain studies, investigators should consider usual-care controls, even if an adequate placebo is available. Employing usual-care controls would be of greatest value for pragmatic trials evaluating treatments to improve clinical care and for which threats to internal validity can be adequately managed without a placebo-control condition. Conclusions Intentionally choosing usual-care controls, even when a satisfactory placebo exists, would allow clinicians to capture the value of non-specific therapeutic benefits that are common to all interventions. The result could be more effective, patient-centered care that makes the best use of both specific and non-specific benefits of medical interventions.

  14. Should we reconsider the routine use of placebo controls in clinical research?

    Science.gov (United States)

    Avins, Andrew L; Cherkin, Daniel C; Sherman, Karen J; Goldberg, Harley; Pressman, Alice

    2012-04-27

    Modern clinical-research practice favors placebo controls over usual-care controls whenever a credible placebo exists. An unrecognized consequence of this preference is that clinicians are more limited in their ability to provide the benefits of the non-specific healing effects of placebos in clinical practice. We examined the issues in choosing between placebo and usual-care controls. We considered why placebo controls place constraints on clinicians and the trade-offs involved in the choice of control groups. We find that, for certain studies, investigators should consider usual-care controls, even if an adequate placebo is available. Employing usual-care controls would be of greatest value for pragmatic trials evaluating treatments to improve clinical care and for which threats to internal validity can be adequately managed without a placebo-control condition. Intentionally choosing usual-care controls, even when a satisfactory placebo exists, would allow clinicians to capture the value of non-specific therapeutic benefits that are common to all interventions. The result could be more effective, patient-centered care that makes the best use of both specific and non-specific benefits of medical interventions.

  15. Developing a placebo-controlled trial in surgery: issues of design, acceptability and feasibility.

    Science.gov (United States)

    Campbell, M K; Entwistle, V A; Cuthbertson, B H; Skea, Z C; Sutherland, A G; McDonald, A M; Norrie, J D; Carlson, R V; Bridgman, S

    2011-02-21

    Surgical placebos are controversial. This in-depth study explored the design, acceptability, and feasibility issues relevant to designing a surgical placebo-controlled trial for the evaluation of the clinical and cost effectiveness of arthroscopic lavage for the management of people with osteoarthritis of the knee in the UK. Two surgeon focus groups at a UK national meeting for orthopaedic surgeons and one regional surgeon focus group (41 surgeons); plenary discussion at a UK national meeting for orthopaedic anaesthetists (130 anaesthetists); three focus groups with anaesthetists (one national, two regional; 58 anaesthetists); two focus groups with members of the patient organisation Arthritis Care (7 participants); telephone interviews with people on consultant waiting lists from two UK regional centres (15 participants); interviews with Chairs of UK ethics committees (6 individuals); postal surveys of members of the British Association of Surgeons of the Knee (382 surgeons) and members of the British Society of Orthopaedic Anaesthetists (398 anaesthetists); two centre pilot (49 patients assessed). There was widespread acceptance that evaluation of arthroscopic lavage had to be conducted with a placebo control if scientific rigour was not to be compromised. The choice of placebo surgical procedure (three small incisions) proved easier than the method of anaesthesia (general anaesthesia). General anaesthesia, while an excellent mimic, was more intrusive and raised concerns among some stakeholders and caused extensive discussion with local decision-makers when seeking formal approval for the pilot.Patients were willing to participate in a pilot with a placebo arm; although some patients when allocated to surgery became apprehensive about the possibility of receiving placebo, and withdrew. Placebo surgery was undertaken successfully. Our study illustrated the opposing and often strongly held opinions about surgical placebos, the ethical issues underpinning this

  16. Developing a placebo-controlled trial in surgery: Issues of design, acceptability and feasibility

    Directory of Open Access Journals (Sweden)

    McDonald AM

    2011-02-01

    Full Text Available Abstract Background Surgical placebos are controversial. This in-depth study explored the design, acceptability, and feasibility issues relevant to designing a surgical placebo-controlled trial for the evaluation of the clinical and cost effectiveness of arthroscopic lavage for the management of people with osteoarthritis of the knee in the UK. Methods Two surgeon focus groups at a UK national meeting for orthopaedic surgeons and one regional surgeon focus group (41 surgeons; plenary discussion at a UK national meeting for orthopaedic anaesthetists (130 anaesthetists; three focus groups with anaesthetists (one national, two regional; 58 anaesthetists; two focus groups with members of the patient organisation Arthritis Care (7 participants; telephone interviews with people on consultant waiting lists from two UK regional centres (15 participants; interviews with Chairs of UK ethics committees (6 individuals; postal surveys of members of the British Association of Surgeons of the Knee (382 surgeons and members of the British Society of Orthopaedic Anaesthetists (398 anaesthetists; two centre pilot (49 patients assessed. Results There was widespread acceptance that evaluation of arthroscopic lavage had to be conducted with a placebo control if scientific rigour was not to be compromised. The choice of placebo surgical procedure (three small incisions proved easier than the method of anaesthesia (general anaesthesia. General anaesthesia, while an excellent mimic, was more intrusive and raised concerns among some stakeholders and caused extensive discussion with local decision-makers when seeking formal approval for the pilot. Patients were willing to participate in a pilot with a placebo arm; although some patients when allocated to surgery became apprehensive about the possibility of receiving placebo, and withdrew. Placebo surgery was undertaken successfully. Conclusions Our study illustrated the opposing and often strongly held opinions about

  17. COSMIC: A Regimen of Intensity Modulated Radiation Therapy Plus Dose-Escalated, Raster-Scanned Carbon Ion Boost for Malignant Salivary Gland Tumors: Results of the Prospective Phase 2 Trial

    Energy Technology Data Exchange (ETDEWEB)

    Jensen, Alexandra D., E-mail: alexdjensen@gmx.de [Department of Radiation Oncology, University of Heidelberg, Heidelberg (Germany); Nikoghosyan, Anna V.; Lossner, Karen [Department of Radiation Oncology, University of Heidelberg, Heidelberg (Germany); Haberer, Thomas; Jäkel, Oliver [Heidelberg Ion Beam Therapy Centre, Heidelberg (Germany); Münter, Marc W.; Debus, Jürgen [Department of Radiation Oncology, University of Heidelberg, Heidelberg (Germany)

    2015-09-01

    Purpose: To investigate the effect of intensity modulated radiation therapy (IMRT) and dose-escalated carbon ion (C12) therapy in adenoid cystic carcinoma (ACC) and other malignant salivary gland tumors (MSGTs) of the head and neck. Patients and Methods: COSMIC (combined treatment of malignant salivary gland tumors with intensity modulated radiation therapy and carbon ions) is a prospective phase 2 trial of 24 Gy(RBE) C12 followed by 50 Gy IMRT in patients with pathologically confirmed MSGT. The primary endpoint is mucositis Common Terminology Criteria grade 3; the secondary endpoints are locoregional control (LC), progression-free survival (PFS), overall survival (OS), and toxicity. Toxicity was scored according to the Common Terminology Criteria for Adverse Events version 3; treatment response was scored according to Response Evaluation Criteria in Solid Tumors 1.1. Results: Between July 2010 and August 2011, 54 patients were accrued, and 53 were available for evaluation. The median follow-up time was 42 months; patients with microscopically incomplete resections (R1, n=20), gross residual disease (R2, n=17), and inoperable disease (n=16) were included. Eighty-nine percent of patients had ACC, and 57% had T4 tumors. The most common primary sites were paranasal sinus (34%), submandibular gland, and palate. At the completion of radiation therapy, 26% of patients experienced grade 3 mucositis, and 20 patients reported adverse events of the ear (38%). The most common observed late effects were grade 1 xerostomia (49%), hearing impairment (25%, 2% ipsilateral hearing loss), and adverse events of the eye (20%), but no visual impairment or loss of vision. Grade 1 central nervous system necrosis occurred in 6%, and 1 grade 4 ICA hemorrhage without neurologic sequelae. The best response was 54% (complete response/partial remission). At 3 years, the LC, PFS, and OS were 81.9%, 57.9%, and 78.4%, respectively. No difference was found regarding resection status. The

  18. Efficacy of peloid therapy in patients with chronic lateral epicondylitis: a randomized, controlled, single blind study

    Science.gov (United States)

    Ökmen, Burcu Metin; Eröksüz, Rıza; Altan, Lale; Aksoy, Meliha Kasapoğlu

    2017-11-01

    The aim of this study was to assess the effect of peloid on pain, functionality, daily life activities, and quality of life of lateral epicondylitis (LE) patients. In this randomized, controlled, single-blind study, 75 patients who were diagnosed with chronic LE were enrolled to the study. Patients were randomized into two groups using the random number table. The patients in the first group (group 1) ( n = 33), were given lateral epicondylitis band (LEB) (during the day for 6 weeks) + peloid therapy (five consecutive days a week for 2 weeks), and the second group (group 2) ( n = 32), received LEB treatment alone. The patients were assessed by using Patient Rated Tennis Elbow Evaluation (PRTEE) and Nottingham Health Profile (NHP). The data were obtained before treatment (W0), immediately after treatment (W2), and 1 month after treatment (W6). In analysis of the collected data, the Wilcoxon signed rank test for intra-group comparisons and Mann-Whitney U test for comparisons between groups were used. Both in groups 1 and 2, there was a statistically significant improvement in all the evaluation parameters at W2 and W6 when compared to W0 ( p 0.05), a statistically significant difference was found in favor of group 1 for all the evaluation parameters at W6 ( p < 0.05). Our results have shown that peloid treatment could be effective in providing improvement in pain relief, function, daily life activities, and quality of life in LE patients.

  19. Effect of cryotherapy after elbow arthrolysis: a prospective, single-blinded, randomized controlled study.

    Science.gov (United States)

    Yu, Shi-yang; Chen, Shuai; Yan, He-de; Fan, Cun-yi

    2015-01-01

    To investigate the effect of cryotherapy after elbow arthrolysis on elbow pain, blood loss, analgesic consumption, range of motion, and long-term elbow function. Prospective, single-blinded, randomized controlled study. University hospital. Patients (N=59; 27 women, 32 men) who received elbow arthrolysis. Patients were randomly assigned into a cryotherapy group (n=31, cryotherapy plus standard care) or a control group (n=28, standard care). Elbow pain at rest and in motion were measured using a visual analog scale (VAS) on postoperative day (POD) 1 to POD 7 and at 2 weeks and 3 months after surgery. Blood loss and analgesic consumption were recorded postoperatively. Elbow range of motion (ROM) was measured before surgery and on POD 1, POD 7, and 3 months after surgery. The Mayo Elbow Performance Score (MEPS) was evaluated preoperatively and 3 months postoperatively. VAS scores were significantly lower in the cryotherapy group during the first 7 PODs, both at rest and in motion (Pcryotherapy group than the control group for pain relief (P.05). Cryotherapy is effective in relieving pain and reducing analgesic consumption for patients received elbow arthrolysis. The application of cryotherapy will not affect blood loss, ROM, or elbow function. Copyright © 2015 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

  20. Complex antioxidants in a randomized single-blinded study of memory in seniors.

    Science.gov (United States)

    Summers, William K; Martin, Roy L; Liu, Yimeng; Peña, Bernice; Marsh, Gary M

    2018-04-01

    Oxidative injury to the brain and aging are theoretical co-causes of Alzheimer's Disease (AD). Amyloid plaques and tangles are then secondary phenomenon. The preclinical state would then be 'normal' elderly. A potent complex antioxidant (antiOx) was tested against a popular one-a-day multivitamin (mV) in a randomized single blind design in 'normal' senior subjects over 6 months. Memory testing was done at baseline, 1, 3, and 6 months. The generalized estimating equation (GEE) approach was used to compare the change score of NLT 100 and 20 WR between two groups over time. Analysis of the antiOx group (30 subjects) demonstrated significant improvement in declarative memory (change score for NLT 100 at month 6 = 6.36 p working memory (change score for 20 WR at month 6 = 3.23, p < 0.0001). A change-score analysis over 6 months suggests possible neurogenesis in the antiOx group. The mV group (33 subjects) had a change score of the NLT 100 and 20WR on the sixth month of 2.20 and 0.32 (p = 0.07, 0.35). A complex antioxidant blend, sold as an over-the-counter (OTC) supplement, can improve memory in elder subjects. Antioxidants may be beneficial in AD and other neurodegerative diseases.

  1. Fractional Carbon Dioxide Laser for Keratosis Pilaris: A Single-Blind, Randomized, Comparative Study

    Directory of Open Access Journals (Sweden)

    Vasanop Vachiramon

    2016-01-01

    Full Text Available Objective. Keratosis pilaris (KP is a common condition which can frequently be cosmetically disturbing. Topical treatments can be used with limited efficacy. The objective of this study is to evaluate the effectiveness and safety of fractional carbon dioxide (CO2 laser for the treatment of KP. Patients and Methods. A prospective, randomized, single-blinded, intraindividual comparative study was conducted on adult patients with KP. A single session of fractional CO2 laser was performed to one side of arm whereas the contralateral side served as control. Patients were scheduled for follow-up at 4 and 12 weeks after treatment. Clinical improvement was graded subjectively by blinded dermatologists. Patients rated treatment satisfaction at the end of the study. Results. Twenty patients completed the study. All patients stated that the laser treatment improved KP lesions. At 12-week follow-up, 30% of lesions on the laser-treated side had moderate to good improvement according to physicians’ global assessment (p=0.02. Keratotic papules and hyperpigmentation appeared to respond better than the erythematous component. Four patients with Fitzpatrick skin type V developed transient pigmentary alteration. Conclusions. Fractional CO2 laser treatment may be offered to patients with KP. Dark-skinned patients should be treated with special caution.

  2. A single-blind trial of reflexology for irritable bowel syndrome.

    Science.gov (United States)

    Tovey, Philip

    2002-01-01

    BACKGROUND: Irritable bowel syndrome (IBS) is a significant problem for primary care, as treatment options are limited and it can frequently develop into a chronic condition. Complementary and alternative medicine, including reflexology, is being turned to increasingly in an attempt to manage symptoms. There are currently no studies which address the effectiveness of reflexology for IBS. Despite this, it continues to be advocated and used. AIM: To provide the first evidence on the effectiveness of reflexology in the management of the core defining symptoms of IBS. DESIGN OF STUDY: A single-blind trial carried out in primary care settings. SETTING: Thirty-four participants diagnosed with IBS on the basis of the Rome Criteria. METHOD: Participants were allocated to receive either a reflexology foot massage or a non-reflexology foot massage control group. RESULTS: On none of the three symptoms monitored--abdominal pain, constipation/diarrhoea, and abdominal distention--was there a statistically or clinically significant difference between reflexology and control groups. CONCLUSION: On the basis of these results there is nothing to suggest that reflexology produces any specific benefit for patients with IBS. There is currently no evidence to support its use. However this was one (relatively) small scale study; further research that, for example, assesses the impact of therapist (professional and lay) versus therapy, is still needed. PMID:11791811

  3. A single-blinded randomised clinical trial of permissive underfeeding in patients requiring parenteral nutrition.

    Science.gov (United States)

    Owais, Anwar Elias; Kabir, Syed Irfan; Mcnaught, Clare; Gatt, Marcel; MacFie, John

    2014-12-01

    The importance of adequate nutritional support is well established, but characterising what 'adequate nutrition' represents remains contentious. In recent years there has been increasing interest in the concept of 'permissive underfeeding' where patients are intentionally prescribed less nutrition than their calculated requirements. The aim of this study was to evaluate the effect of permissive underfeeding on septic and nutrition related morbidity in patients requiring short term parenteral nutrition (PN). This was a single-blinded randomised clinical trial of 50 consecutive patients requiring parenteral nutritional support. Patients were randomized to receive either normocaloric or hypocaloric feeding (respectively 100% vs. 60% of estimated requirements). The primary end point was septic complications. Secondary end points included the metabolic, physiological and clinical outcomes to the two feeding protocols. Permissive underfeeding was associated with fewer septic complications (3 vs. 12 patients; p = 0.003), and a lower incidence of the systemic inflammatory response syndrome (9 vs. 16 patients; p = 0.017). Permissively underfed patients had fewer feed related complications (2 vs. 9 patients; p = 0.016). Permissive underfeeding in patients requiring short term PN appears to be safe and may results in reduced septic and feed-related complications. NCT01154179 TRIAL REGISTRY: http://clinicaltrials.gov/ct2/show/NCT01154179. Copyright © 2014 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

  4. Effects of trans fatty acids on glucose homeostasis: a meta-analysis of randomized, placebo-controlled clinical trials123

    OpenAIRE

    Aronis, Konstantinos N; Khan, Sami M; Mantzoros, Christos S

    2012-01-01

    Background: Although evidence from cohort studies has suggested that trans fatty acid (TFA) consumption may be associated with insulin resistance and diabetes, randomized placebo-controlled trials (RCTs) have yielded conflicting results.

  5. Fusidic acid cream in the treatment of impetigo in general practice: double blind randomised placebo controlled trial

    NARCIS (Netherlands)

    S. Koning (Sander); L.W.A. van Suijlekom-Smit (Lisette); J.L. Nouwen (Jan); C.M. Verduin (Cees); R.M.D. Bernsen (Roos); A.P. Oranje (Arnold); S. Thomas (Siep); J.C. van der Wouden (Hans)

    2002-01-01

    textabstractOBJECTIVE: To test the hypothesis that fusidic acid would not increase the treatment effect of disinfecting with povidone-iodine alone in children with impetigo. DESIGN: Randomised placebo controlled trial. SETTING: General practices in Greater Rotterdam.

  6. Treatments for acute bipolar depression: meta-analyses of placebo-controlled, monotherapy trials of anticonvulsants, lithium and antipsychotics

    NARCIS (Netherlands)

    Selle, V.; Schalkwijk, S.J.; Vazquez, G.H.; Baldessarini, R.J.

    2014-01-01

    BACKGROUND: Optimal treatments for bipolar depression, and the relative value of specific drugs for that purpose, remain uncertain, including agents other than antidepressants. METHODS: We searched for reports of placebo-controlled, monotherapy trials of mood-stabilizing anticonvulsants,

  7. Facilitation of fear extinction in phobic participants with a novel cognitive enhancer: a randomized placebo controlled trial of yohimbine augmentation

    NARCIS (Netherlands)

    Powers, M.B.; Smits, J.A.J.; Otto, M.W.; Sanders, C.; Emmelkamp, P.M.G.

    2009-01-01

    Preliminary animal research suggests that yohimbine hydrochloride, a selective competitive alpha2-adrenergic receptor antagonist, accelerates fear extinction and converts ineffective extinction regimens (long intertrial intervals) to effective ones. This randomized placebo controlled study examined

  8. Misoprostol for cervical priming prior to hysteroscopy in postmenopausal and premenopausal nulliparous women; a multicentre randomised placebo controlled trial

    NARCIS (Netherlands)

    Tasma, M L; Louwerse, M D; Hehenkamp, W J; Geomini, P M; Bongers, M Y; Veersema, S; van Kesteren, P J; Tromp, E; Huirne, J A; Graziosi, G C

    OBJECTIVE: To evaluate the reduction of pain by misoprostol compared with placebo prior to hysteroscopy in postmenopausal and premenopausal nulliparous women. DESIGN: Randomised multicentre double-blind placebo controlled trial. SETTING: Two Dutch teaching hospitals and one Dutch university medical

  9. High-dose radiation improved local tumor control and overall survival in patients with inoperable/unresectable non-small-cell lung cancer: Long-term results of a radiation dose escalation study

    International Nuclear Information System (INIS)

    Kong, F.-M.; Haken, Randall K. ten; Schipper, Matthew J.; Sullivan, Molly A.; Chen, Ming; Lopez, Carlos; Kalemkerian, Gregory P.; Hayman, James A.

    2005-01-01

    Purpose: To determine whether high-dose radiation leads to improved outcomes in patients with non-small-cell lung cancer (NSCLC). Methods and Materials: This analysis included 106 patients with newly diagnosed or recurrent Stages I-III NSCLC, treated with 63-103 Gy in 2.1-Gy fractions, using three-dimensional conformal radiation therapy (3D-CRT) per a dose escalation trial. Targets included the primary tumor and any lymph nodes ≥1 cm, without intentionally including negative nodal regions. Nineteen percent of patients (20/106) received neoadjuvant chemotherapy. Patient, tumor, and treatment factors were evaluated for association with outcomes. Estimated median follow-up was 8.5 years. Results: Median survival was 19 months, and 5-year overall survival (OS) was 13%. Multivariate analysis revealed weight loss (p = 0.011) and radiation dose (p = 0.0006) were significant predictors for OS. The 5-year OS was 4%, 22%, and 28% for patients receiving 63-69, 74-84, and 92-103 Gy, respectively. Although presence of nodal disease was negatively associated with locoregional control under univariate analysis, radiation dose was the only significant predictor when multiple variables were included (p = 0.015). The 5-year control rate was 12%, 35%, and 49% for 63-69, 74-84, and 92-103 Gy, respectively. Conclusions: Higher dose radiation is associated with improved outcomes in patients with NSCLC treated in the range of 63-103 Gy

  10. 153Sm-lexidronam for augmentation of chemotherapy-based myeloablative regimes in patients with multiple myeloma and other haematological conditions undergoing bone marrow transplantation: a phase I dose-escalation trial

    International Nuclear Information System (INIS)

    Macfarlane, D.J.; Durrant, S.; Gillett, E.A.; Bartlett, M.; Allison, R.; Hicks, R.; Prince, M.

    1999-01-01

    Full text: Total body irradiation (TBI) is a useful conditioning regimen for bone marrow transplantation (BMT), but has unacceptable toxicity in some patients. High doses of bone-seeking radiopharmaceuticals may offer a useful alternative to TBI in BMT patients with marrow-based tumours. Nine patients (5 multiple myeloma [MM], 2 leukaemia, 1 lymphoma, I myelodysplasia) were enrolled in a dose escalation protocol based upon retained skeletal activity. Infused doses have ranged between 18 and 32 GBq of 153 Sm-EDTMP in six patients treated. No adverse effects related to the infusion have been seen. Peripheral blood counts fell from day 7 post-treatment, persisting to the start of cytotoxic conditioning regimen at days 11-14 post-treatment. Five patients have engrafted, with one allogeneic transplant patient dying from acute rejection. Pre-treatment dosimetry was performed by gamma camera and whole-body probe counts. Post-therapy activities were estimated by serial dose meter readings and gamma camera images. The pre-treatment skeletal retention by gamma camera was 1.7-2.4 times the values based on probe data. Retained post-treatment skeletal activity predicted by dosimetry was significantly greater than that actually measured, confirmed in one case by urinary collection. This latter fact is most likely due to the nature of the interaction of 153 Sm-EDTMP with bone at high doses

  11. Penile bulb dose and impotence after three-dimensional conformal radiotherapy for prostate cancer on RTOG 9406: Findings from a prospective, multi-institutional, phase I/II dose-escalation study

    International Nuclear Information System (INIS)

    Roach, Mack; Winter, Kathryn; Michalski, Jeffrey M.; Cox, James D.; Purdy, James A.; Bosch, Walter; Lin Xiao; Shipley, William S.

    2004-01-01

    Purpose: To assess the relationship between the dose to the bulb of the penis and the risk of impotence in men treated on Radiation Therapy Oncology Group (RTOG) 9406. Methods and materials: Men enrolled on a Phase I/II dose-escalation study, RTOG 9406, who were reported to be potent at entry and evaluable (n = 158) were selected for inclusion. Follow-up evaluations were scheduled every 3, 4, and 6 months for the first, second, and the third through fifth years, then annually. At each follow-up visit an assessment of potency status was made. Penile structures were defined by a single observer blinded to the potency status, using Web-based, on-line software. The dosimetry for penile structures was calculated at the Quality Assurance Center at Washington University and provided to RTOG Statistical Headquarters to determine whether there was a relationship between dose and impotence. Results: Patients whose median penile dose was ≥52.5 Gy had a greater risk of impotence compared with those receiving <52.5 Gy (p = 0.039). In a multivariate analysis neither age, the dose to the prostate, nor the use of hormonal therapy correlated with the risk of impotence. Conclusions: Dose to the bulb of the penis seems to be associated with the risk of radiation-induced impotence

  12. New validated recipes for double-blind placebo-controlled low-dose food challenges.

    Science.gov (United States)

    Winberg, Anna; Nordström, Lisbeth; Strinnholm, Åsa; Nylander, Annica; Jonsäll, Anette; Rönmark, Eva; West, Christina E

    2013-05-01

    Double-blind placebo-controlled food challenges are considered the most reliable method to diagnose or rule out food allergy. Despite this, there are few validated challenge recipes available. The present study aimed to validate new recipes for low-dose double-blind placebo-controlled food challenges in school children, by investigating whether there were any sensory differences between the active materials containing cow's milk, hen's egg, soy, wheat or cod, and the placebo materials. The challenge materials contained the same hypoallergenic amino acid-based product, with or without added food allergens. The test panels consisted of 275 school children, aged 8-10 and 14-15 yr, respectively, from five Swedish schools. Each participant tested at least one recipe. Standardized blinded triangle tests were performed to investigate whether any sensory differences could be detected between the active and placebo materials. In our final recipes, no significant differences could be detected between the active and placebo materials for any challenge food (p > 0.05). These results remained after stratification for age and gender. The taste of challenge materials was acceptable, and no unfavourable side effects related to test materials were observed. In summary, these new validated recipes for low-dose double-blinded food challenges contain common allergenic foods in childhood; cow's milk, hen's egg, soy, wheat and cod. All test materials contain the same liquid vehicle, which facilitates preparation and dosing. Our validated recipes increase the range of available recipes, and as they are easily prepared and dosed, they may facilitate the use of double-blind placebo-controlled food challenges in daily clinical practice. © 2013 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.

  13. Dense cranial electroacupuncture stimulation for major depressive disorder--a single-blind, randomized, controlled study.

    Directory of Open Access Journals (Sweden)

    Zhang-Jin Zhang

    Full Text Available BACKGROUND: Previous studies suggest that electroacupuncture possesses therapeutic benefits for depressive disorders. The purpose of this study was to determine whether dense cranial electroacupuncture stimulation (DCEAS could enhance the antidepressant efficacy in the early phase of selective serotonin reuptake inhibitor (SSRI treatment of major depressive disorder (MDD. METHODS: In this single-blind, randomized, controlled study, patients with MDD were randomly assigned to 9-session DCEAS or noninvasive electroacupuncture (n-EA control procedure in combination with fluoxetine (FLX for 3 weeks. Clinical outcomes were measured using the 17-item Hamilton Depression Rating Scale (HAMD-17, Clinical Global Impression-severity (CGI-S, and Self-rating Depression Scale (SDS as well as the response and remission rates. RESULTS: Seventy-three patients were randomly assigned to n-EA (n = 35 and DCEAS (n = 38, of whom 34 in n-EA and 36 in DCEAS group were analyzed. DCEAS-treated patients displayed a significantly greater reduction from baseline in HAMD-17 scores at Day 3 through Day 21 and in SDS scores at Day 3 and Day 21 compared to patients receiving n-EA. DCEAS intervention also produced a higher rate of clinically significant response compared to n-EA procedure (19.4% (7/36 vs. 8.8% (3/34. The incidence of adverse events was similar in the two groups. CONCLUSIONS: DCEAS is a safe and effective intervention that augments the antidepressant efficacy. It can be considered as an additional therapy in the early phase of SSRI treatment of depressed patients. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN88008690.

  14. The effects of assertiveness training in patients with schizophrenia: a randomized, single-blind, controlled study.

    Science.gov (United States)

    Lee, Tso-Ying; Chang, Shih-Chin; Chu, Hsin; Yang, Chyn-Yng; Ou, Keng-Liang; Chung, Min-Huey; Chou, Kuei-Ru

    2013-11-01

    In this study, we investigated the effects of group assertiveness training on assertiveness, social anxiety and satisfaction with interpersonal communication among patients with chronic schizophrenia. Only limited studies highlighted the effectiveness of group assertiveness training among inpatients with schizophrenia. Given the lack of group assertiveness training among patients with schizophrenia, further development of programmes focusing on facilitating assertiveness, self-confidence and social skills among inpatients with chronic schizophrenia is needed. This study used a prospective, randomized, single-blinded, parallel-group design. This study employed a prospective, randomized, parallel-group design. Seventy-four patients were randomly assigned to experimental group receiving 12 sessions of assertiveness training, or a supportive control group. Data collection took place for the period of June 2009-July 2010. Among patients with chronic schizophrenia, assertiveness, levels of social anxiety and satisfaction with interpersonal communication significantly improved immediately after the intervention and at the 3-month follow-up in the intervention group. The results of a generalized estimating equation (GEE) indicated that: (1) assertiveness significantly improved from pre- to postintervention and was maintained until the follow-up; (2) anxiety regarding social interactions significantly decreased after assertiveness training; and (3) satisfaction with interpersonal communication slightly improved after the 12-session intervention and at the 3-month follow-up. Assertivenss training is a non-invasive and inexpensive therapy that appears to improve assertiveness, social anxiety and interpersonal communication among inpatients with chronic schizophrenia. These findings may provide a reference guide to clinical nurses for developing assertiveness-training protocols. © 2013 Blackwell Publishing Ltd.

  15. Distance education and diabetes empowerment: A single-blind randomized control trial.

    Science.gov (United States)

    Zamanzadeh, Vahid; Zirak, Mohammad; Hemmati Maslakpak, Masomeh; Parizad, Naser

    2017-11-01

    Diabetes is one of the biggest problems in healthcare systems and kills many people every year. Diabetes management is impossible when only utilizing medication. So, patients must be educated to manage their diabetes. This study aims to assess the effect of education by telephone and short message service on empowering patients with type 2 diabetes (primary outcome). A single-blind randomized controlled trial was conducted in the Urmia diabetes association in Iran. Sixty six participants with definitive diagnosis of type 2 diabetes entered into the study. Patients with secondary health problems were excluded. Patients were selected by simple random sampling then allocated into intervention (n=33) and control (n=33) groups. The intervention group received an educational text message daily and instructive phone calls three days a week for three months along with usual care. The Diabetes Empowerment Scale (DES) with confirmed validity and reliability was used for collecting data. Data was analyzed using SPSS V6.1. Independent t-test, paired t-test and chi-square were used to analyze the data. The empowerment of the intervention group compared with the control group significantly improved after three months of distance education (p<0.00, EF=1. 16). The study findings show that the distance education has a significant effect on empowering patients with type 2 diabetes. Therefore, using distance education along with other diabetes management intervention is highly effective and should be part of the care in diabetes treatment. Copyright © 2016 Diabetes India. Published by Elsevier Ltd. All rights reserved.

  16. Effectiveness of PELOID therapy in carpal tunnel syndrome: A randomized controlled single blind study

    Science.gov (United States)

    Metin Ökmen, Burcu; Kasapoğlu Aksoy, Meliha; Güneş, Aygül; Eröksüz, Riza; Altan, Lale

    2017-08-01

    Carpal tunnel syndrome(CTS) is the most common neuromuscular cause of upper extremity disability. We aimed to investigate the effectiveness of peloid therapy in patients with CTS. This randomized, controlled, single-blind study enrolled 70 patients between the ages of 30 to 65 who had a diagnosis of either mild, mild-to-moderate, or moderate CTS. The patients were randomized into two groups using random number table. In the first group, (Group 1)( n = 35), patients were given splint (every night for 6 weeks) + peloid treatment(five consecutive days a week for 2 weeks) and in the second group, (Group 2)( n = 28), patients received splint treatment(every night for 6 weeks) alone. The patients were assessed by using visual analog scale(VAS) for pain, electroneuromyography(ENMG), the Boston Carpal Tunnel Syndrome Questionnaire(BCTSQ), hand grip strength(HGS), finger grip strength(FGS), and Short Form-12(SF-12). The data were obtained before treatment(W0), immediately after treatment(W2), and one month after treatment(W6). Both in Group 1 and 2, there was a statistically significant improvement in all the evaluation parameters at W2 and W6 when compared to W0( p < 0.05). Comparison of the groups with each other revealed significantly better results for VAS, BCTSQ, mSNCV, SF-12 in Group 1 than in Group 2 at W2( p < 0.05). There was also a statistically significant difference in favor of Group 1 for VAS, BCTSQ, FGS and MCS at W6 when compared to W0 ( p < 0.05). The results of our study demonstrated that in patients with CTS; peloid + splint treatment was more effective than splint treatment alone in pain, functionality and life quality both at after treatment(W2) and one month after treatment (W6). We may suggest peloid as a supplementary therapeutic agent in CTS.

  17. A double-blind, placebo controlled trial of high-dose lecithin in Alzheimer's disease.

    OpenAIRE

    Little, A; Levy, R; Chuaqui-Kidd, P; Hand, D

    1985-01-01

    The first long-term double-blind placebo controlled trial of high dose lecithin in senile dementia of the Alzheimer type is reported. Fifty one subjects were given 20-25 g/day of purified soya lecithin (containing 90% phosphatidyl plus lysophosphatidyl choline) for six months and followed up for at least a further six months. Plasma choline levels were monitored throughout the treatment period. There were no differences between the placebo group and the lecithin group but there was an improve...

  18. Escitalopram in painful polyneuropathy: A randomized, placebo-controlled, cross-over trial

    DEFF Research Database (Denmark)

    Otto, Marit; Bach, Flemming W; Jensen, Troels S

    2008-01-01

    Serotonin (5-HT) is involved in pain modulation via descending pathways in the central nervous system. The aim of this study was to test if escitalopram, a selective serotonin reuptake inhibitor (SSRI), would relieve pain in polyneuropathy. The study design was a randomized, double-blind, placebo......-controlled cross-over trial. The daily dose of escitalopram was 20mg once daily. During the two treatment periods of 5 weeks duration, patients rated pain relief (primary outcome variable) on a 6-point ordered nominal scale. Secondary outcome measures comprised total pain and different pain symptoms (touch...

  19. EFFICACY OF HYOSCINE BUTYLBROMIDE IN TREATMENT OF IRRITABLE BOWEL SYNDROME IN CHILDREN: PLACEBO-CONTROLLED TRIAL

    Directory of Open Access Journals (Sweden)

    K.V. Arifullina

    2008-01-01

    Full Text Available The activity of hyoscine butylbromide (buscopan was evaluated in a placebobcontrolled trial, on pediatric patients with algid type of irritable bowel syndrome. Hyoscine butylbromide favored to the increase of quality of life in pediatric patients, alleviation of clinical symptoms of disease, reliable decrease of malonic dialdehyde and increase of antioxidant activity of blood plasma significantly superior to placebo. Clinical efficacy of hyoscine butylbromide accompanies to its good tolerance and safety.Key words: children, irritable bowel syndrome, hyoscine butylbromide, placebo controlled trial.

  20. "Live high-train low" using normobaric hypoxia: a double-blinded, placebo-controlled study

    DEFF Research Database (Denmark)

    Siebenmann, Christoph; Robach, Paul; Jacobs, Robert A

    2012-01-01

    The combination of living at altitude and training near sea level [live high-train low (LHTL)] may improve performance of endurance athletes. However, to date, no study can rule out a potential placebo effect as at least part of the explanation, especially for performance measures. With the use o...... of a placebo-controlled, double-blinded design, we tested the hypothesis that LHTL-related improvements in endurance performance are mediated through physiological mechanisms and not through a placebo effect. Sixteen endurance cyclists trained for 8 wk at low altitude (...

  1. Brief report: Pilot single-blind placebo lead-in study of acamprosate in youth with autistic disorder.

    Science.gov (United States)

    Erickson, Craig A; Wink, Logan K; Early, Maureen C; Stiegelmeyer, Elizabeth; Mathieu-Frasier, Lauren; Patrick, Vanessa; McDougle, Christopher J

    2014-04-01

    An excitatory/inhibitory (E:I) imbalance marked by enhanced glutamate and deficient gamma-aminobutyric acid (GABA) neurotransmission may contribute to the pathophysiology of autism spectrum disorders (ASD). We report on the first single-blind placebo lead-in trial of acamprosate, a drug with putative mechanisms restoring E:I imbalance, in twelve youth with ASD. We conducted a 12-week single-blind, placebo lead-in study of acamprosate in youth age 5-17 years with autistic disorder. Six of nine subjects who received active drug treatment were deemed treatment responders (defined by a score at final visit of "very much improved" or "much improved" on the Clinical Global Impressions Improvement scale) and ≥25% improvement on the Aberrant Behavior Checklist Social Withdrawal subscale. Future larger-scale dose finding studies of acamprosate in ASD may be warranted given this preliminary indication of benefit.

  2. Relay model for recruiting alcohol dependent patients in general hospitals--a single-blind pragmatic randomized trial

    DEFF Research Database (Denmark)

    Schwarz, Anne-Sophie; Bilberg, Randi; Bjerregaard, Lene Berit Skov

    2016-01-01

    - The Relay Model. METHOD/DESIGN: The study is a single-blind pragmatic randomized controlled trial including patients admitted to the hospital. The study group (n = 500) will receive an intervention, and the control group (n = 500) will be referred to treatment by usual procedures. All patients complete......://register.clinicaltrials.gov/by identifier: RESCueH_Relay NCT02188043 Project Relay Model for Recruiting Alcohol Dependent Patients in General Hospitals (TRN Registration: 07/09/2014)....

  3. Placebo-Controlled Study of Pimozide Augmentation of Fluoxetine in Body Dysmorphic Disorder

    Science.gov (United States)

    Phillips, Katharine A.

    2006-01-01

    Objective Although body dysmorphic disorder often responds to serotonin reuptake inhibitors (SRIs), most patients do not respond or respond only partially. However, placebo-controlled studies of augmentation of SRIs have not been done. Furthermore, although 40%–50% of patients are delusional, studies of antipsychotic medications have not been done. Method Twenty-eight patients with body dysmorphic disorder or its delusional variant participated in an 8-week, placebo-controlled, double-blind, parallel-group study of pimozide augmentation of fluoxetine. Results Pimozide was not more effective than placebo: two (18.2%) of 11 subjects responded to pimozide and three (17.6%) of 17 subjects responded to placebo. There was no significant effect of baseline delusionality on endpoint severity of body dysmorphic disorder. Delusionality did not decrease significantly more with pimozide than placebo. Conclusions Pimozide augmentation of fluoxetine treatment for body dysmorphic disorder was not more effective than placebo, even in more delusional patients. Further studies of augmentation for SRIs are needed. PMID:15677604

  4. A placebo-controlled investigation of synaesthesia-like experiences under LSD.

    Science.gov (United States)

    Terhune, Devin B; Luke, David P; Kaelen, Mendel; Bolstridge, Mark; Feilding, Amanda; Nutt, David; Carhart-Harris, Robin; Ward, Jamie

    2016-07-29

    The induction of synaesthesia in non-synaesthetes has the potential to illuminate the mechanisms that contribute to the development of this condition and the shaping of its phenomenology. Previous research suggests that lysergic acid diethylamide (LSD) reliably induces synaesthesia-like experiences in non-synaesthetes. However, these studies suffer from a number of methodological limitations including lack of a placebo control and the absence of rigorous measures used to test established criteria for genuine synaesthesia. Here we report a pilot study that aimed to circumvent these limitations. We conducted a within-groups placebo-controlled investigation of the impact of LSD on colour experiences in response to standardized graphemes and sounds and the consistency and specificity of grapheme- and sound-colour associations. Participants reported more spontaneous synaesthesia-like experiences under LSD, relative to placebo, but did not differ across conditions in colour experiences in response to inducers, consistency of stimulus-colour associations, or in inducer specificity. Further analyses suggest that individual differences in a number of these effects were associated with the propensity to experience states of absorption in one's daily life. Although preliminary, the present study suggests that LSD-induced synaesthesia-like experiences do not exhibit consistency or inducer-specificity and thus do not meet two widely established criteria for genuine synaesthesia. Copyright © 2016 Elsevier Ltd. All rights reserved.

  5. The effect of Neuragen PN® on Neuropathic pain: A randomized, double blind, placebo controlled clinical trial

    Directory of Open Access Journals (Sweden)

    Li Li

    2010-05-01

    Full Text Available Abstract Background A double blind, randomized, placebo controlled study to evaluate the safety and efficacy of the naturally derived topical oil, "Neuragen PN®" for the treatment of neuropathic pain. Methods Sixty participants with plantar cutaneous (foot sole pain due to all cause peripheral neuropathy were recruited from the community. Each subject was randomly assigned to receive one of two treatments (Neuragen PN® or placebo per week in a crossover design. The primary outcome measure was acute spontaneous pain level as reported on a visual analog scale. Results There was an overall pain reduction for both treatments from pre to post application. As compared to the placebo, Neuragen PN® led to significantly (p ® reported pain reduction within 30 minutes. This reduction within 30 minutes occurred in only twenty one of sixty (35.0% subjects receiving the placebo. In a break out analysis of the diabetic only subgroup, 94% of subjects in the Neuragen PN® group achieved pain reduction within 30 minutes vs 11.0% of the placebo group. No adverse events were observed. Conclusions This randomized, placebo controlled, clinical trial with crossover design revealed that the naturally derived oil, Neuragen PN®, provided significant relief from neuropathic pain in an all cause neuropathy group. Participants with diabetes within this group experienced similar pain relief. Trial registration ISRCTN registered: ISRCTN13226601

  6. Duloxetine in the treatment of binge eating disorder with depressive disorders: a placebo-controlled trial.

    Science.gov (United States)

    Guerdjikova, Anna I; McElroy, Susan L; Winstanley, Erin L; Nelson, Eric B; Mori, Nicole; McCoy, Jessica; Keck, Paul E; Hudson, James I

    2012-03-01

    This study evaluated duloxetine in the treatment of binge eating disorder (BED) with comorbid current depressive disorders. In this 12-week, double-blind, placebo-controlled trial, 40 patients with Diagnostic and Statistical Manual of Mental Disorders-IV-TR BED and a comorbid current depressive disorder received duloxetine (N = 20) or placebo (N = 20). The primary outcome measure was weekly binge eating day frequency. In the primary analysis, duloxetine (mean 78.7 mg/day) was superior to placebo in reducing weekly frequency of binge eating days (p = .04), binge eating episodes (p = .02), weight (p = .04), and Clinical Global Impression-Severity of Illness ratings for binge eating (p = .02) and depressive disorders (p = .01). Changes in body mass index and measures of eating pathology, depression, and anxiety did not differ between the two groups. Duloxetine may be effective for reducing binge eating, weight, and global severity of illness in BED with a comorbid current depressive disorder, but this finding needs confirmation in larger, placebo-controlled trials. Copyright © 2011 Wiley Periodicals, Inc.

  7. Moderate risk-adapted dose escalation with 3D-conformal radiotherapy for prostate cancer from 70 to 74 Gy : long-term morbidity and survival from a prospective phase II trial

    International Nuclear Information System (INIS)

    Bombosch, V. B.

    2015-01-01

    Abstract English Background and Purpose: Evaluation of late side-effects and survival more than 60 months after 3-dimensional conformal radiotherapy with moderate, risk adapted dose escalation from 70 to 74 Gy in patients with localized prostate cancer within a prospective Austrian-German phase II multicenter trial. Material and Methods: Between 03/1999 and 07/2002 486 patients were registered in the prospective Austrian-German multicenter phase II trial. 441 (90.7%) patients were evaluated. Patients in the low and intermediate risk group were treated with 70Gy, patients in the high risk group received 74Gy. Additional hormonal-therapy was recommended for intermediate- and high-risk group patients. Gastrointestinal (GI) and genitourinary (GU) late toxicity according to EORTC/RTOG criteria, initial appearance, prevalence and duration of grade >=2 side-effects were investigated. Furthermore bNED (Phoenix/Nadir + 2), overall and disease specific survival were prospectively assessed. Results: Median follow-up was 90 (2-158) months in all 441 patients and 99 (18-158) months in living patients. 154 patients (35%) had a follow-up of longer or equal 120 months. Distribution among risk groups was 26% (low), 51% (intermediate) and 23% (high). HT was administered in 86% of patients prior to RT. Late gastrointestinal side-effects at 5- and 10 years were 29%/32% (70/74Gy) and 30%/35% (70/74Gy) as actuarial rates; p=0.67. Late genitourinary side-effects at 5- and 10 years were 17%/26% (70/74Gy) and 27%/34% (70/74Gy); p=0.12. No more than 15% (GI) and 15% (GU) of patients suffered from side-effects >=2 at any time after the end of therapy (prevalence). The proportion of patients suffering from severe toxicity was low (Grade 3 GI: 2%, GU: 10%). 10 year actuarial bNED rate was 65%, 70% and 58% in the low-, intermediate- and high risk group according to Phoenix (Nadir +2) criteria. Overall and disease specific survival were 67% and 91% in all patients. Conclusion: Dose escalation

  8. Novel sublingual low-dose zolpidem tablet reduces latency to sleep onset following spontaneous middle-of-the-night awakening in insomnia in a randomized, double-blind, placebo-controlled, outpatient study.

    Science.gov (United States)

    Roth, Thomas; Krystal, Andrew; Steinberg, Frank J; Singh, Nikhilesh N; Moline, Margaret

    2013-02-01

    To evaluate efficacy and safety of 3.5-mg zolpidem tartrate sublingual tablets (ZST) on latency to sleep onset after middle-of-the-night (MOTN) awakenings in patients with insomnia characterized by difficulty returning to sleep after MOTN awakenings. Multicenter randomized, double-blind, placebo-controlled, parallel-group. Outpatient. There were 295 adults (median age 43 y; 68.1% female) with primary insomnia and difficulty returning to sleep after MOTN awakenings (three or more MOTN awakenings/wk during screening). After a 2-wk, single-blind placebo eligibility period, participants were randomized 1:1 to as-needed MOTN dosing with 3.5 mg ZST or placebo for 28 nights. An interactive voice response system determined if the study drug could be taken and recorded sleep/wake efficacy measures. ZST significantly (P Zolpidem Tartrate Tablet in Adult Patients with Insomnia" http://www.clinicaltrials.gov/ct2/show/NCT00466193?spons=%22Transcept+Pharmaceuticals%22&spons_ex=Y&rank=2

  9. Long-term efficacy of modified-release recombinant human TSH (MRrhTSH) augmented radioiodine (131I) therapy for benign multinodular goiter. Results from a multicenter international, randomized, placebo-controlled dose-selection study

    DEFF Research Database (Denmark)

    Fast, Søren; Hegedus, Laszlo; Pacini, Furio

    2014-01-01

    with 131I-therapy. Methods: In this phase II, single-blinded, placebo-controlled study, 95 patients (57.2±9.6 years old, 85% women, 83% Caucasians) with MNG (median size 96.0 ml (31.9 - 242.2 ml)) were randomized to receive placebo (n=32), 0.01 mg MRrhTSH (n=30) or 0.03 mg MRrhTSH (n=33), 24 hours before...... a calculated 131I activity. Thyroid volume (TV) and smallest cross-sectional area of trachea (SCAT) were measured (by CT-scan) at baseline, month 6 and month 36. Thyroid function and quality of life (QoL) was evaluated at 3 month and yearly intervals, respectively. Results: At 6 months, TV reduction...... was enhanced in the 0.03 mg MRrhTSH group (32.9% versus 23.1% in the placebo group, p=0.03), but not in the 0.01 mg MRrhTSH group. At month 36 the mean percent TV reduction from baseline was 44 ± 12.7% (SD) in the placebo group, 41 ± 21.0% in the 0.01 mg MRrhTSH-group and 53 ± 18.6% in the 0.03 mg MRrh...

  10. Therapist guided internet based cognitive behavioural therapy for body dysmorphic disorder: single blind randomised controlled trial.

    Science.gov (United States)

    Enander, Jesper; Andersson, Erik; Mataix-Cols, David; Lichtenstein, Linn; Alström, Katarina; Andersson, Gerhard; Ljótsson, Brjánn; Rück, Christian

    2016-02-02

    To evaluate the efficacy of therapist guided internet based cognitive behavioural therapy (CBT) programme for body dysmorphic disorder (BDD-NET) compared with online supportive therapy. A 12 week single blind parallel group randomised controlled trial. Academic medical centre. 94 self referred adult outpatients with a diagnosis of body dysmorphic disorder and a modified Yale-Brown obsessive compulsive scale (BDD-YBOCS) score of ≥ 20. Concurrent psychotropic drug treatment was permitted if the dose had been stable for at least two months before enrolment and remained unchanged during the trial. Participants received either BDD-NET (n=47) or supportive therapy (n=47) delivered via the internet for 12 weeks. The primary outcome was the BDD-YBOCS score after treatment and follow-up (three and six months from baseline) as evaluated by a masked assessor. Responder status was defined as a ≥ 30% reduction in symptoms on the scale. Secondary outcomes were measures of depression (MADRS-S), global functioning (GAF), clinical global improvement (CGI-I), and quality of life (EQ5D). The six month follow-up time and all outcomes other than BDD-YBOCS and MADRS-S at 3 months were not pre-specified in the registration at clinicaltrials.gov because of an administrative error but were included in the original trial protocol approved by the regional ethics committee before the start of the trial. BDD-NET was superior to supportive therapy and was associated with significant improvements in severity of symptoms of body dysmorphic disorder (BDD-YBOCS group difference -7.1 points, 95% confidence interval -9.8 to -4.4), depression (MADRS-S group difference -4.5 points, -7.5 to -1.4), and other secondary measures. At follow-up, 56% of those receiving BDD-NET were classed as responders, compared with 13% receiving supportive therapy. The number needed to treat was 2.34 (1.71 to 4.35). Self reported satisfaction was high. CBT can be delivered safely via the internet to patients with body

  11. Efficacy of paraffin bath therapy in hand osteoarthritis: a single-blinded randomized controlled trial.

    Science.gov (United States)

    Dilek, Banu; Gözüm, Mehtap; Şahin, Ebru; Baydar, Meltem; Ergör, Gül; El, Ozlem; Bircan, Çigdem; Gülbahar, Selmin

    2013-04-01

    To evaluate the efficacy of paraffin bath therapy on pain, function, and muscle strength in patients with hand osteoarthritis. Prospective single-blinded randomized controlled trial. Department of physical medicine and rehabilitation in a university hospital. Patients with bilateral hand osteoarthritis (N=56). Patients were randomized into 2 groups with a random number table by using block randomization with 4 patients in a block. Group 1 (n=29) had paraffin bath therapy (5 times per week, for 3-week duration) for both hands. Group 2 (n=27) was the control group. All patients were informed about joint-protection techniques, and paracetamol intake was recorded. The primary outcome measures were pain (at last 48h) at rest and during activities of daily living (ADL), assessed with a visual analog scale (0-10cm) at 12 weeks. The secondary outcome measures were the Australian Canadian Osteoarthritis Hand Index (AUSCAN) and the Dreiser Functional Index (DFI), used for subjective functional evaluation, loss of range of motion (ROM), grip and pinch strength, painful and tender joint counts, and paracetamol intake. A researcher blind to group allocation recorded the measures for both hands at baseline, 3 weeks, and 12 weeks at the hospital setting. At baseline, there were no significant differences between groups in any of the parameters (P>.05). After treatment, the paraffin group exhibited significant improvement in pain at rest and during ADL, ROM of the right hand, and pain and stiffness dimensions of the AUSCAN (P.05). The control group showed a significant deterioration in right hand grip and bilateral lateral pinch and right chuck pinch strength (Pparaffin group (Pparaffin group were significantly higher than the control group at 12 weeks (PParaffin bath therapy seemed to be effective both in reducing pain and tenderness and maintaining muscle strength in hand osteoarthritis. It may be regarded as a beneficial short-term therapy option, which is effective for a 12

  12. Induction therapy with carboplatin/paclitaxel followed by concurrent carboplatin/paclitaxel and dose-escalating conformal radiotherapy in the treatment of locally advanced, unresectable non-small cell lung cancer: preliminary report of a phase I trial.

    Science.gov (United States)

    Socinski, M A; Clark, J A; Halle, J; Steagall, A; Kaluzny, B; Rosenman, J G

    1997-08-01

    Locally advanced non-small cell lung cancer is optimally managed with chemotherapy and thoracic irradiation, although the most appropriate strategy is not yet defined. In this phase I trial, we use two 21-day cycles of induction chemotherapy with paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) (225 mg/m2 over 3 hours) and carboplatin (area under the concentration-time curve = 6) followed by concurrent weekly paclitaxel (45 mg/m2/wk x 6) and carboplatin (area under the concentration-time curve = 2/wk x 6) and thoracic irradiation. Patients undergo three-dimensional treatment planning (conformal radiotherapy) to define the cancer target volume precisely. The phase I question being addressed in this study is the maximum tolerated radiation dose given concurrently with low-dose paclitaxel and carboplatin. The initial radiation dose is 60 Gy, with dose escalations to 66 Gy, 70 Gy, and 74 Gy being planned. Ten patients have been entered thus far (eight men and two women). Their median age is 67 years (range, 59 to 78 years), and none of the patients has had greater than 5% pretreatment weight loss. Seven of 10 are evaluable for response to induction carboplatin and paclitaxel, with a response rate of 57% (three partial responses and one minor response). Three patients had stable disease and none of the patients had evidence of progressive disease during induction chemotherapy. Three patients have completed all treatment at 60 Gy and one has completed all treatment at 66 Gy. Three of the four patients have had partial responses (75%), with the remaining patient having stable disease. Toxicity in the concurrent chemoradiotherapy portion of the trial thus far has consisted of grade 3 neutropenia in one patient and grade 4 lymphocytopenia in all four patients. No grade 3 or 4 nonhematologic toxicity has been seen. The trial data are not yet mature enough to report on survival. Accrual and treatment is continuing at the 66 Gy radiation dose level.

  13. Phase I dose-escalation study to examine the safety and tolerability of LY2603618, a checkpoint 1 kinase inhibitor, administered 1 day after pemetrexed 500 mg/m(2) every 21 days in patients with cancer.

    Science.gov (United States)

    Weiss, Glen J; Donehower, Ross C; Iyengar, Tara; Ramanathan, Ramesh K; Lewandowski, Karen; Westin, Eric; Hurt, Karla; Hynes, Scott M; Anthony, Stephen P; McKane, Scott

    2013-02-01

    This phase I study aims at assessing the safety and tolerability of LY2603618, a selective inhibitor of Checkpoint Kinase 1, in combination with pemetrexed and determining the maximum tolerable dose and the pharmacokinetic parameters. This was an open-label, multicenter, dose-escalation study in patients with advanced solid tumors. Increasing doses of LY2603618 (40-195 mg/m(2)) were combined with 500 mg/m(2) of pemetrexed. LY2603618 was administered on Days 1 and 9 and pemetrexed on Day 8 in a 28-day cycle. For all subsequent 21-day cycles, pemetrexed was administered on Day 1 and LY2603618 on Day 2. Antitumor activity was evaluated as per Response Evaluation Criteria in Solid Tumors 1.0. A total of 31 patients were enrolled into six cohorts (three at 40 mg/m(2) over 4.5-hour infusion, 1-hour infusion in subsequent cohorts: three each at 40 mg/m(2), 70 mg/m(2), and 195 mg/m(2); 13 at 105 mg/m(2); six at 150 mg/m(2)). Four patients experienced a dose-limiting toxicity: diarrhea (105 mg/m(2)); reversible infusion-related reaction (150 mg/m(2)); thrombocytopenia (195 mg/m(2)); and fatigue (195 mg/m(2)). The maximum tolerated dose was defined as 150 mg/m(2). The pharmacokinetic data demonstrated that the exposure of LY2603618 increased in a dose-dependent manner, displayed a suitable half-life for maintaining required human exposures while minimizing the intra- and inter-cycle accumulation, and was unaffected by the pemetrexed administration. The pharmacokinetic-defined biologically efficacious dose was achieved at doses ≥105 mg/m(2). LY2603618 administered approximately 24 h after pemetrexed showed acceptable safety and pharmacokinetic profiles.

  14. IDEAL-CRT: A Phase 1/2 Trial of Isotoxic Dose-Escalated Radiation Therapy and Concurrent Chemotherapy in Patients With Stage II/III Non-Small Cell Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Landau, David B., E-mail: david.landau@kcl.ac.uk [Guy' s & St. Thomas' NHS Trust, King' s College London, London (United Kingdom); Hughes, Laura [Cancer Research UK and UCL Cancer Trials Centre, London (United Kingdom); Baker, Angela [Clatterbridge Cancer Centre, Bebington (United Kingdom); Bates, Andrew T. [Southampton General Hospital, Southampton (United Kingdom); Bayne, Michael C. [Poole Hospital, Poole (United Kingdom); Counsell, Nicholas [Cancer Research UK and UCL Cancer Trials Centre, London (United Kingdom); Garcia-Alonso, Angel [North Wales Cancer Centre, Rhyl (United Kingdom); Harden, Susan V. [Addenbrookes Hospital, Cambridge (United Kingdom); Hicks, Jonathan D. [Beatson West of Scotland Cancer Centre, Glasgow (United Kingdom); Hughes, Simon R. [Guy' s & St. Thomas' NHS Trust, King' s College London, London (United Kingdom); Illsley, Marianne C. [Royal Surrey County Hospital, Guilford (United Kingdom); Khan, Iftekhar [Cancer Research UK and UCL Cancer Trials Centre, London (United Kingdom); Laurence, Virginia [Poole Hospital, Poole (United Kingdom); Malik, Zafar; Mayles, Helen; Mayles, William Philip M. [Clatterbridge Cancer Centre, Bebington (United Kingdom); Miles, Elizabeth [Mount Vernon Hospital, Middlesex (United Kingdom); Mohammed, Nazia [Beatson West of Scotland Cancer Centre, Glasgow (United Kingdom); Ngai, Yenting [Cancer Research UK and UCL Cancer Trials Centre, London (United Kingdom); Parsons, Emma [Mount Vernon Hospital, Middlesex (United Kingdom); and others

    2016-08-01

    Purpose: To report toxicity and early survival data for IDEAL-CRT, a trial of dose-escalated concurrent chemoradiotherapy (CRT) for non-small cell lung cancer. Patients and Methods: Patients received tumor doses of 63 to 73 Gy in 30 once-daily fractions over 6 weeks with 2 concurrent cycles of cisplatin and vinorelbine. They were assigned to 1 of 2 groups according to esophageal dose. In group 1, tumor doses were determined by an experimental constraint on maximum esophageal dose, which was escalated following a 6 + 6 design from 65 Gy through 68 Gy to 71 Gy, allowing an esophageal maximum tolerated dose to be determined from early and late toxicities. Tumor doses for group 2 patients were determined by other tissue constraints, often lung. Overall survival, progression-free survival, tumor response, and toxicity were evaluated for both groups combined. Results: Eight centers recruited 84 patients: 13, 12, and 10, respectively, in the 65-Gy, 68-Gy, and 71-Gy cohorts of group 1; and 49 in group 2. The mean prescribed tumor dose was 67.7 Gy. Five grade 3 esophagitis and 3 grade 3 pneumonitis events were observed across both groups. After 1 fatal esophageal perforation in the 71-Gy cohort, 68 Gy was declared the esophageal maximum tolerated dose. With a median follow-up of 35 months, median overall survival was 36.9 months, and overall survival and progression-free survival were 87.8% and 72.0%, respectively, at 1 year and 68.0% and 48.5% at 2 years. Conclusions: IDEAL-CRT achieved significant treatment intensification with acceptable toxicity and promising survival. The isotoxic design allowed the esophageal maximum tolerated dose to be identified from relatively few patients.

  15. A phase I dose escalation trial of AXP107-11, a novel multi-component crystalline form of genistein, in combination with gemcitabine in chemotherapy-naive patients with unresectable pancreatic cancer.

    Science.gov (United States)

    Löhr, Johannes-Matthias; Karimi, Masoud; Omazic, Brigitta; Kartalis, Nikolaos; Verbeke, Caroline Sabine; Berkenstam, Anders; Frödin, Jan-Erik

    2016-01-01

    AXP107-11 is a novel, multi-component crystalline form of the naturally occurring compound genistein. AXP107-11 has improved physiochemical properties and oral bioavailability compared to the natural form of genistein, and it is possible that combining AXP107-11 with chemotherapy may increase the effect and reduce chemoresistance. The purpose of this dose escalation phase Ib study was to assess the safety, maximum tolerated dose (MTD) and pharmacokinetics (PK) of AXP107-11 in combination with gemcitabine in treatment-naïve patients with inoperable pancreatic carcinoma. AXP107-11 was given orally in escalating doses (400 mg-1600 mg daily) in combination with standard gemcitabine treatment (1000 mg/m(2)/week) for the first seven of eight weeks and thereafter for a maximum of four × four-week treatment cycles. PK, safety, MTD and efficacy of AXP107-11 in combination with gemcitabine were evaluated. Sixteen patients were enrolled and received AXP107-11. The maximum concentration in serum of unconjugated (free) genistein was 1 μM. Neither dose-limiting toxicities (DLTs) nor signs of hematological or non-hematological toxicities related to AXP107-11 were observed over a period ranging from 0.7 to 13.2 months. The median overall survival time was 4.9 months (range 1.5-19.5 months). Seven patients (44%) survived longer than six months and 19% were alive at the one-year follow-up. Treatment of pancreatic cancer patients with AXP107-11 in combination with gemcitabine resulted in a favorable PK-profile with high serum levels without signs of either hematological or non-hematological toxicity. Accordingly, we suggest further studies with AXP107-11 in pancreatic cancer patients. Copyright © 2016 IAP and EPC. Published by Elsevier B.V. All rights reserved.

  16. A phase I open-label dose-escalation study of the anti-HER3 monoclonal antibody LJM716 in patients with advanced squamous cell carcinoma of the esophagus or head and neck and HER2-overexpressing breast or gastric cancer.

    Science.gov (United States)

    Reynolds, Kerry Lynn; Bedard, Philippe L; Lee, Se-Hoon; Lin, Chia-Chi; Tabernero, Josep; Alsina, Maria; Cohen, Ezra; Baselga, José; Blumenschein, George; Graham, Donna M; Garrido-Laguna, Ignacio; Juric, Dejan; Sharma, Sunil; Salgia, Ravi; Seroutou, Abdelkader; Tian, Xianbin; Fernandez, Rose; Morozov, Alex; Sheng, Qing; Ramkumar, Thiruvamoor; Zubel, Angela; Bang, Yung-Jue

    2017-09-12

    Human epidermal growth factor receptor 3 (HER3) is important in maintaining epidermal growth factor receptor-driven cancers and mediating resistance to targeted therapy. A phase I study of anti-HER3 monoclonal antibody LJM716 was conducted with the primary objective to identify the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE), and dosing schedule. Secondary objectives were to characterize safety/tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity. This open-label, dose-finding study comprised dose escalation, followed by expansion in patients with squamous cell carcinoma of the head and neck or esophagus, and HER2-overexpressing metastatic breast cancer or gastric cancer. During dose escalation, patients received LJM716 intravenous once weekly (QW) or every two weeks (Q2W), in 28-day cycles. An adaptive Bayesian logistic regression model was used to guide dose escalation and establish the RDE. Exploratory pharmacodynamic tumor studies evaluated modulation of HER3 signaling. Patients received LJM716 3-40 mg/kg QW and 20 mg/kg Q2W (54 patients; 36 patients at 40 mg/kg QW). No dose-limiting toxicities (DLTs) were reported during dose-escalation. One patient experienced two DLTs (diarrhea, hypokalemia [both grade 3]) in the expansion phase. The RDE was 40 mg/kg QW, providing drug levels above the preclinical minimum effective concentration. One patient with gastric cancer had an unconfirmed partial response; 17/54 patients had stable disease, two lasting >30 weeks. Down-modulation of phospho-HER3 was observed in paired tumor samples. LJM716 was well tolerated; the MTD was not reached, and the RDE was 40 mg/kg QW. Further development of LJM716 is ongoing. Clinicaltrials.gov registry number NCT01598077 (registered on 4 May, 2012).

  17. A double-blind, placebo-controlled trial of sibutramine for clozapine-associated weight gain.

    Science.gov (United States)

    Henderson, D C; Fan, X; Copeland, P M; Borba, C P; Daley, T B; Nguyen, D D; Zhang, H; Hayden, D; Freudenreich, O; Cather, C; Evins, A E; Goff, D C

    2007-02-01

    This study sought to examine the effectiveness of sibutramine, a weight loss agent, on clozapine-associated weight gain. This was a 12-week double-blind, placebo controlled, randomized trial of sibutramine for weight loss in obese clozapine-treated schizophrenia or schizoaffective disorder subjects. Ten patients were enrolled into the placebo group and 11 patients into the sibutramine group. There were no significant baseline differences between the two groups on age, gender, education, ethnicity, diagnosis, weight, body mass index (BMI), and blood pressure. At week 12, there were no significant differences in changes in weight, BMI, abdominal and waist circumferences, Hba1c, fasting glucose, or cholesterol levels. Sibutramine treatment did not show significant weight loss compared with placebo in clozapine-treated patients with schizophrenia or schizoaffective disorder. Further research with a larger sample size and longer follow-up duration is warranted.

  18. A randomized placebo-controlled phase III trial of oral laquinimod for multiple sclerosis

    DEFF Research Database (Denmark)

    Vollmer, T L; Sorensen, P S; Selmaj, K

    2014-01-01

    The phase III placebo-controlled BRAVO study assessed laquinimod effects in patients with relapsing-remitting MS (RRMS), and descriptively compared laquinimod with interferon beta (IFNβ)-1a (Avonex(®) reference arm). RRMS patients age 18-55 years with Expanded Disability Status Scale (EDSS) scores...... months. The primary endpoint was annualized relapse rate (ARR); secondary endpoints included percent brain volume change (PBVC) and 3-month confirmed disability worsening. In all, 1,331 patients were randomized: laquinimod (n = 434), placebo (n = 450), and IFNβ-1a (n = 447). ARR was not significantly...... reduced with laquinimod [-18 %, risk ratio (RR) = 0.82, 95 % CI 0.66-1.02; p = 0.075] vs. placebo. Laquinimod significantly reduced PBVC (28 %, p change in confirmed disability worsening with laquinimod measured...

  19. Pregabalin for anxiety in patients with schizophrenia - A randomized, double-blind placebo-controlled study

    DEFF Research Database (Denmark)

    Schjerning, Ole; Damkier, Per; Lykkegaard, Signe Engelhardt

    2017-01-01

    INTRODUCTION: Anxiety is frequent in patients with schizophrenia and poses a major impact on patients perceived quality of life, daily functioning and risk of suicide. Pregabalin has shown effective in the treatment of generalized anxiety disorder and has been suggested for the treatment of anxiety...... in patients with schizophrenia. As evidence is sparse regarding treatment of anxiety in this patient group, we aimed to investigate the use of pregabalin for anxiety in patients with schizophrenia. METHODS: A randomized, double-blind placebo controlled study was used. Patients were randomized to either...... placebo or pregabalin (≤600mg/d) as add-on treatment. Primary analyses were intention-to-treat based with change in Hamilton Anxiety Scale after 4 and 8weeks of treatment as primary outcome. Secondary outcomes were change in psychopathology, quality-of-life, cognitive functioning and sleep. The study used...

  20. Randomized clinical trial of transversus abdominis plane block versus placebo control in live-donor nephrectomy.

    Science.gov (United States)

    Hosgood, Sarah A; Thiyagarajan, Umasanker M; Nicholson, Harriet F L; Jeyapalan, Inthira; Nicholson, Michael L

    2012-09-15

    Laparoscopic surgery reduces pain after donor nephrectomy; however, most patients still require a significant amount of postoperative parenteral opiate analgesia. Therefore, there is a need to investigate techniques that might further reduce postoperative pain. This study assessed the safety and efficacy of using a transversus abdominis plane (TAP) block in a randomized, double-blind, placebo-controlled trial. Forty-six patients were analyzed in the trial and were randomized to undergo the TAP block procedure with either bupivacaine (n=24) or saline placebo (Control n=22) injected into the muscle plane. Prefilled syringes were dispensed with the group allocation concealed to maintain blinding. After surgery, the amount of morphine, level of pain, and measures of recovery were recorded. The amount of morphine used 6 hr after surgery was significantly lower in patients receiving TAP block with bupivacaine compared with the control (presented as mean [SD], 12.4 [8.4] vs. 21.2 [14.0] mg; P=0.015). However, the total amount of morphine used was similar in both groups 45.6 [31.4] vs. 52.7 [28.8] mg; P=0.771. Patients in the bupivacaine group experienced significantly less pain on postoperative days 1 (score, 19 [15] vs. 37 [20]; P=0.003) and 2 (score, 11 [10] vs. 19 [13]; P=0.031). Recovery and postoperative hospital stay were similar in both groups. There were no complications associated with the procedure. The TAP block procedure is beneficial in reducing postoperative pain and early morphine requirements in laparoscopic live-donor nephrectomy.

  1. A randomized, placebo-controlled trial of repetitive spinal magnetic stimulation in lumbosacral spondylotic pain.

    Science.gov (United States)

    Lo, Yew L; Fook-Chong, Stephanie; Huerto, Antonio P; George, Jane M

    2011-07-01

    Lumbar spondylosis is a degenerative disorder of the spine, whereby pain is a prominent feature that poses therapeutic challenges even after surgical intervention. There are no randomized, placebo-controlled studies utilizing repetitive spinal magnetic stimulation (SMS) in pain associated with lumbar spondylosis. In this study, we utilize SMS technique for patients with this condition in a pilot clinical trial. We randomized 20 patients into SMS treatment or placebo arms. All patients must have clinical and radiological evidence of lumbar spondylosis. Patients should present with pain in the lumbar region, localized or radiating down the lower limbs in a radicular distribution. SMS was delivered with a Medtronic R30 repetitive magnetic stimulator (Medtronic Corporation, Skovlunde, Denmark) connected to a C-B60 figure of eight coil capable of delivering a maximum output of 2 Tesla per pulse. The coil measured 90 mm in each wing and was centered over the surface landmark corresponding to the cauda equina region. The coil was placed flat over the back with the handle pointing cranially. Each patient on active treatment received 200 trains of five pulses delivered at 10 Hz, at an interval of 5 seconds between each train. "Sham" SMS was delivered with the coil angled vertically and one of the wing edges in contact with the stimulation point. All patients tolerated the procedure well and no side effects of SMS were reported. In the treatment arm, SMS had resulted in significant pain reduction immediately and at Day 4 after treatment (P lumbar spondylosis in a randomized, double-blind, placebo-controlled setting. The novel findings support the potential of this technique for future studies pertaining to neuropathic pain. Wiley Periodicals, Inc.

  2. A randomized placebo-controlled study of noninvasive cortical electrostimulation in the treatment of fibromyalgia patients.

    Science.gov (United States)

    Hargrove, Jeffrey B; Bennett, Robert M; Simons, David G; Smith, Susan J; Nagpal, Sunil; Deering, Donald E

    2012-01-01

    The aim of this multicenter study was to evaluate the efficacy, safety, and tolerability of noninvasive cortical electrostimulation in the management of fibromyalgia (FM). A prospective, randomized, double-blind, placebo-controlled design was used. Setting.  Subjects received therapy at two different outpatient clinical locations. There were 77 subjects meeting the American College of Rheumatology 1990 classification criteria for FM. Intervention.  Thirty-nine (39) active treatment (AT) FM patients and 38 placebo controls received 22 applications of either noninvasive cortical electrostimulation or a sham therapy over an 11-week period. The primary outcome measures were the number of tender points (TePs) and pressure pain threshold (PPT). Secondary outcome measures were responses to the Fibromyalgia Impact Questionnaire (FIQ), Symptom Checklist-90 (SCL-90), Beck Depression Inventory-II, and a novel sleep questionnaire, all evaluated at baseline and at the end of treatment. Intervention provided significant improvements in TeP measures: compared with placebo, the AT patients improved in the number of positive TePs (-7.4 vs -0.2, PFIQ score (-15.5 vs -5.6, P=0.03), FIQ pain (-2.0 vs -0.6, P=0.03), FIQ fatigue (-2.0 vs -0.4, P=0.02), and FIQ refreshing sleep (-2.1 vs -0.7, P=0.02); and while FIQ function improved (-1.0 vs -0.2), the between-group change had a 14% likelihood of occurring due to chance (P=0.14). There were no significant side effects observed. Noninvasive cortical electrostimulation in FM patients provided modest improvements in pain, TeP measures, fatigue, and sleep; and the treatment was well tolerated. This form of therapy could potentially provide worthwhile adjunctive symptom relief for FM patients. Wiley Periodicals, Inc.

  3. Safety of Flibanserin in Women Treated With Antidepressants: A Randomized, Placebo-Controlled Study.

    Science.gov (United States)

    Clayton, Anita H; Croft, Harry A; Yuan, James; Brown, Louise; Kissling, Robert

    2018-01-01

    Depression is often associated with sexual dysfunction, and pharmacologic treatment for hypoactive sexual desire disorder can be considered in women receiving treatment for depression. To evaluate the safety of flibanserin in women treated for depression with selective serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors. In this double-blinded, randomized, placebo-controlled trial, women with remitted or mild depression treated with selective serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors who were not postmenopausal and were experiencing symptoms of hypoactive sexual desire disorder (ie, decreased sexual desire and related distress) received flibanserin 50 mg at bedtime (qhs) for 2 weeks and up-titrated to 100 mg qhs, flibanserin 100 mg qhs for the entire treatment period, or placebo for up to 12 weeks. Safety assessment included adverse events and symptoms of depression and anxiety. 73 patients were randomly assigned to flibanserin (both dose groups combined) and 38 to placebo. The sponsor terminated the study early at discontinuation of the development of flibanserin. Treatment duration was at least 8 weeks for 84.9% and 94.7% of patients in the flibanserin and placebo groups, respectively. The most common adverse events (incidence ≥ 2% in the flibanserin group and higher than that in the placebo group) included dry mouth (5.5% for flibanserin vs 2.6% for placebo), insomnia (5.5% vs 2.6%), back pain (4.1% vs 2.6%), and dizziness (4.1% vs 0.0%). There were no serious adverse events and no instances of suicidal ideation or behavior. The proportions of patients with symptom worsening in the flibanserin and placebo groups, respectively, were 6.9% and 21.6% for depression and 1.4% and 2.7% for anxiety. Remission of depression at study end point, as measured by the Quick Inventory of Depressive Symptomatology-Self Report, was experienced by 19.4% of flibanserin-treated patients and 10.8% of patients

  4. Sodium valproate in the treatment of aggressive behavior in patients with dementia--a randomized placebo controlled clinical trial

    NARCIS (Netherlands)

    Sival, Rob C.; Haffmans, P. M. Judith; Jansen, Paul A. F.; Duursma, Sijmen A.; Eikelenboom, Piet

    2002-01-01

    OBJECTIVES: The efficacy and tolerability of sodium valproate 2 x 240 mg compared to placebo were investigated in aggressive behavior in dementia. DESIGN: A randomized, placebo controlled, double-blind cross-over design. The trial included a baseline period (one week); a placebo period (three

  5. PLACEBO-CONTROLLED STUDY OF MYCOPHENOLATE MOFETIL COMBINED WITH CYCLOSPORINE AND CORTICOSTEROIDS FOR PREVENTION OF ACUTE REJECTION

    NARCIS (Netherlands)

    GRINYO, J; GROTH, C; PICHLMAYR, R; SADEK, SA; VANRENTERGHEM, Y; BEHREND, M; LUCK, R; MORESO, F; PEETERS, J; RODICIO, J; MORALES, J; ALBRECHTSEN, D; FAUCHALD, P; SADEK, S; LODGE, J; SOULILLOU, JP; CANTAROVICH, D; van Son, W; Tegzess, Adam; WAGNER, K; ERHARD, J; BRATTSTROM, C; MJORNSTEDT, L; WIESEL, M; CARL, S; NEUMAYER, HH; HAUSER, [No Value; LANG, P; BOURGEON, B; TUFVESON, G; GANNEDAHL, G; EKBERG, H; PERSSON, N; TARANTINO, A; CAMPISE, M; THIEL, G; ZEILER, M; HENE, R; LIGTENBERG, G; MORGAN, A; RIGG, K; HOOFTMAN, L; HUTCHINSON, K

    1995-01-01

    Preliminary studies suggested that mycophenolate mofetil (MMF), which inhibits proliferation of T and B cells, may reduce the frequency of acute rejection after renal transplantation. Our randomised, double-blind, multicentre, placebo-controlled study compared the efficacy and safety of MMF with

  6. High-volume infiltration analgesia in total knee arthroplasty: a randomized, double-blind, placebo-controlled trial

    DEFF Research Database (Denmark)

    Andersen, L.O.; Husted, H.; Otte, K.S.

    2008-01-01

    with a detailed description of the infiltration technique. METHODS: In a randomized, double-blind, placebo-controlled trial in 12 patients undergoing bilateral knee arthroplasty, saline or high-volume (170 ml) ropivacaine (0.2%) with epinephrine was infiltrated around each knee, with repeated doses administered...

  7. Validation of novel recipes for double-blind, placebo-controlled food challenges in children and adults

    NARCIS (Netherlands)

    Vlieg-Boerstra, B. J.; Herpertz, I.; Pasker, L.; van der Heide, S.; Kukler, J.; Jansink, C.; Vaessen, W.; Beusekamp, B. J.; Dubois, A. E. J.

    P>Background: In double-blind, placebo-controlled food challenges (DBPCFCs), the use of challenge materials in which blinding is validated is a prerequisite for obtaining true blinded conditions during the test procedure. Therefore, the aim of this study was to enlarge the available range of

  8. Validation of novel recipes for double-blind, placebo-controlled food challenges in children and adults

    NARCIS (Netherlands)

    Vlieg-Boerstra, B. J.; Herpertz, I.; Pasker, L.; van der Heide, S.; Kukler, J.; Jansink, C.; Vaessen, W.; Beusekamp, B. J.; Dubois, A. E. J.

    2011-01-01

    In double-blind, placebo-controlled food challenges (DBPCFCs), the use of challenge materials in which blinding is validated is a prerequisite for obtaining true blinded conditions during the test procedure. Therefore, the aim of this study was to enlarge the available range of validated recipes for

  9. Topical glyceryl trinitrate treatment of chronic patellar tendinopathy : a randomised, double-blind, placebo-controlled clinical trial

    NARCIS (Netherlands)

    Steunebrink, Mirjam; Zwerver, Johannes; Brandsema, Ruben; Groenenboom, Petra; van den Akker-Scheek, Inge; Weir, Adam

    Objectives To assess if continuous topical glyceryl trinitrate (GTN) treatment improves outcome in patients with chronic patellar tendinopathy when compared with eccentric training alone. Methods Randomised double-blind, placebo-controlled clinical trial comparing a 12-week programme of using a GTN

  10. OVULATION INDUCTION IN PREMATURE OVARIAN FAILURE - A PLACEBO-CONTROLLED RANDOMIZED TRIAL COMBINING PITUITARY SUPPRESSION WITH GONADOTROPIN STIMULATION

    NARCIS (Netherlands)

    VANKASTEREN, YM; HOEK, A; SCHOEMAKER, J

    Objectives: To determine the effect of pituitary suppression with a GnRH agonist (GnRH-a) on the success of ovulation induction with exogenous gonadotropins in patients with premature ovarian failure (POF). Design: Placebo-controlled, randomized, double-blind study. The data were analyzed with a

  11. Suicide risk in placebo-controlled trials of treatment for acute manic episode and prevention of manic-depressive episode

    NARCIS (Netherlands)

    Storosum, Jitschak G.; Wohlfarth, Tamar; Gispen-de Wied, Christine C.; Linszen, Don H.; Gersons, Berthold P. R.; van Zwieten, Barbara J.; van den Brink, Wim

    2005-01-01

    Objective: The authors' goal was to investigate whether there is a greater suicide risk in the placebo arms of placebo-controlled studies of active medication for the treatment of acute manic episode and the prevention of manic/depressive episode. If so, this would be a strong ethical argument

  12. Cognitive, health and psychosocial effects of melatonin and light therapy in childhood insomnia. Double-blind placebo-controlled study

    NARCIS (Netherlands)

    Smits, M.; van Maanen, A.; Meijer, A.M.; van der Heijden, K.; Oort, F.

    2017-01-01

    Introduction: To examine effects of melatonin and light therapy on cognitive, health and psychosocial outcomes in children with chronic sleep onset insomnia; and to disentangle direct effects from indirect effects through sleep improvement. Methods: A randomized, double-blind placebo-controlled

  13. Relapse prevention in pediatric patients with ADHD treated with atomoxetine: a randomized, double-blind, placebo-controlled study.

    NARCIS (Netherlands)

    Michelson, D.; Danckaerts, M.; Gillberg, C.; Spencer, T.J.; Zuddas, A.; Faries, D.E.; Zhang, S.; Biederman, J.

    2004-01-01

    OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) is typically treated over extended periods; however, few placebo-controlled, long-term studies of efficacy have been reported. METHOD: In a global multicenter study, children and adolescents who responded to an initial 12-week, open-label

  14. Masking foods for food challenge: practical aspects of masking foods for a double-blind, placebo-controlled food challenge

    NARCIS (Netherlands)

    Huijbers, G. B.; Colen, A. A.; Jansen, J. J.; Kardinaal, A. F.; Vlieg-Boerstra, B. J.; Martens, B. P.

    1994-01-01

    In diagnosing a food allergy or food intolerance, a double-blind, placebo-controlled food challenge (DBPCFC) with the suspected food or food substance is the only method available for objective confirmation of an assumed relationship between a suspected agent and a complaint. When the use of

  15. Identification of hazelnut major allergens in sensitive patients with positive double-blind, placebo-controlled food challenge results

    DEFF Research Database (Denmark)

    Pastorello, Elide A; Vieths, Stefan; Pravettoni, Valerio

    2002-01-01

    The hazelnut major allergens identified to date are an 18-kd protein homologous to Bet v 1 and a 14-kd allergen homologous to Bet v 2. No studies have reported hazelnut allergens recognized in patients with positive double-blind, placebo-controlled food challenge (DBPCFC) results or in patients...

  16. Placebo-controlled comparison of captopril, metoprolol, and hydrochlorothiazide therapy in non-insulin-dependent diabetic patients with primary hypertension

    DEFF Research Database (Denmark)

    Gall, M A; Rossing, P; Skøtt, P

    1992-01-01

    The antihypertensive effect of captopril, metoprolol, and hydrochlorothiazide was compared in 23 non-insulin-dependent (NIDDM) diabetic patients less than or equal to 75 years of age, with borderline to moderate primary hypertension. In a double blind, placebo-controlled cross-over trial...

  17. Skeletal effects and functional outcome with olpadronate in children with osteogenesis imperfecta: a 2-year randomised placebo-controlled study

    NARCIS (Netherlands)

    Sakkers, Ralph; Kok, Dieke; Engelbert, Raoul; van Dongen, Alice; Jansen, Maarten; Pruijs, Hans; Verbout, Ab; Schweitzer, Dave; Uiterwaal, Cuno

    2004-01-01

    Non-randomised studies have suggested beneficial effects of bisphosphonates in osteogenesis imperfecta. We assessed the effects of oral olpadronate in children with this disorder in a randomised double-blind placebo-controlled trial. 34 children recruited from the Dutch national centre for

  18. A double-blind placebo-controlled study of controlled release fluvoxamine for the treatment of generalized social anxiety disorder

    NARCIS (Netherlands)

    Westenberg, HGM; Stein, DJ; Yang, HC; Li, D; Barbato, LM

    This was a randomized double-blind placebo-controlled multicenter study to assess the efficacy, safety, and tolerability of fluvoxamine in a controlled release (CR) formulation for treatment of generalized social anxiety disorder (GSAD). A total of 300 subjects with GSAD were randomly assigned to

  19. Treatment of knee osteoarthritis with pulsed electromagnetic fields: a randomized, double-blind, placebo-controlled study

    DEFF Research Database (Denmark)

    Thamsborg, G; Florescu, A; Oturai, P

    2005-01-01

    OBJECTIVE: The investigation aimed at determining the effectiveness of pulsed electromagnetic fields (PEMF) in the treatment of osteoarthritis (OA) of the knee by conducting a randomized, double-blind, placebo-controlled clinical trial. DESIGN: The trial consisted of 2h daily treatment 5 days per...

  20. Implant decontamination during surgical peri-implantitis treatment : a randomized, double-blind, placebo-controlled trial

    NARCIS (Netherlands)

    de Waal, Yvonne C. M.; Raghoebar, Gerry M.; Huddleston Slater, James J. R.; Meijer, Henny J. A.; Winkel, Edwin G.; van Winkelhoff, Arie Jan

    Aim The objective of this randomized, double-blind, placebo-controlled trial was to study the effect of implant surface decontamination with chlorhexidine (CHX)/cetylpyridinium chloride (CPC) on microbiological and clinical parameters. Material & Methods Thirty patients (79 implants) with

  1. Implant decontamination during surgical peri-implantitis treatment : a randomized, double-blind, placebo-controlled trial

    NARCIS (Netherlands)

    de Waal, Yvonne C.M.; Raghoebar, Gerry M; Huddleston Slater, James J R; Meijer, Hendrikus; Winkel, Edwin G; van Winkelhoff, Arie Jan

    AIM: The objective of this randomized, double-blind, placebo-controlled trial was to study the effect of implant surface decontamination with chlorhexidine (CHX)/cetylpyridinium chloride (CPC) on microbiological and clinical parameters. MATERIAL & METHODS: Thirty patients (79 implants) with

  2. Prospective double blind randomized placebo-controlled clinical trial of the pectoral nerves (Pecs) block type II

    NARCIS (Netherlands)

    Versyck, B.; Geffen, G.J. van; Houwe, P. Van

    2017-01-01

    STUDY OBJECTIVE: The aim of this clinical trial was to test the hypothesis whether adding the pectoral nerves (Pecs) block type II to the anesthetic procedure reduces opioid consumption during and after breast surgery. DESIGN: A prospective randomized double blind placebo-controlled study. SETTING:

  3. A Randomized Double-Blind Placebo-Controlled Trial of Lactobacillus reuteri for Chronic Functional Abdominal Pain in Children

    OpenAIRE

    Kambiz Eftekhari; Zahra Vahedi; Mojtaba Kamali Aghdam; Diana Noemi Diaz

    2015-01-01

    Background: Functional abdominal pain (FAP) is one of the most common diseases, and large percentages of children suffer from it. Objectives: The purpose of the study was to evaluate the effect of Lactobacillus reuteri in treatment of children with functional abdominal pain. Patients and Methods: This study was a randomized double-blind placebo-controlled trial. Children aged 4 to ...

  4. Development and validation of challenge materials for double-blind, placebo-controlled food challenges in children

    NARCIS (Netherlands)

    Vlieg-Boerstra, BJ; Bijleveld, CMA; van der Heide, S; Beusekamp, BJ; Wolt-Plompen, SAA; Kukler, J; Brinkman, J; Duiverman, EJ; Dubois, AEJ

    Background: The use of double-blind, placebo-controlled food challenges (DBPCFCs) is considered the gold standard for the diagnosis of food allergy. Despite this, materials and methods used in DBPCFCs have not been standardized. Objective: The purpose of this study was to develop and validate

  5. Renal Hemodynamic Effects of Serelaxin in Patients With Chronic Heart Failure A Randomized, Placebo-Controlled Study

    NARCIS (Netherlands)

    Voors, Adriaan A.; Dahlke, Marion; Meyer, Sven; Stepinska, Janina; Gottlieb, Stephen S.; Jones, Andrew; Zhang, Yiming; Laurent, Didier; Slart, Riemer H. J. A.; Navis, Gerjan J.

    2014-01-01

    Background-Serelaxin is a promising therapy for acute heart failure. The renal hemodynamic effects of serelaxin in patients with chronic heart failure are unknown. Methods and Results-In this double-blind, randomized, placebo-controlled, multicenter study, patients with New York Heart Association

  6. Treatment of chronic tension-type headache with botulinum toxin: a double-blind, placebo-controlled clinical trial

    NARCIS (Netherlands)

    Padberg, M.; de Bruijn, S. F. T. M.; de Haan, R. J.; Tavy, D. L. J.

    2004-01-01

    Botulinum toxin is increasingly advocated as effective treatment in chronic tension-type headache. We conducted a randomized, placebo-controlled clinical trial to prove efficacy of botulinum toxin in chronic tension-type headache. Patients were randomly assigned to receive botulinum toxin (maximum

  7. Bell's Palsy in Children (BellPIC): protocol for a multicentre, placebo-controlled randomized trial.

    Science.gov (United States)

    Babl, Franz E; Mackay, Mark T; Borland, Meredith L; Herd, David W; Kochar, Amit; Hort, Jason; Rao, Arjun; Cheek, John A; Furyk, Jeremy; Barrow, Lisa; George, Shane; Zhang, Michael; Gardiner, Kaya; Lee, Katherine J; Davidson, Andrew; Berkowitz, Robert; Sullivan, Frank; Porrello, Emily; Dalziel, Kim Marie; Anderson, Vicki; Oakley, Ed; Hopper, Sandy; Williams, Fiona; Wilson, Catherine; Williams, Amanda; Dalziel, Stuart R

    2017-02-13

    Bell's palsy or acute idiopathic lower motor neurone facial paralysis is characterized by sudden onset paralysis or weakness of the muscles to one side of the face controlled by the facial nerve. While there is high level evidence in adults demonstrating an improvement in the rate of complete recovery of facial nerve function when treated with steroids compared with placebo, similar high level studies on the use of steroids in Bell's palsy in children are not available. The aim of this study is to assess the utility of steroids in Bell's palsy in children in a randomised placebo-controlled trial. We are conducting a randomised, triple-blinded, placebo controlled trial of the use of prednisolone to improve recovery from Bell's palsy at 1 month. Study sites are 10 hospitals within the Australian and New Zealand PREDICT (Paediatric Research in Emergency Departments International Collaborative) research network. 540 participants will be enrolled. To be eligible patients need to be aged 6 months to Bell's palsy to one of the participating hospital emergency departments. Patients will be excluded in case of current use of or contraindications to steroids or if there is an alternative diagnosis. Participants will receive either prednisolone 1 mg/kg/day to a maximum of 50 mg/day or taste matched placebo for 10 days. The primary outcome is complete recovery by House-Brackmann scale at 1 month. Secondary outcomes include assessment of recovery using the Sunnybrook scale, the emotional and functional wellbeing of the participants using the Pediatric Quality of Life Inventory and Child Health Utility 9D Scale, pain using Faces Pain Scale Revised or visual analogue scales, synkinesis using a synkinesis assessment questionnaire and health utilisation costs at 1, 3 and 6 months. Participants will be tracked to 12 months if not recovered earlier. Data analysis will be by intention to treat with primary outcome presented as differences in proportions and an odds ratio

  8. Efficacy of antidepressants for dysthymia: a meta-analysis of placebo-controlled randomized trials.

    Science.gov (United States)

    Levkovitz, Yeciel; Tedeschini, Enrico; Papakostas, George I

    2011-04-01

    The authors sought to determine the efficacy of antidepressants in dysthymic disorder and to compare antidepressant and placebo response rates between major depressive disorder (MDD) and dysthymic disorder. PubMed/MEDLINE databases were searched for double-blind, randomized, placebo-controlled trials of antidepressants used as monotherapy for treatment of MDD or dysthymic disorder. We defined antidepressants as those with a letter of approval by the US, Canadian, or European Union drug regulatory agencies for treatment of MDD or dysthymic disorder, which included the following: amitriptyline, nortriptyline, imipramine, desipramine, clomipramine, trimipramine, protriptyline, dothiepin, doxepin, lofepramine, amoxapine, maprotiline, amineptine, nomifensine, bupropion, phenelzine, tranylcypromine, isocarboxazid, moclobemide, brofaromine, fluoxetine, sertraline, paroxetine, citalopram, escitalopram, fluvoxamine, zimelidine, tianeptine, ritanserin, trazodone, nefazodone, agomelatine, venlafaxine, desvenlafaxine, duloxetine, milnacipran, reboxetine, mirtazapine, and mianserin. Eligible studies were identified by cross-referencing the search term placebo with each of the above-mentioned agents. The search was limited to articles published between January 1, 1980, and November 20, 2009 (inclusive). To expand our database, we also reviewed the reference lists of the identified studies. We selected randomized, double-blind, placebo-controlled trials of antidepressants for either MDD or dysthymic disorder according to preset criteria relating to comorbidities, patient age, drug formulation, study duration, diagnostic criteria, choice of assessment scales, and whether or not the study reported original data. Final selection of articles was determined by consensus among the authors. A total of 194 studies were found that were eligible for inclusion in our analysis. Of these, 177 focused on the treatment of MDD and 17 on the treatment of dysthymic disorder. We found that

  9. Meta-Analysis: Risk of Tics Associated With Psychostimulant Use in Randomized, Placebo-Controlled Trials.

    Science.gov (United States)

    Cohen, Stephanie C; Mulqueen, Jilian M; Ferracioli-Oda, Eduardo; Stuckelman, Zachary D; Coughlin, Catherine G; Leckman, James F; Bloch, Michael H

    2015-09-01

    Clinical practice currently restricts the use of psychostimulant medications in children with tics or a family history of tics for fear that tics will develop or worsen as a side effect of treatment. Our goal was to conduct a meta-analysis to examine the risk of new onset or worsening of tics as an adverse event of psychostimulants in randomized, placebo-controlled trials. We conducted a PubMed search to identify all double-blind, randomized, placebo-controlled trials examining the efficacy of psychostimulant medications in the treatment of children with attention-deficit/hyperactivity disorder (ADHD). We used a fixed effects meta-analysis with risk ratio of new onset or worsening tics in children treated with psychostimulants compared to placebo. We used stratified subgroup analysis and meta-regression to examine the effects of stimulant type, dose, duration of treatment, recorder of side effect data, trial design, and mean age of participants on the measured risk of tics. We identified 22 studies involving 2,385 children with ADHD for inclusion in our meta-analysis. New onset tics or worsening of tic symptoms were commonly reported in the psychostimulant (event rate = 5.7%, 95% CI = 3.7%-8.6%) and placebo groups (event rate = 6.5%, 95% CI = 4.4%-9.5%). The risk of new onset or worsening of tics associated with psychostimulant treatment was similar to that observed with placebo (risk ratio = 0.99, 95% CI = 0.78-1.27, z = -0.05, p = .962). Type of psychostimulant, dose, duration of treatment, recorder, and participant age did not affect risk of new onset or worsening of tics. Crossover studies were associated with a significantly greater measured risk of tics with psychostimulant use compared to parallel group trials. Meta-analysis of controlled trials does not support an association between new onset or worsening of tics and psychostimulant use. Clinicians may want to consider rechallenging children who report new onset or worsening of tics with psychostimulant

  10. The Effect of Platelet-Rich Plasma in Hair Regrowth: A Randomized Placebo-Controlled Trial.

    Science.gov (United States)

    Gentile, Pietro; Garcovich, Simone; Bielli, Alessandra; Scioli, Maria Giovanna; Orlandi, Augusto; Cervelli, Valerio

    2015-11-01

    Platelet-rich plasma (PRP) has emerged as a new treatment modality in regenerative plastic surgery, and preliminary evidence suggests that it might have a beneficial role in hair regrowth. Here, we report the results of a randomized, evaluator-blinded, placebo-controlled, half-head group study to compare, with the aid of computerized trichograms, hair regrowth with PRP versus placebo. The safety and clinical efficacy of autologous PRP injections for pattern hair loss were investigated. PRP, prepared from a small volume of blood, was injected on half of the selected patients' scalps with pattern hair loss. The other half was treated with placebo. Three treatments were administered to each patient at 30-day intervals. The endpoints were hair regrowth, hair dystrophy as measured by dermoscopy, burning or itching sensation, and cell proliferation as measured by Ki67 evaluation. Patients were followed for 2 years. Of the 23 patients enrolled, 3 were excluded. At the end of the 3 treatment cycles, the patients presented clinical improvement in the mean number of hairs, with a mean increase of 33.6 hairs in the target area, and a mean increase in total hair density of 45.9 hairs per cm² compared with baseline values. No side effects were noted during treatment. Microscopic evaluation showed the increase of epidermis thickness and of the number of hair follicles 2 weeks after the last PRP treatment compared with baseline value (p plastic surgery, and preliminary evidence suggests that it might have a beneficial role in hair regrowth. Here, the results of a randomized, placebo-controlled, half-head group study to compare the hair regrowth with PRP versus placebo are reported. Hair regrowth was quantified by a blinded evaluator using computerized trichograms. The safety and clinical efficacy of autologous PRP injections for pattern hair loss were investigated. Of the 23 patients enrolled, 3 were excluded. At the end of the 3 treatment cycles, the patients presented clinical

  11. Influence of oxytocin on emotion recognition from body language: A randomized placebo-controlled trial.

    Science.gov (United States)

    Bernaerts, Sylvie; Berra, Emmely; Wenderoth, Nicole; Alaerts, Kaat

    2016-10-01

    The neuropeptide 'oxytocin' (OT) is known to play a pivotal role in a variety of complex social behaviors by promoting a prosocial attitude and interpersonal bonding. One mechanism by which OT is hypothesized to promote prosocial behavior is by enhancing the processing of socially relevant information from the environment. With the present study, we explored to what extent OT can alter the 'reading' of emotional body language as presented by impoverished biological motion point light displays (PLDs). To do so, a double-blind between-subjects randomized placebo-controlled trial was conducted, assessing performance on a bodily emotion recognition task in healthy adult males before and after a single-dose of intranasal OT (24 IU). Overall, a single-dose of OT administration had a significant effect of medium size on emotion recognition from body language. OT-induced improvements in emotion recognition were not differentially modulated by the emotional valence of the presented stimuli (positive versus negative) and also, the overall tendency to label an observed emotional state as 'happy' (positive) or 'angry' (negative) was not modified by the administration of OT. Albeit moderate, the present findings of OT-induced improvements in bodily emotion recognition from whole-body PLD provide further support for a link between OT and the processing of socio-communicative cues originating from the body of others. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  12. Pindolol augmentation in treatment-resistant obsessive compulsive disorder: a double-blind placebo controlled trial.

    Science.gov (United States)

    Dannon, P N; Sasson, Y; Hirschmann, S; Iancu, I; Grunhaus, L J; Zohar, J

    2000-05-01

    To evaluate the efficacy of pindolol augmentation in treatment-resistant obsessive compulsive disorder (OCD) patients who were unsuccessfully treated with serotonin reuptake inhibitors. Fourteen treatment-resistant OCD patients were treated with paroxetine for 17.4+/-2.1 weeks up to 60 mg/d after they failed at least two other serotonin reuptake inhibitor trials. The patients, who did not respond to open-label paroxetine treatment, were assigned to a double-blind, placebo-controlled pindolol (2.5 mgx3/d) augmentation. All the subjects were evaluated biweekly for a six-week period with the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), Hamilton Anxiety Scale (HAM-Anx), and Montgomery Asberg Depression Rating Scale (MADRS). Data was analyzed by paired t-test, and ANOVA with repeated measures. Pindolol augmentation to paroxetine (n=8) as compared to placebo augmentation (n=6), was associated with a significant (P<0.01) improvement in Y-BOCS as measured by paired t-test after the fourth week of the treatment and by ANOVA with repeated measures (df: 4.9, f: 3,3, P<0.006). Although no significant differences were found between placebo and pindolol groups on HAM-Anx and MADRS, a trend for improvement in the pindolol group was noted. The results of our study demonstrated that pindolol may augment the therapeutic effect of paroxetine in treatment-resistant OCD patients.

  13. Randomized double-blind placebo-controlled crossover study of caffeine in patients with intermittent claudication.

    Science.gov (United States)

    Momsen, A H; Jensen, M B; Norager, C B; Madsen, M R; Vestersgaard-Andersen, T; Lindholt, J S

    2010-10-01

    Intermittent claudication is a disabling symptom of peripheral arterial disease for which few medical treatments are available. This study investigated the effect of caffeine on physical capacity in patients with intermittent claudication. This randomized double-blind placebo-controlled crossover study included 88 patients recruited by surgeons from outpatient clinics. The participants abstained from caffeine for 48 h before each test and then received either a placebo or oral caffeine (6 mg/kg). After 75 min, pain-free and maximal walking distance on a treadmill, perceived pain, reaction times, postural stability, maximal isometric knee extension strength, submaximal knee extension endurance and cognitive function were measured. The analysis was by intention to treat. Caffeine increased the pain-free walking distance by 20.0 (95 per cent confidence interval 3.7 to 38.8) per cent (P = 0.014), maximal walking distance by 26.6 (12.1 to 43.0) per cent (P postural stability was reduced significantly, by 22.1 (11.7 to 33.4) per cent with eyes open (P < 0.001) and by 21.8 (7.6 to 37.8) per cent with eyes closed (P = 0.002). Neither reaction time nor cognition was affected. In patients with moderate intermittent claudication, caffeine increased walking distance, maximal strength and endurance, but affected balance adversely.

  14. A randomized, placebo-controlled trial of levetiracetam in central pain in multiple sclerosis

    DEFF Research Database (Denmark)

    Falah, M; Madsen, C; Holbech, J V

    2012-01-01

    sclerosis. This was a randomized, double-blind, placebo-controlled, cross-over trial with levetiracetam 3000 mg/day versus placebo (6-week treatment periods). Patients with multiple sclerosis, symptoms and signs complying with central neuropathic pain and pain symptoms for more than 6 months, as well....... Twenty-seven patients were included in the data analysis. There were no differences in the ratings of pain relief (levetiracetam 2.4 vs. placebo 2.1, p = 0.169), total pain intensity (levetiracetam 5.3 vs. placebo 5.7, p = 0.147) or any of the other outcome measures (p = 0.086-0.715) in the total sample...... of patients. However, there was significant reduction of pain, increased pain relief and/or more favourable pain relief with levetiracetam than with placebo in patients with lancinating or without touch-evoked pain (p = 0.025-0.046). This study found no effect of the anticonvulsant levetiracetam in non...

  15. Sweeten, soother and swaddle for retinopathy of prematurity screening: a randomised placebo controlled trial.

    LENUS (Irish Health Repository)

    O'Sullivan, A

    2012-02-01

    OBJECTIVE: To assess the efficacy of oral sucrose combined with swaddling and non-nutritive suck (NNS) as a method for reducing pain associated with retinopathy of prematurity (ROP) screening. DESIGN: Randomised placebo controlled study. SETTING: Tertiary level neonatal intensive care unit. SAMPLE: 40 infants undergoing primary eye examination for ROP screening. INTERVENTION: The control group were swaddled, and received 0.2 ml of sterile water given by mouth using a syringe and a soother. The intervention group were swaddled, and received 0.2 ml of sucrose 24% given by mouth using a syringe and a soother. RESULTS: 40 infants were included in the study. There was no difference in mean gestational age at birth, mean birth weight or corrected gestational age at first examination between both groups. The sucrose group had a significantly lower median Neonatal Pain, Agitation and Sedation Scale (N-PASS) score during ROP screening, initially following insertion of the speculum (6.5 vs 5, p=0.02) and subsequently during scleral indentation (9.5 vs 7.5, p=0.03). Fewer infants experienced episodes of desaturations or bradycardia in the intervention group (1 vs 4, p=0.18). CONCLUSION: ROP screening is a necessary but recognised painful procedure. Sucrose combined with NNS and swaddling reduced the behavioural and physiological pain responses. However, pain scores remained consistently high and appropriate pain relief for ROP screening remains a challenge.

  16. Estrogen for Alzheimer's disease in women: randomized, double-blind, placebo-controlled trial.

    Science.gov (United States)

    Henderson, V W; Paganini-Hill, A; Miller, B L; Elble, R J; Reyes, P F; Shoupe, D; McCleary, C A; Klein, R A; Hake, A M; Farlow, M R

    2000-01-25

    AD, the most prevalent cause of dementia, affects twice as many women as men. Therapeutic options are limited, but results of prior studies support the hypothesis that estrogen treatment may improve symptoms of women with this disorder. Forty-two women with mild-to-moderate dementia due to AD were enrolled into a randomized, double-blind, placebo-controlled, parallel-group trial of unopposed conjugated equine estrogens (1.25 mg/day) for 16 weeks. Outcome data were available for 40 women at 4 weeks and 36 women at 16 weeks. At both 4 and 16 weeks, there were no significant differences or statistical trends between treatment groups on the primary outcome measure (the cognitive subscale of the Alzheimer's Disease Assessment Scale), clinician-rated global impression of change, or caregiver-rated functional status. Exploratory analyses of mood and specific aspects of cognitive performance also failed to demonstrate substantial group differences. Although conclusions are limited by small sample size and the possibility of a type II error, results suggest that short-term estrogen therapy does not improve symptoms of most women with AD. These findings do not address possible long-term effects of estrogen in AD, possible interactions between estrogen and other treatment modalities, or putative effects of estrogen in preventing or delaying onset of this disorder.

  17. Placebo-controlled study of fluvoxamine in the treatment of patients with compulsive buying.

    Science.gov (United States)

    Ninan, P T; McElroy, S L; Kane, C P; Knight, B T; Casuto, L S; Rose, S E; Marsteller, F A; Nemeroff, C B

    2000-06-01

    Compulsive buying is a syndrome characterized by the impulsive and/or compulsive buying of unneeded objects that results in personal distress, impairment in vocational or social functioning, and/or financial problems. Results from a two-site, double-blind, placebo-controlled 13-week trial of fluvoxamine are presented. Subjects had problematic buying behavior that they could not control for the previous 6 months or longer and met DSM-IV criteria for impulse control disorder-not otherwise specified (ICD-NOS) and the University of Cincinnati criteria for compulsive buying. Assessments included clinician-rated scales-the Yale-Brown Obsessive Compulsive Scale modified for compulsive buying, the Clinical Global Impression Scale, the Global Assessment of Functioning, and the Hamilton Rating Scale for Depression-and patient self-reports using daily diaries, which measured episodes of compulsive buying. Forty-two subjects gave informed consent, with 37 subjects providing evaluable information and 23 completing the study. Current or past psychiatric comorbidity was present in 74% of subjects. Intent-to-treat and completer analyses failed to show a significant difference between treatments on any measures of outcome. A high placebo-response rate, possibly from the behavioral benefits of maintaining a daily diary, prevents any definitive statement on the efficacy of fluvoxamine in treating compulsive buying.

  18. Recruitment and accrual of women in a placebo-controlled clinical pilot study on manual therapy.

    Science.gov (United States)

    Cambron, Jerrilyn A; Hawk, Cheryl; Evans, Roni; Long, Cynthia R

    2004-06-01

    To investigate the accrual rates and recruitment processes among 3 Midwestern sites during a pilot study on manual therapy for chronic pelvic pain. Multisite pilot study for a randomized, placebo-controlled clinical trial. Three chiropractic institutions in or near major metropolitan cities in the Midwestern United States. Thirty-nine women aged 18 to 45 with chronic pelvic pain of at least 6 months duration, diagnosed by a board certified gynecologist. The method of recruitment was collected for each individual who responded to an advertisement and completed an interviewer-administered telephone screen. Participants who were willing and eligible after 3 baseline visits were entered into a randomized clinical trial. The number of responses and accrual rates were determined for the overall study, each of the 3 treatment sites, and each of the 5 recruitment efforts. In this study, 355 women were screened over the telephone and 39 were randomized, making the rate of randomization approximately 10%. The most effective recruitment methods leading to randomization were direct mail (38%) and radio advertisements (34%). However, success of the recruitment process differed by site. Based on the accrual of this multisite pilot study, a full-scale trial would not be feasible using this study's parameters. However, useful information was gained on recruitment effectiveness, eligibility criteria, and screening protocols among the 3 metropolitan sites.

  19. Lycopene in the management of oral lichen planus: A placebo-controlled study

    Directory of Open Access Journals (Sweden)

    Nisheeth Saawarn

    2011-01-01

    Settings and Design: This prospective, randomized, double-blind, placebo-controlled study was done in the Oral Medicine Department of a postgraduate teaching dental hospital in India. Materials and Methods: Thirty symptomatic OLP patients, randomly divided into two groups of 15 each, were administered lycopene 8 mg/day and an identical placebo, respectively, for 8 consecutive weeks. Burning sensation using visual analogue scale and overall treatment response using Tel Aviv-San Francisco scale were recorded at every visit. The data obtained were analyzed statistically using Wilcoxon Rank test, Mann-Whitney and Fischer′s Exact test. Results: A higher (84% reduction in burning sensation was seen in lycopene than in the placebo group (67%. All 15 (100% patients in the lycopene group showed 50% or more benefit and 11 (73.3% patients showed 70-100% benefit, while this number was only 10 and 4 (26.7%, respectively, in the placebo group. Conclusion: Lycopene was very effective in the management of OLP, and oxidative stress may have a role in disease pathogenesis.

  20. A Randomized, Placebo-Controlled, Crossover Trial of Cannabis Cigarettes in Neuropathic Pain

    Science.gov (United States)

    Wilsey, Barth; Marcotte, Thomas; Tsodikov, Alexander; Millman, Jeanna; Bentley, Heather; Gouaux, Ben; Fishman, Scott

    2016-01-01

    The Food and Drug Administration (FDA), Substance Abuse and Mental Health Services Administration (SAMHSA), and the National Institute for Drug Abuse (NIDA) report that no sound scientific studies support the medicinal use of cannabis. Despite this lack of scientific validation, many patients routinely use “medical marijuana,” and in many cases this use is for pain related to nerve injury. We conducted a double-blinded, placebo-controlled, crossover study evaluating the analgesic efficacy of smoking cannabis for neuropathic pain. Thirty-eight patients with central and peripheral neuropathic pain underwent a standardized procedure for smoking either high-dose (7%), low-dose (3.5%), or placebo cannabis. In addition to the primary outcome of pain intensity, secondary outcome measures included evoked pain using heat-pain threshold, sensitivity to light touch, psychoactive side effects, and neuropsychological performance. A mixed linear model demonstrated an analgesic response to smoking cannabis. No effect on evoked pain was seen. Psychoactive effects were minimal and well-tolerated, with some acute cognitive effects, particularly with memory, at higher doses. PMID:18403272

  1. Randomised, Double Blind, Placebo-Controlled Trial of Echinacea Supplementation in Air Travellers

    Directory of Open Access Journals (Sweden)

    E. Tiralongo

    2012-01-01

    Full Text Available Objective. To identify whether a standardised Echinacea formulation is effective in the prevention of respiratory and other symptoms associated with long-haul flights. Methods. 175 adults participated in a randomised, double-blind placebo-controlled trial travelling back from Australia to America, Europe, or Africa for a period of 1–5 weeks on commercial flights via economy class. Participants took Echinacea (root extract, standardised to 4.4 mg alkylamides or placebo tablets. Participants were surveyed before, immediately after travel, and at 4 weeks after travel regarding upper respiratory symptoms and travel-related quality of life. Results. Respiratory symptoms for both groups increased significantly during travel (P<0.0005. However, the Echinacea group had borderline significantly lower respiratory symptom scores compared to placebo (P=0.05 during travel. Conclusions. Supplementation with standardised Echinacea tablets, if taken before and during travel, may have preventive effects against the development of respiratory symptoms during travel involving long-haul flights.

  2. Treatment for the premenstrual syndrome with agnus castus fruit extract: prospective, randomised, placebo controlled study.

    Science.gov (United States)

    Schellenberg, R

    2001-01-20

    To compare the efficacy and tolerability of agnus castus fruit (Vitex agnus castus L extract Ze 440) with placebo for women with the premenstrual syndrome. Randomised, double blind, placebo controlled, parallel group comparison over three menstrual cycles. General medicine community clinics. 178 women were screened and 170 were evaluated (active 86; placebo 84). Mean age was 36 years, mean cycle length was 28 days, mean duration of menses was 4.5 days. Agnus castus (dry extract tablets) one tablet daily or matching placebo, given for three consecutive cycles. Main efficacy variable: change from baseline to end point (end of third cycle) in women's self assessment of irritability, mood alteration, anger, headache, breast fullness, and other menstrual symptoms including bloating. Secondary efficacy variables: changes in clinical global impression (severity of condition, global improvement, and risk or benefit) and responder rate (50% reduction in symptoms). Improvement in the main variable was greater in the active group compared with placebo group (Pagnus castus fruit is an effective and well tolerated treatment for the relief of symptoms of the premenstrual syndrome.

  3. Tribulus terrestris for treatment of sexual dysfunction in women: randomized double-blind placebo - controlled study

    Science.gov (United States)

    2014-01-01

    Background Tribulus terrestris as a herbal remedy has shown beneficial aphrodisiac effects in a number of animal and human experiments. This study was designed as a randomized double-blind placebo-controlled trial to assess the safety and efficacy of Tribulus terrestris in women with hypoactive sexual desire disorder during their fertile years. Sixty seven women with hypoactive sexual desire disorder were randomly assigned to Tribulus terrestris extract (7.5 mg/day) or placebo for 4 weeks. Desire, arousal, lubrication, orgasm, satisfaction, and pain were measured at baseline and after 4 weeks after the end of the treatment by using the Female Sexual Function Index (FSFI). Two groups were compared by repeated measurement ANOVA test. Results Thirty women in placebo group and thirty women in drug group completed the study. At the end of the fourth week, patients in the Tribulus terrestris group had experienced significant improvement in their total FSFI (p Tribulus terrestris may safely and effectively improve desire in women with hypoactive sexual desire disorder. Further investigation of Tribulus terrestris in women is warranted. PMID:24773615

  4. Oxytocin Effect on Collective Decision Making: A Randomized Placebo Controlled Study.

    Directory of Open Access Journals (Sweden)

    Uri Hertz

    Full Text Available Collective decision making often benefits both the individuals and the group in a variety of contexts. However, for the group to be successful, individuals should be able to strike a balance between their level of competence and their influence on the collective decisions. The hormone oxytocin has been shown to promote trust, conformism and attention to social cues. We wondered if this hormone may increase participants' (unwarranted reliance on their partners' opinion, resulting in a reduction in collective benefit by disturbing the balance between influence and competence. To test this hypothesis we employed a randomized double-blind placebo-controlled design in which male dyads self-administered intranasal oxytocin or placebo and then performed a visual search task together. Compared to placebo, collective benefit did not decrease under oxytocin. Using an exploratory time dependent analysis, we observed increase in collective benefit over time under oxytocin. Moreover, trial-by-trial analysis showed that under oxytocin the more competent member of each dyad was less likely to change his mind during disagreements, while the less competent member showed a greater willingness to change his mind and conform to the opinion of his more reliable partner. This role-dependent effect may be mediated by enhanced monitoring of own and other's performance level under oxytocin. Such enhanced social learning could improve the balance between influence and competence and lead to efficient and beneficial collaboration.

  5. Oxytocin Effect on Collective Decision Making: A Randomized Placebo Controlled Study.

    Science.gov (United States)

    Hertz, Uri; Kelly, Maria; Rutledge, Robb B; Winston, Joel; Wright, Nicholas; Dolan, Raymond J; Bahrami, Bahador

    2016-01-01

    Collective decision making often benefits both the individuals and the group in a variety of contexts. However, for the group to be successful, individuals should be able to strike a balance between their level of competence and their influence on the collective decisions. The hormone oxytocin has been shown to promote trust, conformism and attention to social cues. We wondered if this hormone may increase participants' (unwarranted) reliance on their partners' opinion, resulting in a reduction in collective benefit by disturbing the balance between influence and competence. To test this hypothesis we employed a randomized double-blind placebo-controlled design in which male dyads self-administered intranasal oxytocin or placebo and then performed a visual search task together. Compared to placebo, collective benefit did not decrease under oxytocin. Using an exploratory time dependent analysis, we observed increase in collective benefit over time under oxytocin. Moreover, trial-by-trial analysis showed that under oxytocin the more competent member of each dyad was less likely to change his mind during disagreements, while the less competent member showed a greater willingness to change his mind and conform to the opinion of his more reliable partner. This role-dependent effect may be mediated by enhanced monitoring of own and other's performance level under oxytocin. Such enhanced social learning could improve the balance between influence and competence and lead to efficient and beneficial collaboration.

  6. Topical undecylenic acid for herpes simplex labialis: a multicenter, placebo-controlled trial.

    Science.gov (United States)

    Shafran, S D; Sacks, S L; Aoki, F Y; Tyrrell, D L; Schlech, W F; Mendelson, J; Rosenthal, D; Gill, M J; Bader, R L; Chang, I

    1997-07-01

    A multicenter, patient-initiated, double-blind, placebo-controlled trial of 15% undecylenic acid cream was conducted with 573 patients with recurrent herpes labialis. Treatment was applied 5 or 6 times daily until crusting and then thrice daily until healing. Patients were assessed daily until 48 h after crusting and then every other day until healing. Undecylenic acid significantly reduced the incidence and duration of viral shedding and the duration and severity of itching but did not increase abortive episodes or reduce times to healing, crusting, or progression of lesion size. When treatment was initiated during the prodrome, the time to crusting was reduced (P = .02) and the area under the symptom-time curve for pain and tenderness was reduced, approaching statistical significance (P = .06). Active treatment was well tolerated but caused dysgeusia and local irritation. Undecylenic acid 15% cream reduces viral shedding in recurrent herpes labialis, but clinical benefits are minimal and largely restricted to patients initiating therapy during the prodrome.

  7. Effect of aromatherapy massage on menopausal symptoms: a randomized placebo-controlled clinical trial.

    Science.gov (United States)

    Darsareh, Fatemeh; Taavoni, Simin; Joolaee, Soodabeh; Haghani, Hamid

    2012-09-01

    Menopause is a significant event in most women's lives because it marks the end of a woman's natural reproductive life. The purpose of this study was to determine the effect of aromatherapy massage on menopausal symptoms. A randomized placebo-controlled clinical trial was conducted at a menopausal clinic at a gynecology hospital in Tehran. The study population comprised 90 women who were assigned to an aromatherapy massage group, a placebo massage group, or a control group. Each participant in the aromatherapy massage group received 30-minute aromatherapy treatment sessions twice a week for 4 weeks with aroma oil, whereas participants in the placebo massage group received the same treatment with plain oil. No treatment was provided to participants in the control group. The outcome measures in this study were menopausal symptoms, as obtained through the Menopause Rating Scale. The mean baseline level of the menopausal score did not differ among all groups. However, after eight sessions of intervention, the Menopause Rating Scale score differed significantly among the three groups (P aromatherapy massage group and the placebo massage group had a lower menopausal score than the control group (P aromatherapy massage and the placebo massage groups were compared, the menopausal score for the aromatherapy massage group was found to be significantly lower (P aromatherapy massage were effective in reducing menopausal symptoms. However, aromatherapy massage was more effective than only massage.

  8. Triiodothyronine Administration in a Model of Septic Shock: A Randomized Blinded Placebo-Controlled Trial.

    Science.gov (United States)

    Maiden, Matthew J; Chapman, Marianne J; Torpy, David J; Kuchel, Timothy R; Clarke, Iain J; Nash, Coralie H; Fraser, Jonathan D; Ludbrook, Guy L

    2016-06-01

    Triiodothyronine concentration in plasma decreases during septic shock and may contribute to multiple organ dysfunction. We sought to determine the safety and efficacy of administering triiodothyronine, with and without hydrocortisone, in a model of septic shock. Randomized blinded placebo-controlled trial. Preclinical research laboratory. Thirty-two sheep rendered septic with IV Escherichia coli and receiving protocol-guided sedation, ventilation, IV fluids, and norepinephrine infusion. Two hours following induction of sepsis, 32 sheep received a 24-hour IV infusion of 1) placebo + placebo, 2) triiodothyronine + placebo, 3) hydrocortisone + placebo, or 4) triiodothyronine + hydrocortisone. Primary outcome was the total amount of norepinephrine required to maintain a target mean arterial pressure; secondary outcomes included hemodynamic and metabolic indices. Plasma triiodothyronine levels increased to supraphysiological concentrations with hormonal therapy. Following 24 hours of study drug infusion, the amount of norepinephrine required was no different between the study groups (mean ± SD μg/kg; placebo + placebo group 208 ± 392; triiodothyronine + placebo group 501 ± 370; hydrocortisone + placebo group 167 ± 286; triiodothyronine + hydrocortisone group 466 ± 495; p = 0.20). There was no significant treatment effect on any hemodynamic variable, metabolic parameter, or measure of organ function. A 24-hour infusion of triiodothyronine, with or without hydrocortisone, in an ovine model of septic shock did not markedly alter norepinephrine requirement or any other physiological parameter.

  9. Benfotiamine in diabetic polyneuropathy (BENDIP): results of a randomised, double blind, placebo-controlled clinical study.

    Science.gov (United States)

    Stracke, H; Gaus, W; Achenbach, U; Federlin, K; Bretzel, R G

    2008-11-01

    Efficacy and safety of benfotiamine in treatment of diabetic polyneuropathy. Double blind, placebo-controlled, phase-III-study. 181 patients were screened. 165 patients with symmetrical, distal diabetic polyneuropathy were randomised to one of three treatment groups entering the wash-out phase and 133/124 patients were analysed in the ITT/PP analysis: Benfotiamine 600 mg per day (n=47/43), benfotiamine 300 mg per day (n=45/42) or placebo (n=41/39). After 6 weeks of treatment, the primary outcome parameter NSS (Neuropathy Symptom Score) differed significantly between the treatment groups (p=0.033) in the PP (per protocol) population. In the ITT (intention to treat) population, the improvement of NSS was slightly above significance (p=0.055). The TSS (Total Symptom Score) showed no significant differences after 6 weeks of treatment. The improvement was more pronounced at the higher benfotiamine dose and increased with treatment duration. In the TSS, best results were obtained for the symptom "pain". Treatment was well tolerated in all groups. Benfotiamine may extend the treatment option for patients with diabetic polyneuropathy based on causal influence on impaired glucose metabolism. Further studies should confirm the positive experiences.

  10. Prophylaxis of irradiation-induced Diarrhea with smectite. Results of a placebo-controlled investigation

    International Nuclear Information System (INIS)

    Hombrink, J.; Froehlich, D.; Glatzel, M.; Krauss, A.; Thiel, H.J.; Meier, J.; Hamann, D.; Muecke, R.; Glaser, F.H.; Koest, S.

    2000-01-01

    Between April 1994 and May 1995, a total of 176 patients obtaining radiotherapy of the pelvis or the abdomen were evaluated in a double-blind, randomized placebo-controlled investigation regarding the prophylactic effect of smectite (=Colina trademark ) against radiotherapy-induced diarrhea. During the whole period of radiotherapy 85 patients obtained 2x6 g smectite daily and 91 patients received 2x6 g placebo. The primary end point of the analysis was the time to the first appearance of diarrhea (≥3 pappy stools). Results: All 176 patients were evaluated according to an intent-to-treat analysis. There was no significant difference between the prophylactic effects of smectite and placebo. For an explorative post-hoc analysis the total study group was split up into 2 subgroups, one with an irradiated small bowel volume ≤837.5 ml, the other with a small bowel volume >837.5 ml (median); the analysis indicated that the first subgroup showed a benefit for the smectite-treated patients in contrast to the placebo treatment (32 vs. 18 calendar days to the first appearance of diarrhea). This benefit was statistically not significant. Conclusion: Prophylactic application of smectite during irradiation of the pelvis and the abdomen can delay the development of radiotherapy-induced diarrhea, a statistical significance could not be verified neither in the total study group nor in the post-hoc subgroup analysis. (orig.) [de

  11. Phenobarbital for acute alcohol withdrawal: a prospective randomized double-blind placebo-controlled study.

    Science.gov (United States)

    Rosenson, Jonathan; Clements, Carter; Simon, Barry; Vieaux, Jules; Graffman, Sarah; Vahidnia, Farnaz; Cisse, Bitou; Lam, Joseph; Alter, Harrison

    2013-03-01

    Acute alcohol withdrawal syndrome (AAWS) is encountered in patients presenting acutely to the Emergency Department (ED) and often requires pharmacologic management. We investigated whether a single dose of intravenous (i.v.) phenobarbital combined with a standardized lorazepam-based alcohol withdrawal protocol decreases intensive care unit (ICU) admission in ED patients with acute alcohol withdrawal. This was a prospective, randomized, double-blind, placebo-controlled study. Patients were randomized to receive either a single dose of i.v. phenobarbital (10 mg/kg in 100 mL normal saline) or placebo (100 mL normal saline). All patients were placed on the institutional symptom-guided lorazepam-based alcohol withdrawal protocol. The primary outcome was initial level of hospital admission (ICU vs. telemetry vs. floor ward). There were 198 patients enrolled in the study, and 102 met inclusion criteria for analysis. Fifty-one patients received phenobarbital and 51 received placebo. Baseline characteristics and severity were similar in both groups. Patients that received phenobarbital had fewer ICU admissions (8% vs. 25%, 95% confidence interval 4-32). There were no differences in adverse events. A single dose of i.v. phenobarbital combined with a symptom-guided lorazepam-based alcohol withdrawal protocol resulted in decreased ICU admission and did not cause increased adverse outcomes. Copyright © 2013 Elsevier Inc. All rights reserved.

  12. The efficacy of azithromycin in pityriasis rosea: A randomized, double-blind, placebo-controlled trial

    Directory of Open Access Journals (Sweden)

    Deepika Pandhi

    2014-01-01

    Full Text Available Background: Macrolides are prescribed in the treatment of pityriasis rosea despite conflicting results of the limited number of studies evaluating their role in its treatment. Aim: A randomized double-blind placebo-controlled trial was conducted to evaluate the effect of azithromycin on the clinical course of pityriasis rosea. Methods: Seventy patients of pityriasis rosea were given either azithromycin (n = 35 or placebo (n = 35 and were followed-up at 2, 4 and 6 weeks. Pruritus was assessed in both groups using the visual analogue scale (VAS . Change in the pityriasis rosea severity score (PRSS and in the VAS were recorded as outcome measures and were compared statistically. Results: The decrease in PRSS from baseline through 2, 4 and 6 weeks within both treatment (P < 0.001 and placebo (P < 0.001 arms was found to be statistically significant; however, this change was not significantly different in the two groups (P = 0.179. Similarly, the decrease in VAS was found to be statistically significant within both groups (P < 0.001; however, the change was comparable between the two groups (P < 0.937. Analysis by Fisher′s exact test did not find a significant difference between the two groups for PRSS and VAS. Conclusion: Azithromycin is not effective in pityriasis rosea and the use of macrolides for this disease should not be encouraged in clinical practice.

  13. Effect of Saccharomyces boulardii in dog with chronic enteropathies: double-blinded, placebo-controlled study.

    Science.gov (United States)

    D'Angelo, Simona; Fracassi, Federico; Bresciani, Francesca; Galuppi, Roberta; Diana, Alessia; Linta, Nikolina; Bettini, Giuliano; Morini, Maria; Pietra, Marco

    2018-03-03

    Saccharomyces boulardii is used to treat acute and chronic enteropathies in humans, but to date, no studies have evaluated the use of this yeast in dogs. The current study, a prospective non-randomised, double-blinded, placebo-controlled study, evaluated the effects of S boulardii in healthy dogs and dogs with chronic enteropathies (CE). Four healthy dogs and 20 dogs with CE were included. In healthy dogs, S boulardii was administered for 10 days. Possible short-term adverse effects were recorded, and quantitative stool cultures for yeasts were performed. In dogs with CE, S boulardii or a placebo was administered in addition to standard treatment protocols. Canine Chronic Enteropathy Clinical Activity Index, abdominal ultrasonography, gastroenteroscopy and histology were performed at the time of diagnosis and after 60 days of treatment. In healthy dogs, S boulardii reached a steady state in five days and was completely eliminated on day 4 after administration. No short-term side effects were seen. Clinical activity index, stool frequency, stool consistency and body condition score improved significantly in dogs with CE receiving S boulardii versus the placebo. In conclusion, S boulardii can be safely used in dogs with CE and seems to achieve better control of clinical signs than standard therapy alone. © British Veterinary Association (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  14. A randomised placebo-controlled trial of early treatment of the patent ductus arteriosus.

    Science.gov (United States)

    Kluckow, Martin; Jeffery, Michele; Gill, Andy; Evans, Nick

    2014-03-01

    Failure of closure of the patent ductus arteriosus (PDA) may be associated with harm. Early cardiac ultrasound-targeted treatment of a large PDA may result in a reduction in adverse outcomes and need for later PDA closure with no increase in adverse effects. Multicentre, double-blind, placebo-controlled randomised trial. Three neonatal intensive care units in Australia. Eligible infants born <29 weeks were screened for a large PDA and received indomethacin or placebo before age 12 h. Death or abnormal cranial ultrasound. The trial ceased enrolment early due to lack of availability of indomethacin. 164 eligible infants were screened before 12 h; of the 92 infants with a large PDA, 44 were randomised to indomethacin and 48 to placebo. There was no difference in the main outcome between groups. Infants receiving early indomethacin had significantly less early pulmonary haemorrhage (PH) (2% vs 21%), a trend towards less periventricular/intraventricular haemorrhage (PIVH) (4.5% vs 12.5%) and were less likely to receive later open-label treatment for a PDA (20% vs 40%). The 72 non-randomised infants with a small PDA were at low risk of pulmonary haemorrhage and had an 80% spontaneous PDA closure rate. Early cardiac ultrasound-targeted treatment of a large PDA is feasible and safe, resulted in a reduction in early pulmonary haemorrhage and later medical treatment but had no effect on the primary outcome of death or abnormal cranial ultrasound. Australian New Zealand Clinical Trials Registry (ACTRN12608000295347).

  15. Memantine enhances the effect of olanzapine in patients with schizophrenia: A randomized, placebo-controlled study

    Directory of Open Access Journals (Sweden)

    Ahmad Fakhri

    2016-12-01

    Full Text Available Glutamate dysregulation may be involved in the neuropathology of schizophrenia. Memantine, a drug approved by the FDA for the treatment of moderate to severe Alzheimer's disease, acts as a partial uncompetitive NMDA receptor antagonist. The aim of this study was to examine the efficacy of memantine as an adjunctive treatment to olanzapine in patients with schizophrenia. In this double-blind, placebo-controlled studies, patients with schizophrenia according to DSM-IV clinical criteria were selected. Patients were randomly assigned to receive either memantine (week 1:10 mg/day; weeks 2-6:20 mg/day plus olanzapine (15-20 mg/day or olanzapine plus placebo. At baseline, no statistically significant difference regarding the mean total PANSS scores between treatment groups was found. Results showed that memantine significantly improved the positive and negative PANSS score in patients maintained on olanzapine after six weeks compared to olanzapine alone (P<0.001. Furthermore, female patients showed significantly better response than males, especially in positive PANSS score. No significant changes in extrapyramidal symptoms were observed.These findings indicate that olanzapine efficacy might be augmented with memantine. Furthermore, this effect is more remarkable in female patients with schizophrenia.

  16. Tribulus terrestris for treatment of sexual dysfunction in women: randomized double-blind placebo - controlled study.

    Science.gov (United States)

    Akhtari, Elham; Raisi, Firoozeh; Keshavarz, Mansoor; Hosseini, Hamed; Sohrabvand, Farnaz; Bioos, Soodabeh; Kamalinejad, Mohammad; Ghobadi, Ali

    2014-04-28

    Tribulus terrestris as a herbal remedy has shown beneficial aphrodisiac effects in a number of animal and human experiments. This study was designed as a randomized double-blind placebo-controlled trial to assess the safety and efficacy of Tribulus terrestris in women with hypoactive sexual desire disorder during their fertile years. Sixty seven women with hypoactive sexual desire disorder were randomly assigned to Tribulus terrestris extract (7.5 mg/day) or placebo for 4 weeks. Desire, arousal, lubrication, orgasm, satisfaction, and pain were measured at baseline and after 4 weeks after the end of the treatment by using the Female Sexual Function Index (FSFI). Two groups were compared by repeated measurement ANOVA test. Thirty women in placebo group and thirty women in drug group completed the study. At the end of the fourth week, patients in the Tribulus terrestris group had experienced significant improvement in their total FSFI (p Tribulus terrestris may safely and effectively improve desire in women with hypoactive sexual desire disorder. Further investigation of Tribulus terrestris in women is warranted.

  17. Electric field-navigated transcranial magnetic stimulation for chronic tinnitus: a randomized, placebo-controlled study.

    Science.gov (United States)

    Sahlsten, Hanna; Virtanen, Juuso; Joutsa, Juho; Niinivirta-Joutsa, Katri; Löyttyniemi, Eliisa; Johansson, Reijo; Paavola, Janika; Taiminen, Tero; Sjösten, Noora; Salonen, Jaakko; Holm, Anu; Rauhala, Esa; Jääskeläinen, Satu K

    2017-09-01

    Repetitive transcranial magnetic stimulation (rTMS) may alleviate tinnitus. We evaluated effects of electric field (E-field) navigated rTMS targeted according to tinnitus pitch. No controlled studies have investigated anatomically accurate E-field-rTMS for tinnitus. Effects of E-field-rTMS were evaluated in a prospective randomised placebo-controlled 6-month follow-up study on parallel groups. Patients received 10 sessions of 1 Hz rTMS or placebo targeted to the left auditory cortex corresponding to tonotopic representation of tinnitus pitch. Effects were evaluated immediately after treatment and at 1, 3 and 6 months. Primary outcome measures were visual analogue scores (VAS 0-100) for tinnitus intensity, annoyance and distress, and the Tinnitus Handicap Inventory (THI). Thirty-nine patients (mean age 50.3 years). The mean tinnitus intensity (F 3  = 15.7, p tinnitus, differences between active and placebo groups remained non-significant, due to large placebo-effect and wide inter-individual variation.

  18. Comparison of Levetiracetam and sodium Valproate in migraine prophylaxis: A randomized placebo-controlled study

    Directory of Open Access Journals (Sweden)

    Homa Sadeghian

    2015-01-01

    Full Text Available Background: Migraine is a chronic and disabling disorder. Treatment of migraine often comprises of symptomatic (abortive and preventive (prophylactic treatment. The current drugs used in migraine prophylaxis include antidepressant drugs (Serotonin Reuptake Inhibitors, Tricyclic antidepressants, and anti-epileptic drugs (valproate, gabapentin, etc. Objective: The objective of our study was to assess the efficacy and tolerability of levetiracetam in adult migraine prophylaxis, compared to valproate and placebo. Materials and Methods: We conducted a prospective, randomized, placebo-controlled study. A total of 85 patients were randomized to receive levetiracetam 500 mg/d (n = 27, valproate 500 mg/d (n = 32 or placebo (n = 26. The patients were evaluated for treatment efficacy after 6 months. Efficacy was assessed as a more than 50% decrease in headache frequency. Results: In levetiracetam group, 17 (63.0% patients experienced a more than 50% decrease in headache frequency, while this efficacy number was 21 (65.6% for valproate group and 4 (15.4% for placebo group. The difference was not statistically significant between levetiracetam and valproate, while it was significant when comparing either levetiracetam or valproate to placebo. Conclusion: Compared to placebo, levetiracetam offers improvement in headache frequency in patients with migraine. The efficacy of levetiracetam in migraine prophylaxis is comparable to currently used drugs such as valproate.

  19. Pentoxifylline, inflammation, and endothelial function in HIV-infected persons: a randomized, placebo-controlled trial.

    Directory of Open Access Journals (Sweden)

    Samir K Gupta

    Full Text Available Untreated HIV may increase the risk of cardiovascular events. Our preliminary in vitro and in vivo research suggests that pentoxifylline (PTX reduces vascular inflammation and improves endothelial function in HIV-infected persons not requiring antiretroviral therapy.We performed a randomized, placebo-controlled trial of PTX 400 mg orally thrice daily for 8 weeks in 26 participants. The primary endpoint was change in flow-mediated dilation (FMD of the brachial artery after 8 weeks. Nitroglycerin-mediated dilation (NTGMD and circulating markers of inflammation, cellular immune activation, coagulation, and metabolism were also assessed.The difference in mean absolute change (SD in FMD after 8 weeks between the placebo [-1.06 (1.45%] and PTX [-1.93 (3.03%] groups was not significant (P = 0.44. No differences in NTGMD were observed. The only significant between-group difference in the changes in biomarkers from baseline to week 8 was in soluble tumor necrosis factor receptor-1 (sTNFRI [-83.2 pg/mL in the placebo group vs. +65.9 pg/mL in the PTX group; P = 0.03]. PTX was generally well-tolerated.PTX did not improve endothelial function and unexpectedly increased the inflammatory biomarker sTNFRI in HIV-infected participants not requiring antiretroviral therapy. Additional interventional research is needed to reduce inflammation and cardiovascular risk in this population.ClinicalTrials.gov NCT00796822.

  20. Effect of Low Concentrations of Apomorphine on Parkinsonism in a Randomized, Placebo-Controlled, Crossover Study

    Science.gov (United States)

    Gunzler, Steven A.; Koudelka, Caroline; Carlson, Nichole E.; Pavel, Misha; Nutt, John G.

    2011-01-01

    Objective To determine whether low concentrations of a dopamine agonist worsen parkinsonism, which would suggest that activation of presynaptic dopamine autoreceptors causes a super-off state. Design Randomized, double-blind, placebo-controlled, crossover clinical trial. Setting Academic movement disorders center. Patients Patients with Parkinson disease and motor fluctuations. Intervention Fourteen patients with Parkinson disease and motor fluctuations were randomized to receive 1 of 6 possible sequences of placebo, low-dose (sub-threshold) apomorphine hydrochloride, and high-dose (threshold to suprathreshold) apomorphine hydrochloride infusions. Subthreshold doses of apomorphine hydrochloride (12.5 μg/kg/h every 2 hours and 25 μg/kg/h every 2 hours), threshold to suprathreshold doses of apomorphine hydrochloride (50 μg/kg/h every 2 hours and 100 μg/kg/h every 2 hours), and placebo were infused for 4 hours daily for 3 consecutive days. Main Outcome Measures Finger and foot tapping rates. Results There was no decline in finger or foot tapping rates during the low-dose apomorphine hydrochloride infusions relative to placebo. The high-dose infusions increased foot tapping (P<.001) and trended toward increasing finger tapping compared with placebo infusions. Conclusions Subthreshold concentrations of apomorphine did not worsen parkinsonism, suggesting that pre-synaptic dopamine autoreceptors are not important to the motor response in moderate to advanced Parkinson disease. PMID:18268187

  1. Does EEG-Neurofeedback Improve Neurocognitive Functioning in Children with Attention-Deficit/Hyperactivity Disorder? A Systematic Review and a Double-Blind Placebo-Controlled Study

    Science.gov (United States)

    Vollebregt, Madelon A.; van Dongen-Boomsma, Martine; Buitelaar, Jan K.; Slaats-Willemse, Dorine

    2014-01-01

    Background: The number of placebo-controlled randomized studies relating to EEG-neurofeedback and its effect on neurocognition in attention-deficient/hyperactivity disorder (ADHD) is limited. For this reason, a double blind, randomized, placebo-controlled study was designed to assess the effects of EEG-neurofeedback on neurocognitive functioning…

  2. Interest of positron emission tomography with [{sup 18}F]-fluoro-misonidazole within the frame of a dose escalation for glioblastomas; Interet de la tomographie par emission de positrons au [{sup 18}F]-fluoromisonidazole dans le cadre d'une escalade de dose pour les glioblastomes

    Energy Technology Data Exchange (ETDEWEB)

    Huchet, A.; Benech, J.; Maire, J.P.; Trouette, R.; Galland-Girodet, S. [Service de radiotherapie, CHU de Bordeaux, Bordeaux (France); Lamare, F.; Mella, C.; Clermont, H. de; Fernandez, P. [Service de medecine nucleaire, CHU de Bordeaux, Bordeaux (France); Loiseau, H. [Service de neurochirurgie, CHU de Bordeaux, Bordeaux (France)

    2011-10-15

    Eleven patients suffering from an unresectable glioblastoma have been treated by positron emission tomography (PET) with [{sup 18}F]-FMiso and submitted to a MRI before treatment. Gross target volumes (GTV) have been determined, as well as hypoxic fraction within the tumours. A complication probability calculation has been performed. It appears that the PET-[{sup 18}F]-FMiso allows a smaller volume than MRI to be defined. A Normal Tissue Complication Probability (NTCP) modelling shows that this volume limits the complication risk increase due to dose escalation. Intensity modulation allows a better taking into account of these potential benefits of this biological target volume definition. Short communication

  3. Safety of a New Compact Male Intermittent Catheter: Randomized, Cross-Over, Single-Blind Study in Healthy Male Volunteers

    DEFF Research Database (Denmark)

    Bagi, Per; Hannibalsen, Jane; Permild, Rikke

    2011-01-01

    in hematuria (p = 0.54) or discomfort/stinging/pain at first micturition (p = 0.56). During insertion, handling was easier (p = 0.0001) and touching the coating was necessary less often (2.2 vs. 81.3% of catheterizations; p catheter; it was preferred by nurses for 20 of 23......Introduction: A new compact male intermittent catheter was compared with a regular intermittent male catheter in terms of safety and acceptability. Methods: In this randomized, single-blind, cross-over study, healthy male volunteers were catheterized twice with a compact catheter and twice...... with a regular catheter. Results: 28 participants were enrolled. Mean ± SD discomfort (visual analogue scale; primary objective) was 2.25 ± 1.5 and 2.52 ± 1.8 for the compact and regular catheters, respectively (difference -0.27; 95% confidence interval -0.73 to 0.19); there was no significant difference...

  4. Gait analysis following treadmill training with body weight support versus conventional physical therapy: a prospective randomized controlled single blind study.

    Science.gov (United States)

    Lucareli, P R; Lima, M O; Lima, F P S; de Almeida, J G; Brech, G C; D'Andréa Greve, J M

    2011-09-01

    Single-blind randomized, controlled clinical study. To evaluate, using kinematic gait analysis, the results obtained from gait training on a treadmill with body weight support versus those obtained with conventional gait training and physiotherapy. Thirty patients with sequelae from traumatic incomplete spinal cord injuries at least 12 months earlier; patients were able to walk and were classified according to motor function as ASIA (American Spinal Injury Association) impairment scale C or D. Patients were divided randomly into two groups of 15 patients by the drawing of opaque envelopes: group A (weight support) and group B (conventional). After an initial assessment, both groups underwent 30 sessions of gait training. Sessions occurred twice a week, lasted for 30 min each and continued for four months. All of the patients were evaluated by a single blinded examiner using movement analysis to measure angular and linear kinematic gait parameters. Six patients (three from group A and three from group B) were excluded because they attended fewer than 85% of the training sessions. There were no statistically significant differences in intra-group comparisons among the spatial-temporal variables in group B. In group A, the following significant differences in the studied spatial-temporal variables were observed: increases in velocity, distance, cadence, step length, swing phase and gait cycle duration, in addition to a reduction in stance phase. There were also no significant differences in intra-group comparisons among the angular variables in group B. However, group A achieved significant improvements in maximum hip extension and plantar flexion during stance. Gait training with body weight support was more effective than conventional physiotherapy for improving the spatial-temporal and kinematic gait parameters among patients with incomplete spinal cord injuries.

  5. Cyproheptadine in the treatment of autistic disorder: a double-blind placebo-controlled trial.

    Science.gov (United States)

    Akhondzadeh, S; Erfani, S; Mohammadi, M R; Tehrani-Doost, M; Amini, H; Gudarzi, S S; Yasamy, M T

    2004-04-01

    Autism is a childhood-onset disorder of unknown, possibly of multiple aetiologies. The core symptoms of autism are abnormalities in social interaction, communication and behaviour. The involvement of neurotransmitters such as 5-HT has been suggested in neuropsychiatric disorders and particularly in autistic disorder. Increased platelet 5-HT levels were found in 40% of the autistic population, suggesting that hyperserotonaemia may be a pathologic factor in infantile autism. Therefore, it is of interest to assess the efficacy of cyproheptadine, a 5-HT2 antagonist in the treatment of autistic disorder. In this 8-week double-blind, placebo-controlled trial, we assessed the effects of cyproheptadine plus haloperidol in the treatment of autistic disorder. Children between the ages 3 and 11 years (inclusive) with a DSM IV clinical diagnosis of autism and who were outpatients from a specialty clinic for children at Roozbeh Psychiatric Teaching Hospital were recruited. The children presented with a chief complaint of severely disruptive symptoms related to autistic disorder. Patients were randomly allocated to cyproheptadine + haloperidol (Group A) or haloperidol + placebo (Group B) for an 8-week, double-blind, placebo-controlled study. The dose of haloperidol and cyproheptadine was titrated up to 0.05 and 0.2 mg/kg/day respectively. Patients were assessed by a third-year resident of psychiatry at baseline and after 2, 4, 6 and 8 weeks of starting medication. The primary measure of the outcome was the Aberrant Behaviour Checklist-Community (ABC-C) and the secondary measure of the outcome was the Childhood Autism Rating Scale (relating to people and verbal communication). Side effects and extrapyramidal symptoms were systematically recorded throughout the study and were assessed using a checklist and the Extrapyramidal Symptoms Rating Scale, administered by a resident of psychiatry during weeks 1, 2, 4, 6 and 8. The ABC-C and the Childhood Autism Rating Scale scores improved

  6. A dietary supplement to improve the quality of sleep: a randomized placebo controlled trial.

    Science.gov (United States)

    Cornu, Catherine; Remontet, Laurent; Noel-Baron, Florence; Nicolas, Alai