Octogenarians with early stage NSCLC undergoing SBRT-same outcomes as younger patients?

DEFF Research Database (Denmark)

Jeppesen, Stefan Starup; Schytte, T.; Brink, C.

2015-01-01

Purpose/Objective: The increase in life expectancy leads to an increased number of elderly patients (pts) diagnosed with NSCLC. Octogenarians can be a treatment challenge due to frailty and comorbidity. Stereotactic Body Radiotherapy (SBRT) has become the standard treatment for medical inoperable...... pts with early stage NSCLC. However, it is unknown if all pts have same benefit of SBRT due to lack of randomized studies. This retrospective single-institution study reports survival and control rates for medical inoperable octogenarians vs. pts 80 and 80 and 137 were 80 and 0.05). No difference...... in comorbidity measured by Charlson Score Index was observed. SBRT was generally well tolerated. A log rank test showed a significant difference of OS between patients >80 and 80 and 80 and...

Association between BIM deletion polymorphism and clinical outcome of EGFR-mutated NSCLC patient with EGFR-TKI therapy: A meta-analysis.

Science.gov (United States)

Ma, Ji-Yong; Yan, Hai-Jun; Gu, Wei

2015-01-01

BIM deletion polymorphism was deemed to be associated with downregulation of BIM, resulting in a decreased apoptosis induced by epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in EGFR mutation-positive non-small cell lung cancer (NSCLC). However, accumulating evidences concerning the association between BIM deletion polymorphism and efficacy of EGFR-TKI and survival in EGFR-mutation-driven NSCLC patient reported contradictory results. A meta-analysis was conducted by combing six original eligible studies including 871 NSCLC patients. Our study showed that BIM deletion polymorphism was significantly associated with poor response to EGFR-TKI therapy in mutant EGFRNSCLC patients (P(h) = 0.309, P(z) = 0.001, OR = 0.39, 95% confidence interval (CI) = 0.23-0.67). Disease control rate (DCR) in mutant EGFRNSCLC patient with treatment of EGFR-TKI was significantly decreased in patients with BIM deletion polymorphism comparing to patients harbored BIM wild variant (P(h) = 0.583, P(Z) = 0.007, OR = 0.46, 95%CI = 0.25-0.85). EGFR mutation-derived NSCLC patient carrying BIM deletion polymorphism had a shorter progression-free survival (PFS; P(h) deletion polymorphism might be a cause that contributes to primary EGFR-TKI resistance, and it could be used as a genetic predictor for EGFR-TKI outcome and an independent prognostic factor of EGFR mutation-driven NSCLC patient.

Fluorine F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) for restaging of non small cell lung cancer (NSCLC): analysis of management change and survival in 63 consecutive patients

International Nuclear Information System (INIS)

Hicks, R.J.; Binns, D.J.; Kalff, V.; Ware, R.E.; Hogg, A.; MacManus, M.P.; Ball, D.L.; Suter, M.E.; Matthews, J.

2000-01-01

Full text: Following treatment with curative intent for non small cell lung cancer (NSCLC), assessment of disease status using conventional techniques is often difficult. We evaluated management impact and prognostic value of FDG PET in 63 consecutive patients undergoing restaging of NSCLC between 11/96 and 12/98. All patients were >6 months from primary treatment with curative intent. Salvage therapy with curative intent was being contemplated in 18 patients. Conventional imaging was abnormal 61/63 patients, two others had recurrent symptoms only. Compared to conventional restaging, 33% of patients were down-staged, and 35% were upstaged by PET. PET led to more aggressive treatment than planned in 7 patients (11%), a change from planned curative to palliative treatment in 8 patients (13%) and 17 patients (27%) thought to have recurrent disease had no further investigation or treatment after negative PET studies. Cox proportional hazards analysis indicated that a positive PET scan had a hazard ratio of 2.95 (95% CI 1.038.50, p = 0.012) compared to negative PET. Extent of active disease on PET was also prognostically significant with each incremental extent category (no disease, local recurrence, limited locoregional, extensive locoregional and systemic) having an estimated 60% increase in the rate of death (95% Cl 24% to 107%, p<0.0001). Stage of disease at initial diagnosis, primary treatment used and disease extent on conventional restaging were not predictive of survival. Thus, PET provided a high impact on management for NSCLC patients with suspected recurrence and more accurate prognostic stratification than conventional staging. Copyright (2000) The Australian and New Zealand Society of Nuclear Medicine Inc

Efficacy and adverse effects of icotinib in treatment of 30 NSCLC patients with brain metastases

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Yu-hong DAI

2016-06-01

Full Text Available Objective 　To evaluate the efficacy and adverse effects of icotinib in the treatment for non-small cell lung cancer (NSCLC patients with brain metastases. Methods 　This study was performed at Tongji Hospital Cancer Center over the period between September 2011 and November 2015. Thirty cases of advanced NSCLC patients with icotinib monotherapy were enrolled, all with brain metastases, the median follow-up time being 24 months (5.5-49.0 months, with no case censored. The follow-up rate was 100%, and the data of efficacy and adverse effects were collected. Results 　The intracranial progression-free survival (iPFS was 9.6 months, while no patient exhibited complete remission (CR, 8 patients showed partial remission (PR and 14 showed stable disease (SD in the intracranial foci. The intracranial disease control rate (DCR was 73.3%, and the objective remission rate (ORR was 26.7%. The extracranial progression-free survival (ePFS was 10.1 months, while no patient exhibited CR, 11 patients showed PR and 11 patients showed SD in the extracranial foci. The extracranial DCR was 73.3%, and the ORR was 36.7%. The one-year survival rate was 63.8% in all the 30 patients. Twelve (40.0% of the total 30 patients developed rash, five (16.7% developed grade 1 diarrhea, one (3.3% developed grade 2 transaminase elevation. None of the patients experienced headache, nausea, vomiting, fatigue, etc. Conclusion 　Icotinib hydrochloride is effective and safe for NSCLC patients with brain metastasis. DOI: 10.11855/j.issn.0577-7402.2016.06.11

Meta-Analysis on Pharmacogenetics of Platinum-Based Chemotherapy in Non Small Cell Lung Cancer (NSCLC) Patients

Science.gov (United States)

Yin, Ji-Ye; Huang, Qiong; Zhao, Ying-Chun; Zhou, Hong-Hao; Liu, Zhao-Qian

2012-01-01

Aim To determine the pharmacogenetics of platinum-based chemotherapy in Non Small Cell Lung Cancer (NSCLC) patients. Methods Publications were selected from PubMed, Cochrane Library and ISI Web of Knowledge. A meta-analysis was conducted to determine the association between genetic polymorphisms and platinum-based chemotherapy by checking odds ratio (OR) and 95% confidence interval (CI). Results Data were extracted from 24 publications, which included 11 polymorphisms in 8 genes for meta-analysis. MDR1 C3435T (OR = 1.97, 95% CI: 1.11–3.50, P = 0.02), G2677A/T (OR = 2.61, 95% CI: 1.44–4.74, P = 0.002) and GSTP1 A313G (OR = 0.32, 95% CI: 0.17–0.58, P = 0.0002) were significantly correlated with platinum-based chemotherapy in Asian NSCLC patients. Conclusion Attention should be paid to MDR1 C3435T, G2677A/T and GSTP1 A313G for personalized chemotherapy treatment for NSCLC patients in Asian population in the future. PMID:22761669

Cardiac Toxicity after definitive Radiotherapy of locally advanced NSCLC

DEFF Research Database (Denmark)

Schytte, Tine; Hansen, Olfred; Stohlberg-Rohr, Thomine

2010-01-01

    Cardiac Toxicity after definitive Radiotherapy of locally advanced NSCLC Tine Schytte, Olfred Hansen, Thomine Stolberg-Rohr* and Carsten Brink*. Dept. Oncology and Radiophysic Lab.* Odense University Hospital, Denmark   Keyword: Radiotherapy, Locally advanced NSCLC, Cardiac toxicity   Backgro......    Cardiac Toxicity after definitive Radiotherapy of locally advanced NSCLC Tine Schytte, Olfred Hansen, Thomine Stolberg-Rohr* and Carsten Brink*. Dept. Oncology and Radiophysic Lab.* Odense University Hospital, Denmark   Keyword: Radiotherapy, Locally advanced NSCLC, Cardiac toxicity......   Background: Lung and oesophageal toxicity have been regarded as main toxicity in definitive radiotherapy (RT) of non-small cell lung cancer (NSCLC), whereas cardiac toxicity has not been offered much concern. This is probably due to the poor prognosis for patients with unresectable NSCLC. In this study we...

IMRT and 3D conformal radiotherapy with or without elective nodal irradiation in locally advanced NSCLC: A direct comparison of PET-based treatment planning.

Science.gov (United States)

Fleckenstein, Jochen; Kremp, Katharina; Kremp, Stephanie; Palm, Jan; Rübe, Christian

2016-02-01

The potential of intensity-modulated radiation therapy (IMRT) as opposed to three-dimensional conformal radiotherapy (3D-CRT) is analyzed for two different concepts of fluorodeoxyglucose positron emission tomography (FDG PET)-based target volume delineation in locally advanced non-small cell lung cancer (LA-NSCLC): involved-field radiotherapy (IF-RT) vs. elective nodal irradiation (ENI). Treatment planning was performed for 41 patients with LA-NSCLC, using four different planning approaches (3D-CRT-IF, 3D-CRT-ENI, IMRT-IF, IMRT-ENI). ENI included a boost irradiation after 50 Gy. For each plan, maximum dose escalation was calculated based on prespecified normal tissue constraints. The maximum prescription dose (PD), tumor control probability (TCP), conformal indices (CI), and normal tissue complication probabilities (NTCP) were analyzed. IMRT resulted in statistically significant higher prescription doses for both target volume concepts as compared with 3D-CRT (ENI: 68.4 vs. 60.9 Gy, p ENI, there was a considerable theoretical increase in TCP (IMRT: 27.3 vs. 17.7 %, p ENI: 12.3 vs. 30.9 % p < 0.0001; IF: 15.9 vs. 24.1 %; p < 0.001). The IMRT technique and IF target volume delineation allow a significant dose escalation and an increase in TCP. IMRT results in an improved sparing of OARs as compared with 3D-CRT at equivalent dose levels.

GrB TWEAK: A Potential Novel Biologic for NSCLC Therapy

Science.gov (United States)

2017-07-01

granzyme B, lung cancer 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 19a. NAME OF RESPONSIBLE PERSON USAMRMC a. REPORT...cost extension period we were able to test whether our therapeutic construct GrB-Fc-IT4 could inhibit NSCLC tumor growth in vivo using the NSCLC patient ...derived Fn14-positive cell line M2010-1005. The M2010-1005 line was established from a NSCLC patient with a tumor harboring the EGFRdel747-752

Dosimetric comparison of peripheral NSCLC SBRT using Acuros XB and AAA calculation algorithms.

Science.gov (United States)

Ong, Chloe C H; Ang, Khong Wei; Soh, Roger C X; Tin, Kah Ming; Yap, Jerome H H; Lee, James C L; Bragg, Christopher M

2017-01-01

There is a concern for dose calculation in highly heterogenous environments such as the thorax region. This study compares the quality of treatment plans of peripheral non-small cell lung cancer (NSCLC) stereotactic body radiation therapy (SBRT) using 2 calculation algorithms, namely, Eclipse Anisotropic Analytical Algorithm (AAA) and Acuros External Beam (AXB), for 3-dimensional conformal radiation therapy (3DCRT) and volumetric-modulated arc therapy (VMAT). Four-dimensional computed tomography (4DCT) data from 20 anonymized patients were studied using Varian Eclipse planning system, AXB, and AAA version 10.0.28. A 3DCRT plan and a VMAT plan were generated using AAA and AXB with constant plan parameters for each patient. The prescription and dose constraints were benchmarked against Radiation Therapy Oncology Group (RTOG) 0915 protocol. Planning parameters of the plan were compared statistically using Mann-Whitney U tests. Results showed that 3DCRT and VMAT plans have a lower target coverage up to 8% when calculated using AXB as compared with AAA. The conformity index (CI) for AXB plans was 4.7% lower than AAA plans, but was closer to unity, which indicated better target conformity. AXB produced plans with global maximum doses which were, on average, 2% hotter than AAA plans. Both 3DCRT and VMAT plans were able to achieve D95%. VMAT plans were shown to be more conformal (CI = 1.01) and were at least 3.2% and 1.5% lower in terms of PTV maximum and mean dose, respectively. There was no statistically significant difference for doses received by organs at risk (OARs) regardless of calculation algorithms and treatment techniques. In general, the difference in tissue modeling for AXB and AAA algorithm is responsible for the dose distribution between the AXB and the AAA algorithms. The AXB VMAT plans could be used to benefit patients receiving peripheral NSCLC SBRT. Copyright © 2017 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights

FOCUS ON NIVOLUMAB IN NSCLC

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Diego Luigi Cortinovis

2016-12-01

Full Text Available Immunotherapy is changing the treatment of non-small cell lung cancer (NSCLC. The PD-1 inhibitor nivolumab has demonstrated meaningful results in terms of efficacy with a good safety profile. The novel approach of treating NSCLC using immunotherapy has still unsolved questions and challenging issues in regard to the optimal selection of the patient, its role in first line of treatment, the individualization of the correct methodology of radiologic assessment and efficacy analysis, the best management of immunomediated adverse events, and how to overcome the immunoresistance.

Prognostic significance of CDH13 hypermethylation and mRNA in NSCLC

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Xue R

2014-10-01

Full Text Available Ruilin Xue,1 Cuili Yang,1 Fang Zhao,2 Dejia Li1 1Global Health Institute, School of Public Health, 2Zhongnan Hospital, Wuhan University, Wuhan, People's Republic of ChinaAbstract: Aberrant methylation of CpG dinucleotides is a commonly observed epigenetic modification in human cancer. Thus, detection of aberrant gene promoter methylation as a tool for diagnosis of tumors or as a prognostic marker has been widely described for many types of cancers, including nonsmall cell lung cancer (NSCLC. Emerging evidence indicates that CDH13 is a candidate tumor suppressor in several types of human tumors, including NSCLC. However, the correlation between CDH13 hypermethylation and clinicopathological characteristics of NSCLC remains unclear. In the current study, we conducted a systematic review and meta-analysis to quantitatively evaluate the effects of CDH13 hypermethylation on the incidence of NSCLC and clinicopathological characteristics. Final analysis of 803 NSCLC patients from eleven eligible studies was performed. CDH13 hypermethylation was observed to be significantly higher in NSCLC than in normal lung tissue, with the pooled odds ratio (OR from seven studies including 448 NSCLC and 345 normal lung tissue (OR, 7.85; 95% confidence interval, 5.12–12.03; P<0.00001. CDH13 hypermethylation was also associated with pathological types. The pooled OR was obtained from four studies, including 111 squamous cell carcinoma and 106 adenocarcinoma (OR, 0.35; 95% confidence interval, 0.19–0.66; P=0.001, which indicated that CDH13 hypermethylation plays a more important role in the pathogenesis of adenocarcinoma. NSCLC with CDH13 hypermethylation was found more frequently in poorly differentiated NSCLC patients. NSCLC patients with CDH13 hypermethylation had a lower survival rate than those without CDH13 hypermethylation. In addition, CDH13 mRNA high expression was found to correlate with better overall survival for all NSCLC patients followed for 20 years

WE-FG-206-08: Pulmonary Functional Imaging Biomarkers of NSCLC to Guide and Optimize Functional Lung Avoidance Radiotherapy

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Sheikh, Khadija; Capaldi, Dante PI; Parraga, Grace [Robarts Research Institute (Canada); Hoover, Douglas A; Palma, David A [Department of Medical Biophysics, Department of Oncology, The University of Western Ontario, London (Canada); Yaremko, Brian P [Department of Oncology, The University of Western Ontario, London (Canada)

2016-06-15

Purpose: Functional lung avoidance radiotherapy promises optimized therapy planning by minimizing dose to well-functioning lung and maximizing dose to the rest of the lung. Patients with NSCLC commonly present with co-morbid COPD and heterogeneously distributed ventilation abnormalities stemming from emphysema, airways disease, and tumour burden. We hypothesized that pulmonary functional imaging methods may be used to optimize radiotherapy plans to avoid regions of well-functioning lung and significantly improve outcomes like quality-of-life and survival. To ascertain the utility of functional lung avoidance therapy in clinical practice, we measured COPD phenotypes in NSCLC patients enrolled in a randomized-controlled-clinical-trial prior to curative intent therapy. Methods: Thirty stage IIIA/IIIB NSCLC patients provided written informed consent to a randomized-controlled-clinical-trial ( http://clinicaltrials.gov/ct2/show/NCT02002052 ) comparing outcomes in patients randomized to standard or image-guided radiotherapy. Hyperpolarized noble gas MRI ventilation-defect-percent (VDP) (Kirby et al, Acad Radiol, 2012) as well as CT-emphysema measurements were determined. Patients were stratified based on quantitative imaging evidence of ventilation-defects and emphysema into two subgroups: 1) tumour-specific ventilation defects only (TSD), and, 2) tumour-specific and other ventilation defects with and without emphysema (TSD{sub VE}). Receiver-operating-characteristic (ROC) curves were used to characterize the performance of clinical measures as predictors of the presence of non-tumour specific ventilation defects. Results: Twenty-one out of thirty subjects (70%) had non-tumour specific ventilation defects (TSD{sub VE}) and nine subjects had ONLY tumour-specific defects (TSD). Subjects in the TSD{sub VE} group had significantly greater smoking-history (p=.006) and airflow obstruction (FEV{sub 1}/FVC) (p=.001). ROC analysis demonstrated an 87% classification rate for

SU-E-T-220: A Web-Based Research System for Outcome Analysis of NSCLC Treated with SABR.

Science.gov (United States)

Le, A; Yang, Y; Michalski, D; Heron, D; Huq, M

2012-06-01

To establish a web-based software system, an electronic patient record (ePR), to consolidate and evaluate clinical data, dose delivery and treatment outcomes for non small cell lung cancer (NSCLC) patients treated with hypofractionated stereotactic ablative radiation therapy (SABR) across institutions. The new trend of information technology in medical imaging and informatics is towards the development of an electronic patient record (ePR), in which all health and medical information of each patient are organized under the patient's name and identification number. The system has been developed using the Wamp Server, a package of Apache web server, PHP and MySQL database to facilitate patient data input and management, and evaluation of patient clinical data and dose delivery across institution using web technology. The data of each patient to be recorded in the database include pre-treatment clinical data, treatment plan in DICOM-RT format and follow-up data. The pre-treatment data include demographics data, pathology condition, cancer staging. The follow-up data include the survival status, local tumor control condition and toxicity. The clinical data are entered to the system through the web page while the treatment plan data will be imported from the treatment planning system (TPS) using DICOM communication. The collection of data of NSCLC patients treated with SABR stored in the ePR is always accessible and can be retrieved and processed in the future. The core of the ePR is the database which integrates all patient data in one location. The web-based DICOM RT ePR system utilizes the current state-of-the-art medical informatics approach to investigate the combination and consolidation of patient data and outcome results. This will allow clinically-driven data mining for dose distributions and resulting treatment outcome in connection with biological modeling of the treatment parameters to quantify the efficacy of SABR in treating NSCLC patients. © 2012

NSCLC and HER2: between lights and shadows.

Science.gov (United States)

Ricciardi, Giuseppina Rosaria Rita; Russo, Alessandro; Franchina, Tindara; Ferraro, Giuseppa; Zanghì, Mariangela; Picone, Antonio; Scimone, Antonino; Adamo, Vincenzo

2014-12-01

The therapeutic landscape of non-small-cell lung cancer (NSCLC) has dramatically changed in the last few years with the introduction of molecularly targeted agents, leading to unprecedented results in lung tumors with a paradigmatic shift from a "one size fits all" approach to an histologic and molecular-based approach. The discovery of epidermal growth factor receptor (EGFR) mutations in NSCLC in 2004 and the marked response to the EGFR tyrosine kinase inhibitor gefitinib, in a small subset of patients harboring these genetic abnormalities, stimulated the study of other kinase mutants involvement in NSCLC. The incredible story of ALK rearranged tumors, with the rapid Food and Drug Administration approval of Crizotinib after only 4 years from the discovery of EML4-ALK translocation in NSCLC, has profoundly influenced the concept of drug development in NSCLC, paving the way to a novel series of molecularly selected studies with specific inhibitors. The identification of these oncogenic drivers has dramatically changed the genetic landscape of NSCLC moving away from the old concept of a large indistinct histological entity to a combination of rare clinically relevant molecular subsets. Recently, a renewed interest has been emerging on the human epidermal growth factor-2 (HER2) pathway. Genetic aberrations of this signaling pathway have been reported over time to be associated in NSCLC with different sensitivity to the EGFR tyrosine kinase inhibitors, to have a possible prognostic role and more recently HER2 amplification has been emerged as a possible mechanism in EGFR-mutated tumors of acquired resistance to the EGFR tyrosine kinase inhibitors. In addition, dysregulation of the HER2 pathway, in particular HER2 mutations (mostly, in-frame exon 20 insertions), may represent a possible novel therapeutic target in NSCLC, paving the way for a new generation of targeted agents in NSCLC. Since anecdotal case reports of clinical activity of anti-HER2 agents in NSCLC

Identification of Reprogrammed Myeloid Cell Transcriptomes in NSCLC.

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Anna Durrans

Full Text Available Lung cancer is the leading cause of cancer related mortality worldwide, with non-small cell lung cancer (NSCLC as the most prevalent form. Despite advances in treatment options including minimally invasive surgery, CT-guided radiation, novel chemotherapeutic regimens, and targeted therapeutics, prognosis remains dismal. Therefore, further molecular analysis of NSCLC is necessary to identify novel molecular targets that impact prognosis and the design of new-targeted therapies. In recent years, tumor "activated/reprogrammed" stromal cells that promote carcinogenesis have emerged as potential therapeutic targets. However, the contribution of stromal cells to NSCLC is poorly understood. Here, we show increased numbers of bone marrow (BM-derived hematopoietic cells in the tumor parenchyma of NSCLC patients compared with matched adjacent non-neoplastic lung tissue. By sorting specific cellular fractions from lung cancer patients, we compared the transcriptomes of intratumoral myeloid compartments within the tumor bed with their counterparts within adjacent non-neoplastic tissue from NSCLC patients. The RNA sequencing of specific myeloid compartments (immature monocytic myeloid cells and polymorphonuclear neutrophils identified differentially regulated genes and mRNA isoforms, which were inconspicuous in whole tumor analysis. Genes encoding secreted factors, including osteopontin (OPN, chemokine (C-C motif ligand 7 (CCL7 and thrombospondin 1 (TSP1 were identified, which enhanced tumorigenic properties of lung cancer cells indicative of their potential as targets for therapy. This study demonstrates that analysis of homogeneous stromal populations isolated directly from fresh clinical specimens can detect important stromal genes of therapeutic value.

A dosimetric comparison between traditionally planned and inverse planned radiation therapy of non-small cell lung cancer

International Nuclear Information System (INIS)

Wu, V.W.C.; Sham, J.S.T.; Kwong, D.L.W.

2003-01-01

This study applied inverse planning in 3-dimensional conformal radiation therapy (3DCRT) of non-small cell lung cancer (NSCLC) patients and evaluated its dosimetric results by comparison with the forward planning of 3DCRT and inverse planning of intensity modulated radiotherapy (IMRT). For each of the 15 NSCLC patients recruited, the forward 3DCRT, inverse 3DCRT and inverse EVIRT plans were produced using the FOCUS treatment planning system. The dosimetric results and the planner's time of all treatment plans were recorded and compared. The inverse 3DCRT plans demonstrated the best target dose homogeneity among the three planning methods. The tumour control probability of the inverse 3DCRT plans was similar to the forward plans (p 0.217) but inferior to the IMRT plans (p < 0.001). A similar pattern was observed in uncomplicated tumour control. The average planning time for the inverse 3DCRT plans was the shortest and its difference was significant compared with the forward 3DCRT plans (p < 0.001) but not with the IMRT plans (p = 0.276). In conclusion, inverse planning for 3DCRT is a reasonable alternative to the forward planning for NSCLC patients with a reduction of the planner's time. However, further dose escalation and improvement of tumour control have to rely on IMRT. Copyright (2003) Australian Institute of Radiography

ERCC1 and histopathology in advanced NSCLC patients randomized in a large multicenter phase III trial

DEFF Research Database (Denmark)

Vilmar, Adam Christian; Santoni-Rugiu, E; Sørensen, J B

2010-01-01

Customized chemotherapy is likely to improve outcome in patients with advanced non-small-cell lung cancer (NSCLC). Excision repair cross-complementation group 1 (ERCC1) is a promising biomarker; however, current evidence is inadequate. Impact of ERCC1 status was evaluated among patients participa...

IMRT and 3D conformal radiotherapy with or without elective nodal irradiation in locally advanced NSCLC. A direct comparison of PET-based treatment planning

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Fleckenstein, Jochen; Kremp, Katharina; Kremp, Stephanie; Palm, Jan; Ruebe, Christian [Saarland University Medical School, Department of Radiotherapy and Radiation Oncology, Homburg/Saar (Germany)

2016-02-15

The potential of intensity-modulated radiation therapy (IMRT) as opposed to three-dimensional conformal radiotherapy (3D-CRT) is analyzed for two different concepts of fluorodeoxyglucose positron emission tomography (FDG PET)-based target volume delineation in locally advanced non-small cell lung cancer (LA-NSCLC): involved-field radiotherapy (IF-RT) vs. elective nodal irradiation (ENI). Treatment planning was performed for 41 patients with LA-NSCLC, using four different planning approaches (3D-CRT-IF, 3D-CRT-ENI, IMRT-IF, IMRT-ENI). ENI included a boost irradiation after 50 Gy. For each plan, maximum dose escalation was calculated based on prespecified normal tissue constraints. The maximum prescription dose (PD), tumor control probability (TCP), conformal indices (CI), and normal tissue complication probabilities (NTCP) were analyzed. IMRT resulted in statistically significant higher prescription doses for both target volume concepts as compared with 3D-CRT (ENI: 68.4 vs. 60.9 Gy, p < 0.001; IF: 74.3 vs. 70.1 Gy, p < 0.03). With IMRT-IF, a PD of at least 66 Gy was achieved for 95 % of all plans. For IF as compared with ENI, there was a considerable theoretical increase in TCP (IMRT: 27.3 vs. 17.7 %, p < 0.00001; 3D-CRT: 20.2 vs. 9.9 %, p < 0.00001). The esophageal NTCP showed a particularly good sparing with IMRT vs. 3D-CRT (ENI: 12.3 vs. 30.9 % p < 0.0001; IF: 15.9 vs. 24.1 %; p < 0.001). The IMRT technique and IF target volume delineation allow a significant dose escalation and an increase in TCP. IMRT results in an improved sparing of OARs as compared with 3D-CRT at equivalent dose levels. (orig.) [German] Das Potenzial der intensitaetsmodulierten Strahlentherapie (IMRT) soll im Rahmen der FDG-PET basierten Bestrahlungsplanung des lokal fortgeschrittenen nichtkleinzelligen Bronchialkarzinoms (LA-NSCLC) fuer 2 Zielvolumenansaetze (Involved-Field-Bestrahlung, IF) sowie elektive Nodalbestrahlung (ENI) geprueft und mit der 3-D-konformalen Strahlentherapie (3-D

Favorable prognosis of operable non-small cell lung cancer (NSCLC) patients harboring an increased expression of tumor endothelial markers (TEMs).

Science.gov (United States)

Pircher, Andreas; Fiegl, Michael; Untergasser, Gerold; Heidegger, Isabel; Medinger, Michael; Kern, Johann; Hilbe, Wolfgang

2013-08-01

Genome analyses of endothelial cells identified genes specifically expressed by tumor endothelial cells, called tumor endothelial markers (TEMs). Currently there are no data available concerning the role of TEMs in non-small cell lung cancer (NSCLC). Therefore, the aim of this study was to investigate the role of TEMs in NSCLC in vitro and in vivo. First we evaluated the expression of various TEMs (Robo4, Clec14 and ECSCR) by qRT-PCR and Western blot analyses in three NSCLC cell lines (A549, Calu1, Colo699) and compared them to human umbilical vein endothelial cells (HUVECs), endothelial colony forming cells (ECFCs) and human bronchial epithelial cells (HBEpCs). Next the expression of TEMs was measured in resected tumor tissue of NSCLC patients (n = 63) by qRT-PCR and compared to adjacent non-cancerous lung tissue (n = 52). Further, immunohistochemical analysis of Robo4 expression in tumor tissue (n = 33) and adjacent non-cancerous tissue (n = 27) was performed. We found that NSCLC cell lines and HBEpC did not express TEMs on the mRNA level compared to HUVECs (p = 0.001). In the contrary, a significant up-regulation of Robo4 and Clec14 was found in tumor samples (Robo4 p = 0.03, Clec14 p = 0.002). Both facts clearly indicate that these proteins are allocated to the tumor stromal department. Correlation with clinical data showed that increased TEM expression correlated with prolonged overall survival of operated NSCLC patients (Robo4 high 120.5 vs. Robo4 low 47.6 months, Clec14 high 108.1 vs. Clec14 low 54.5 months and ECSCR high 120.5 vs. ECSCR low 42.2 months). In summary, we found that TEMs are overexpressed in NSCLC stromal tissue and that an increased TEM expression correlated with an increased overall survival in early stage NSCLC. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

The Predictive Value of Germline Polymorphisms in Patients with NSCLC

DEFF Research Database (Denmark)

Nygaard, Anneli Dowler; Spindler, Karen-Lise Garm; Andersen, Rikke Fredslund

2010-01-01

urgently needed. Single Nucleotide Polymorphisms (SNPs) are stable markers of potential clinical value and the study aimed at evaluating their use in lung cancer patients given standard chemotherapy. Genomic DNA was extracted from a pre-treatment blood sample drawn from patients with advanced Non....... Haplotypes were estimated and analyzed when relevant. There were no significant associations between SNPs in the EGF system or the DNA-repair system and RR, PFS or OS. In contrast, the VEGF+405, VEGF-460 and VEGF-2579, heterozygous patients had a higher response rate and longer PFS than homozygous patients....... Haplotype analysis of the VEGF+405 and VEGF- 460 supported our findings. These results were, however, not confirmed in the validation cohort. Although significant results regarding VEGF related SNPs, in the primary analysis, no predictive value of a broad panel of SNPs in NSCLC was found in the validation...

Cost-effective analysis of PET application in NSCLC

International Nuclear Information System (INIS)

Gu Aichun; Liu Jianjun; Sun Xiaoguang; Shi Yiping; Huang Gang

2006-01-01

Objective: To evaluate the cost-effectiveness of PET and CT application for diagnosis of non-small cell lung cancer (NSCLC) in China. Methods: Using decision analysis method the diagnostic efficiency of PET and CT for diagnosis of NSCLC in china was analysed. And also the value of cost for accurate diagnosis (CAD), cost for accurate staging (CAS) and cost for effective therapy (CAT) was calculated. Results: (1) For the accurate diagnosis, CT was much more cost-effective than PET. (2) For the accurate staging, CT was still more cost-effective than PET. (3) For the all over diagnostic and therapeutic cost, PET was more cost-effective than CT. (4) The priority of PET to CT was for the diagnosis of stage I NSCLC. Conclusion: For the management of NSCLC patient in China, CT is more cost-effective for screening, whereas PET for clinical staging and monitoring therapeutic effect. (authors)

CyberKnife with tumor tracking: An effective alternative to wedge resection for high-risk surgical patients with stage I non-small cell lung cancer (NSCLC

Directory of Open Access Journals (Sweden)

Sean eCollins

2012-02-01

Full Text Available Published data suggests that wedge resection for stage I NSCLC results in improved overall survival compared to stereotactic body radiation therapy (SBRT. We report CyberKnife outcomes for high-risk surgical patients with biopsy-proven stage I NSCLC. PET/CT imaging was completed for staging. Three-to-five gold fiducial markers were implanted in or near tumors to serve as targeting references. Gross tumor volumes (GTVs were contoured using lung windows; the margins were expanded by 5 mm to establish the planning treatment volume (PTV. Treatment plans were designed using hundreds of pencil beams. Doses delivered to the PTV ranged from 42-60 Gy in 3 fractions. The 30-Gy isodose contour extended at least 1cm from the GTV to eradicate microscopic disease. Treatments were delivered using the CyberKnife system with tumor tracking. Examination and PET/CT imaging occurred at 3-month follow-up intervals. Forty patients (median age 76 with a median maximum tumor diameter of 2.6 cm (range, 1.4-5.0 cm and a mean post-bronchodilator percent predicted forced expiratory volume in 1 second (FEV1 of 57% (range, 21 - 111% were treated. A mean dose of 50 Gy was delivered to the PTV over 3 to 13 days (median, 7 days. The 30-Gy isodose contour extended a mean 1.9 cm from the GTV. At a median 44 months (range, 12 -72 months follow-up, the 3-year Kaplan-Meier locoregional control and overall survival estimates compare favorably with contemporary wedge resection outcomes at 91% and 75% , respectively. CyberKnife is an effective treatment approach for stage I NSCLC that is similar to wedge resection, eradicating tumors with 1 to 2 cm margins in order to preserve lung function. Prospective randomized trials comparing CyberKnife with wedge resection are necessary to confirm equivalence.

The effectiveness of RECIST on survival in patients with NSCLC receiving chemotherapy with or without target agents as first-line treatment.

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Zhou, Ting; Zheng, Lie; Hu, Zhihuang; Zhang, Yang; Fang, Wenfeng; Zhao, Yuanyuan; Ge, Jieying; Zhao, Hongyun; Zhang, Li

2015-01-08

We analyzed the correlation between survival and antitumor effect evaluated by RECIST in advanced NSCLC patients with chemotherapy plus target therapy or not as first-line treatment, to examine the applicability of RECIST in this population. The patients were screened from 4 clinical trials (12621, 12006, FASTACT-I, and FASTACT-II), and those who received chemotherapy plus target therapy or chemotherapy alone were eligible. Among the 59 enrolled patients, 29 received combination therapy, while the other 30 received chemotherapy only. In the combination therapy group, patients with PR or SD had longer overall survival (OS) than those with PD (P chemotherapy alone group, compared with PD patients, either PR or SD group had no significant overall survival benefit (P = 0.690 and P = 0.528, respectively). In summary, for advanced NSCLC patients receiving chemotherapy plus target therapy as first-line treatment and evaluated by RECIST criteria, SD has the same overall survival benefit as PR, suggesting that antitumor effective evaluation by RECIST criteria cannot be translated to overall survival benefit especially for this kind of patients. Therefore, developing a more comprehensive evaluation method to perfect RECIST criteria is thus warranted for patients received target therapy in NSCLC.

IMRT and 3D conformal radiotherapy with or without elective nodal irradiation in locally advanced NSCLC. A direct comparison of PET-based treatment planning

International Nuclear Information System (INIS)

Fleckenstein, Jochen; Kremp, Katharina; Kremp, Stephanie; Palm, Jan; Ruebe, Christian

2016-01-01

The potential of intensity-modulated radiation therapy (IMRT) as opposed to three-dimensional conformal radiotherapy (3D-CRT) is analyzed for two different concepts of fluorodeoxyglucose positron emission tomography (FDG PET)-based target volume delineation in locally advanced non-small cell lung cancer (LA-NSCLC): involved-field radiotherapy (IF-RT) vs. elective nodal irradiation (ENI). Treatment planning was performed for 41 patients with LA-NSCLC, using four different planning approaches (3D-CRT-IF, 3D-CRT-ENI, IMRT-IF, IMRT-ENI). ENI included a boost irradiation after 50 Gy. For each plan, maximum dose escalation was calculated based on prespecified normal tissue constraints. The maximum prescription dose (PD), tumor control probability (TCP), conformal indices (CI), and normal tissue complication probabilities (NTCP) were analyzed. IMRT resulted in statistically significant higher prescription doses for both target volume concepts as compared with 3D-CRT (ENI: 68.4 vs. 60.9 Gy, p < 0.001; IF: 74.3 vs. 70.1 Gy, p < 0.03). With IMRT-IF, a PD of at least 66 Gy was achieved for 95 % of all plans. For IF as compared with ENI, there was a considerable theoretical increase in TCP (IMRT: 27.3 vs. 17.7 %, p < 0.00001; 3D-CRT: 20.2 vs. 9.9 %, p < 0.00001). The esophageal NTCP showed a particularly good sparing with IMRT vs. 3D-CRT (ENI: 12.3 vs. 30.9 % p < 0.0001; IF: 15.9 vs. 24.1 %; p < 0.001). The IMRT technique and IF target volume delineation allow a significant dose escalation and an increase in TCP. IMRT results in an improved sparing of OARs as compared with 3D-CRT at equivalent dose levels. (orig.) [de

Positive expression of p53, c-erbB2 and MRP proteins is correlated with survival rates of NSCLC patients.

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Xu, Yujin; Wang, Liancong; Zheng, Xiao; Liu, Guan; Wang, Yuezhen; Lai, Xiaojing; Li, Jianqiang

2013-05-01

The incidence of lung cancer is one of the leading causes of mortality. This study aimed to investigate the prognostic and predictive importance of p53, c-erbB2 and multidrug resistance proteins (MRP) expression and its correlation with clinicopathological characteristics of patients with non-small cell lung cancer (NSCLC). Expression of p53, c-erbB2 and MRP proteins in 152 tumor samples from resected primary NSCLCs was detected by immunohistochemical staining. The correlation of proteins, survival and clinicopathological characteristics was investigated in 152 patients undergoing potentially curative surgery. The positive rates of p53, c-erbB2 and MRP expression were 53.9 (82/152), 44.1 (67/152) and 43.4% (66/152), respectively. Overall survival rates of patients were markedly correlated with the overexpression of p53, c-erbB2 and MRP proteins. One, 2- and 3-year survival rates of patients exhibiting a positive expression of these proteins were 72.6, 54.8 and 32.2%, respectively. These rates were lower compared with those of patients with a negative expression of these proteins (92.1, 78.5 and 63.4%) (P=0.02, 0.01 or 0.00, respectively). Results of Cox's regression analysis showed that c-erbB2 expression and cell differentiation were independent prognostic factors in patients with NSCLC. These findings suggest that the positive expression of p53, c-erbB2 and MRP proteins is correlated with the survival rates of NSCLC patients. Detection of positive p53, c-erbB2 and MRP expression may be a useful predictive indicator of prognosis. Positive c-erbB2 expression is an independent prognostic factor, with a potential to be used as a predictive indicator of chemotherapy efficacy in NSCLC patients.

Time and dose-related changes in lung perfusion after definitive radiotherapy for NSCLC

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Farr, Katherina P; Khalil, Azza A; Møller, Ditte S

2018-01-01

BACKGROUND AND PURPOSE: To examine radiation-induced changes in regional lung perfusion per dose level in 58 non-small-cell lung cancer (NSCLC) patients treated with intensity-modulated radiotherapy (IMRT). MATERIAL AND METHODS: NSCLC patients receiving chemo-radiotherapy (RT) of minimum 60 Gy we...

Anamorelin hydrochloride for the treatment of cancer-anorexia-cachexia in NSCLC.

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Zhang, Hongjie; Garcia, Jose M

2015-06-01

Cancer anorexia-cachexia syndrome (CACS) is associated with increased morbidity and mortality. Anamorelin is a novel, orally active ghrelin receptor agonist in clinical development for the treatment of CACS in NSCLC. The aim of this review is to summarize preclinical and clinical studies evaluating anamorelin as a potential promising treatment for CACS in NSCLC. Pharmacodynamics, pharmacokinetics and metabolism, clinical efficacy, safety and tolerability of anamorelin for the treatment of CACS in NSCLC were reviewed. Anamorelin administration may lead to increases in food intake, body weight and lean body mass, and a stimulatory effect on growth hormone secretion in NSCLC patients. Anamorelin is well tolerated with no dose-limiting toxicities identified to date. Targeting ghrelin receptors presents the advantage of potentially addressing multiple mechanisms of CACS simultaneously including appetite, muscle protein balance, adipose tissue metabolism, energy expenditure and inflammation. Clinical data suggest that anamorelin is well tolerated and it effectively increases appetite, body weight and lean mass in patients with advanced NSCLC. Long-term safety remains unknown at this time. The potential synergistic effects of anamorelin with nutritional support or exercise as well as its efficacy/safety in other tumor types are also unknown.

Chemotherapy with cisplatin and vinorelbine for elderly patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC

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Nikaedo Sueli M

2004-09-01

Full Text Available Abstract Background Although modest improvements in the survival of patients with non-small cell lung cancer (NSCLC can be achieved with cisplatin-based chemotherapy (CT, its value is disputed in the geriatric setting. In this study, we evaluate the feasibility of vinorelbine/cisplatin CT for elderly NSCLC patients. Methods In this pilot phase I/II trial, all patients received CT with vinorelbine 25 mg/m2, on day 1 and 8, and cisplatin on day 1, in 28 days-cycles. After stratification for age (up to 75 years, younger patients were sequentially allocated to moderate cisplatin doses (80 mg/m2 or 90 mg/m2, and older patients were allocated to lower cisplatin doses (60 mg/m2 or 70 mg/m2. We recruited patients aged over 70 years with newly diagnosed NSCLC, clinical stage III or IV, Karnofsky performance status ≥ 70%, normal serum creatinine, peripheral neuropathy ≤ grade 1, and no prior cancer therapy. Results Analysis was by intention to treat. Main toxicities (grade 3–4 was as follows: neutropenia, 20%; anemia, 11%; and thrombocytopenia, 2%; alopecia, 55%; fatigue, 11%; and peripheral neurotoxicity, 2%. No grade 3–4 emesis or renal toxicity occurred. Global median time to progression (TTP and overall survival (OS were 27.0 (95% CI: 10.1 to 43.7 weeks and 30.1 (95% CI: 24.4 to 35.8 weeks; 1- and 2-year survival rates were 36.3% and 13.2%, respectively. Overall response rate was 50.0% (95% CI: 35.4% to 64.5%, with 1 complete response; no difference on response rate was noticed according to cisplatin dose. Median overall survival was 30.1 weeks, with 1- and 2-year survival rates of 36.3% and 13.2%, respectively. Conclusion Age does not preclude assessment on the role of cisplatin-vinorelbine CT for elderly NSCLC patients with good performance status and adequate bodily functions.

Chemotherapy with cisplatin and vinorelbine for elderly patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC)

International Nuclear Information System (INIS)

Pereira, José Rodrigues; Martins, Sandro J; Nikaedo, Sueli M; Ikari, Flora K

2004-01-01

Although modest improvements in the survival of patients with non-small cell lung cancer (NSCLC) can be achieved with cisplatin-based chemotherapy (CT), its value is disputed in the geriatric setting. In this study, we evaluate the feasibility of vinorelbine/cisplatin CT for elderly NSCLC patients. In this pilot phase I/II trial, all patients received CT with vinorelbine 25 mg/m 2 , on day 1 and 8, and cisplatin on day 1, in 28 days-cycles. After stratification for age (up to 75 years), younger patients were sequentially allocated to moderate cisplatin doses (80 mg/m 2 or 90 mg/m 2 ), and older patients were allocated to lower cisplatin doses (60 mg/m 2 or 70 mg/m 2 ). We recruited patients aged over 70 years with newly diagnosed NSCLC, clinical stage III or IV, Karnofsky performance status ≥ 70%, normal serum creatinine, peripheral neuropathy ≤ grade 1, and no prior cancer therapy. Analysis was by intention to treat. Main toxicities (grade 3–4) was as follows: neutropenia, 20%; anemia, 11%; and thrombocytopenia, 2%; alopecia, 55%; fatigue, 11%; and peripheral neurotoxicity, 2%. No grade 3–4 emesis or renal toxicity occurred. Global median time to progression (TTP) and overall survival (OS) were 27.0 (95% CI: 10.1 to 43.7) weeks and 30.1 (95% CI: 24.4 to 35.8) weeks; 1- and 2-year survival rates were 36.3% and 13.2%, respectively. Overall response rate was 50.0% (95% CI: 35.4% to 64.5%), with 1 complete response; no difference on response rate was noticed according to cisplatin dose. Median overall survival was 30.1 weeks, with 1- and 2-year survival rates of 36.3% and 13.2%, respectively. Age does not preclude assessment on the role of cisplatin-vinorelbine CT for elderly NSCLC patients with good performance status and adequate bodily functions

TU-F-12A-05: Sensitivity of Textural Features to 3D Vs. 4D FDG-PET/CT Imaging in NSCLC Patients

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Yang, F; Nyflot, M; Bowen, S; Kinahan, P; Sandison, G [University of Washington Medical Center, Seattle, WA (United States)

2014-06-15

Purpose: Neighborhood Gray-level difference matrices (NGLDM) based texture parameters extracted from conventional (3D) 18F-FDG PET scans in patients with NSCLC have been previously shown to associate with response to chemoradiation and poorer patient outcome. However, the change in these parameters when utilizing respiratory-correlated (4D) FDG-PET scans has not yet been characterized for NSCLC. The Objectives: of this study was to assess the extent to which NGLDM-based texture parameters on 4D PET images vary with reference to values derived from 3D scans in NSCLC. Methods: Eight patients with newly diagnosed NSCLC treated with concomitant chemoradiotherapy were included in this study. 4D PET scans were reconstructed with OSEM-IR in 5 respiratory phase-binned images and corresponding CT data of each phase were employed for attenuation correction. NGLDM-based texture features, consisting of coarseness, contrast, busyness, complexity and strength, were evaluated for gross tumor volumes defined on 3D/4D PET scans by radiation oncologists. Variation of the obtained texture parameters over the respiratory cycle were examined with respect to values extracted from 3D scans. Results: Differences between texture parameters derived from 4D scans at different respiratory phases and those extracted from 3D scans ranged from −30% to 13% for coarseness, −12% to 40% for contrast, −5% to 50% for busyness, −7% to 38% for complexity, and −43% to 20% for strength. Furthermore, no evident correlations were observed between respiratory phase and 4D scan texture parameters. Conclusion: Results of the current study showed that NGLDM-based texture parameters varied considerably based on choice of 3D PET and 4D PET reconstruction of NSCLC patient images, indicating that standardized image acquisition and analysis protocols need to be established for clinical studies, especially multicenter clinical trials, intending to validate prognostic values of texture features for NSCLC.

Treatment paradigms for patients with metastatic non small cell lung cancer (NSCLC, squamous lung cancer: first, second and third-line

Directory of Open Access Journals (Sweden)

Abdulaziz eAl Farsi

2014-06-01

Full Text Available Historically, the treatment algorithm applied to non small cell lung cancer (NSCLC was the same for all histologic subtypes. However, recent advances in our understanding of the molecular profiles of squamous and non-squamous NSCLC have changed this perspective. Histologic subtype and the presence of specific molecular abnormalities have predictive value for response to and toxicity from therapy, as well as overall survival. For patients with squamous NSCLC, a platinum agent plus gemcitabine, or paclitaxel is recommended as first-line therapy. The role of EGFR monoclonal antibodies is uncertain. Maintenance therapy is not widely recommended, although data exist for the use of erlotinib. The standard recommendation for second-line therapy is docetaxel and erlotinib should be considered as second or third-line therapy. There is ongoing research identifying molecular targets in squamous NSCLC and many agents are in early phase clinical trials. Immunotherapeutic approaches targeting programmed death 1 receptor (PD-1 and its ligand (PD-L1 appear promising.

Mortality in asymptomatic vs. symptomatic patients surgically treated for non-small cell lung cancer (NSCLC)

DEFF Research Database (Denmark)

Madsen, Kirsten Riis; Bødtger, Uffe

, tobacco pack years, or FEV1. Former malignancy was significantly more prevalent among asymptomatic than symptomatic subjects (33 % vs. 11%), with insignificant differences in prevalence of other co-morbidities or in post-surgical TNM (82% vs 85% in stages IA-IIB). 12-months mortality was insignificantly...... higher in asymptomatic than symptomatic subjects (23% vs. 12%), and in patients with former malignancy compared to patients with no former cancer (17% vs. 16%). Discussion: Symptoms at diagnosis per se appear unrelated to mortality in patients with NSCLC referred for surgery. Asymptomatic patients were...

Chemotherapy in the management of brain metastases: the emerging role of fotemustine for patients with melanoma and NSCLC.

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Addeo, Raffaele; Zappavigna, Silvia; Luce, Amalia; Facchini, Sergio; Caraglia, Michele

2013-09-01

An estimated 20 - 40% of cancer patients will develop brain metastases that are the most common intracranial tumors in adults. Patients with cerebral metastases represent a variegate group where selection of the most appropriate treatment depends on many patient- and disease-related factors. The impact of therapeutic option on overall survival is lacking and it is important to consider quality of life (QOL) when treating patients with brain metastases. A considerable proportion of patients are treated with palliative approaches such as whole-brain radiotherapy. The role of chemotherapy was limited in the past. Recently, several chemotherapeutic agents have been identified as potentially useful. This article examines the pharmacokinetics, efficacy and safety and tolerability of fotemustine (FTM) for the management of patients with cerebral metastasis from melanoma and non-small cell lung cancer (NSCLC). FTM is a third-generation nitrosourea that has proved its efficacy on brain metastases of melanoma and showed promising results for the treatment of brain metastasis of NSCLC because of its ability to pass the blood-brain barrier.

miR-151a induces partial EMT by regulating E-cadherin in NSCLC cells

DEFF Research Database (Denmark)

Daugaard, Iben; Sanders, K J; Idica, A

2017-01-01

mortality. Here, we demonstrate that miR-151a is overexpressed in non-small cell lung cancer (NSCLC) patient specimens, as compared to healthy lung. In addition, miR-151a overexpression promotes proliferation, epithelial-to-mesenchymal transition (EMT) and induces tumor cell migration and invasion of NSCLC......-cadherin in miR-151a NSCLC cell lines potently repressed miR-151a-induced partial EMT and cell migration of NSCLC cells. In conclusion, our findings suggest that miR-151a functions as an oncomiR in NSCLC by targeting E-cadherin mRNA and inducing proliferation, migration and partial EMT....

Recent Advances in Targetable Therapeutics in Metastatic Non-Squamous NSCLC

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Pranshu eBansal

2016-05-01

Full Text Available Lung adenocarcinoma is the most common subtype of non-small cell lung cancer (NSCLC. With the discovery of epidermal growth factor receptor (EGFR mutations, anaplastic lymphoma kinase (ALK rearrangements and effective targeted therapies, therapeutic options are expanding for patients with lung adenocarcinoma. Here, we review novel therapies in non-squamous NSCLC, which are directed against oncogenic targets, including EGFR, ALK, ROS1, BRAF, MET, human epidermal growth factor receptor 2 (HER2, vascular endothelial growth factor receptor 2 (VEGFR2, RET and NTRK. With the rapidly evolving molecular testing and development of new targeted agents, our ability to further personalize therapy in non-squamous NSCLC is rapidly expanding.

Mathematical modeling for Phase I cancer trials: A study of metronomic vinorelbine for advanced non-small cell lung cancer (NSCLC) and mesothelioma patients.

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Barlesi, Fabrice; Imbs, Diane-Charlotte; Tomasini, Pascale; Greillier, Laurent; Galloux, Melissa; Testot-Ferry, Albane; Garcia, Mélanie; Elharrar, Xavier; Pelletier, Annick; André, Nicolas; Mascaux, Céline; Lacarelle, Bruno; Cheikh, Raouf El; Serre, Raphaël; Ciccolini, Joseph; Barbolosi, Dominique

2017-07-18

Using mathematical modelling allows to select a treatment's regimen across infinite possibilities. Here, we report the phase I assessment of a new schedule for metronomic vinorelbine in treating refractory advanced NSCLC and mesothelioma patients. Overall, 13 patients were screened and 12 were treated (50% male, median age: 68yrs), including 9 NSCLC patients. All patients received at least one week (3 doses) of treatment. At data cut-off, the median length of treatment was 6.5 weeks (1-32+). All the patients presented with at least one adverse event (AE) and six patients with a severe AE (SAE). One partial response and 5 stable diseases were observed. The median OS was 6.4 months (95% CI, 4.8 to 12 months). The median and mean vinorelbine's AUC were 122 ng/ml*h and 159 ng/ml*h, respectively, with the higher plasmatic vinorelbine exposure associated with the best ORR (difference of AUC comparison between responders and non-responders, p-value 0.017). The mathematical modelling determined the administration of vinorelbine, 60 mg on Day 1, 30 mg on Day 2 and 60 mg on Day 4 weekly until progression, as the best schedule. Advanced NSCLC or mesothelioma patients progressing after standard treatment were eligible for the trial. NCT02555007. Responses with acceptable safety profile were observed in heavily pretreated NSCLC and mesothelioma patients using oral vinorelbine at this metronomic dosage based on a mathematic modeling. This study demonstrates the feasibility of this new type of approach, as mathematical modeling may help to rationally decide the better regimen to be clinically tested across infinite possibilities.

Combination of paclitaxel and bevacizumab in heavily pre-treated non-small-cell lung cancer (NSCLC) patients: a case series study on 15 patients.

Science.gov (United States)

Le Moulec, Sylvestre; Hadoux, Julien; Gontier, Eric; Chargari, Cyrus; Helissey, Carole; Lamand, Virginie; Tanz, Rachid; Farace, Françoise; Vedrine, Lionel; Bonardel, Gérald; Soria, Jean-Charles; Besse, Benjamin

2013-12-01

The combination of paclitaxel and bevacizumab was EMA-approved as first-line therapy in metastatic breast cancer. Moreover, in vitro studies showed a potential antiangiogenic synergistic effect of paclitaxel and bevacizumab. Between November 2008 and March 2010, this case series study included 15 patients with metastatic non squamous-cell lung carcinoma (NSCLC). Those were bevacizumab eligible and received the same regimen used in metastatic breast cancer with weekly paclitaxel (80 mg/m(2), days 1, 8 and 15) and bevacizumab (10 mg/kg at days 1 and 15) after at least one prior line of chemotherapy. Efficacy was evaluated by CT-scan and PET-FDG every two months. Circulating endothelial progenitor cells (CEP) and circulating endothelial cells (CEC) levels were explored in a subset of patients. Median age 56 (36-75), female: 47%, never smokers: 27%, adenocarcinoma: 100%, PS 0-1: 87% and PS 3: 13%. All patients were treated with a first-line platinum-based doublet with or without bevacizumab and 70% of them with erlotinib in the second-line. No major toxicity was observed. Partial response (PR) rate was 44% (31-63%) using RECIST criteria on CT-scan, and 65% (29-88%) with PET FDG. PS improved in 33% of the cases. Median progression free survival was 4.6 months. An increase of CEC and CEP was observed in patients with NSCLC treated with paclitaxel and bevacizumab. In this retrospective series, our results suggest efficacy signal in pre-treated metastatic NSCLC and warrant further assessment in a randomized clinical trial.

Src mediates cigarette smoke-induced resistance to tyrosine kinase inhibitors in NSCLC cells.

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Filosto, Simone; Baston, David S; Chung, Samuel; Becker, Cathleen R; Goldkorn, Tzipora

2013-08-01

The EGF receptor (EGFR) is a proto-oncogene commonly dysregulated in several cancers including non-small cell lung carcinoma (NSCLC) and, thus, is targeted for treatment using tyrosine kinase inhibitors (TKI) such as erlotinib. However, despite the efficacy observed in patients with NSCLC harboring oncogenic variants of the EGFR, general ineffectiveness of TKIs in patients with NSCLC who are current and former smokers necessitates identification of novel mechanisms to overcome this phenomenon. Previously, we showed that NSCLC cells harboring either wild-type (WT) EGFR or oncogenic mutant (MT) L858R EGFR become resistant to the effects of TKIs when exposed to cigarette smoke, evidenced by their autophosphorylation and prolonged downstream signaling. Here, we present Src as a target mediating cigarette smoke-induced resistance to TKIs in both WT EGFR- and L858R MT EGFR-expressing NSCLC cells. First, we show that cigarette smoke exposure of A549 cells leads to time-dependent activation of Src, which then abnormally binds to the WT EGFR causing TKI resistance, contrasting previous observations of constitutive binding between inactive Src and TKI-sensitive L858R MT EGFR. Next, we show that Src inhibition restores TKI sensitivity in cigarette smoke-exposed NSCLC cells, preventing EGFR autophosphorylation in the presence of erlotinib. Furthermore, we show that overexpression of a dominant-negative Src (Y527F/K295R) restores TKI sensitivity to A549 exposed to cigarette smoke. Importantly, the TKI resistance that emerges even in cigarette smoke-exposed L858R EGFR-expressing NSCLC cells could be eliminated with Src inhibition. Together, these findings offer new rationale for using Src inhibitors for treating TKI-resistant NSCLC commonly observed in smokers.

The APPLE Trial: Feasibility and Activity of AZD9291 (Osimertinib) Treatment on Positive PLasma T790M in EGFR-mutant NSCLC Patients. EORTC 1613.

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Remon, Jordi; Menis, Jessica; Hasan, Baktiar; Peric, Aleksandra; De Maio, Eleonora; Novello, Silvia; Reck, Martin; Berghmans, Thierry; Wasag, Bartosz; Besse, Benjamin; Dziadziuszko, Rafal

2017-09-01

The AZD9291 (Osimertinib) Treatment on Positive PLasma T790M in EGFR-mutant NSCLC Patients (APPLE) trial is a randomized, open-label, multicenter, 3-arm, phase II study in advanced, epidermal growth factor receptor (EGFR)-mutant and EGFR tyrosine kinase inhibitor (TKI)-naive non-small-cell lung cancer (NSCLC) patients, to evaluate the best strategy for sequencing gefitinib and osimertinib treatment. Advanced EGFR-mutant NSCLC patients, with World Health Organization performance status 0-2 who are EGFR TKI treatment-naive and eligible to receive first-line treatment with EGFR TKI will be randomized to: In all arms, a plasmatic ctDNA T790M test will be performed by a central laboratory at the Medical University of Gdansk (Poland) but will be applied as a predictive marker for making treatment decisions only in arm B. The primary objective is to evaluate the best strategy for sequencing of treatment with gefitinib and osimertinib in advanced NSCLC patients with common EGFR mutations, and to understand the value of liquid biopsy for the decision-making process. The progression-free survival rate at 18 months is the primary end point of the trial. The activity of osimertinib versus gefitinib to prevent brain metastases will be evaluated. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Treatment outcome in performance status 2 advanced NSCLC patients administered platinum-based combination chemotherapy

DEFF Research Database (Denmark)

Helbekkmo, Nina; Aasebø, Ulf; Sundstrøm, Stein H

2008-01-01

BACKGROUND: There is no consensus regarding chemotherapy to patients with advanced NSCLC (ANSCLC) and performance status (PS) 2. Using data from a national multicenter study comparing two third-generation carboplatin-based regimens in ANSCLC patients, we evaluated the outcome of PS 2 patients....... PATIENTS AND METHODS: The 123 PS 2 patients were compared to 309 PS 0/1 patients regarding survival, quality of life (QOL) and treatment toxicity. RESULTS: PS 2 patients had lower haemoglobin, lower global QOL and more pain, nausea/vomiting and dyspnea at inclusion. 68% of PS 2 patients received three...... chemotherapy courses vs. 85% in the PS 0/1 group (PPS 2 group, 4.5 vs. 8.9 months and 10% vs. 37% (PPS 2 patients needed blood transfusions (P=0.03) and hospitalization (PPS 2 patients had better relief of pain and dyspnea...

Small suitability of the DLEC1, MLH1 and TUSC4 mRNA expression analysis as potential prognostic or differentiating markers for NSCLC patients in the Polish population.

Science.gov (United States)

Kordiak, Jacek; Czarnecka, Karolina H; Pastuszak-Lewandoska, Dorota; Antczak, Adam; Migdalska-Sęk, Monika; Nawrot, Ewa; Domańska-Senderowska, Daria; Kiszałkiewicz, Justyna; Brzeziańska-Lasota, Ewa

2017-06-01

According to the latest data, lung cancer is one of the most common cancer worldwide, men contributing nearly 21.2% and women 8.6% of all diagnosed cancers. Late detection of tumour drastically reduces the chance for a cure. Thus, it is important to search for candidate biomarkers for screening of early stage nonsmall cell lung carcinoma (NSCLC). Tumour suppressor genes, DLEC1, TUSC4 and MLH1, localized on 3p21 are recognized to play a role in NSCLC carcinogenesis. The aim of this study was to assess the relationship between the DLEC1, TUSC4 and MLH1 mRNA expression, and clinical features of NSCLC patients, tobacco addiction, and tumour histopathological characteristics. The DLEC1, TUSC4 and MLH1 expression was analysed in lung tumour tissue samples obtained from 69 patients diagnosed with NSCLC: squamous cell carcinoma (n = 34), adenocarcinoma (n = 24), large cell carcinoma (n = 5), carcinoma adenosquamosum (n = 5). A decreased gene expression (RQ MLH1 in 50.7% and for TUSC4 in 26% of NSCLC samples. DLEC1 was decreased in more aggressive subtypes: large cell carcinoma and adenocarcinoma-squamous cell carcinoma. The simultaneous downregulation of two of the studied genes, DLEC1 andMLH1,was observed in 30.4% of NSCLCsamples, highlighting the importance of these two genes in lung carcinogenesis. We found no correlation between the DLEC1, TUSC4 and MLH1 gene expression and NSCLC patient characteristics (gender, age and smoking) or cancer histopathology. No significant differences in the gene expression among NSCLC subtypes indicate the weakness of DLEC1, TUSC4 and MLH1 expression analysis as potential differentiating markers of NSCLC subtypes in the Polish population.

Evaluation of Circulating Tumor Cells and Related Events as Prognostic Factors and Surrogate Biomarkers in Advanced NSCLC Patients Receiving First-Line Systemic Treatment

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Laura Muinelo-Romay

2014-01-01

Full Text Available In the present study we investigated the prognostic value of Circulating Tumour Cells (CTC and their utility for therapy monitoring in non-small cell lung cancer (NSCLC. A total of 43 patients newly diagnosed with NSCLC were prospectively enrolled. Blood samples were obtained before the 1st, 2nd and 5th cycles of chemotherapy and analyzed using CellSearch technology. Both CTC and CTC-related objects (not morphological standard or broken epithelial cells were counted. At baseline 18 (41.9% patients were positive for intact CTC count and 10 (23.2% of them had ≥5 CTC, while CK positive events were found in 79.1% of patients. The group of patients with CTC ³5 at baseline presented worse PFS and OS than those with <5 CTC (p = 0.034 and p = 0.008, respectively. Additionally, high levels of total CK positive events were associated with poor prognosis in the group of patients with <5 CTC. Regarding therapy monitoring, patients presenting increased levels of CTC during the treatment demonstrated lower OS and PFS rates. All these data supported the value of CTC as a prognostic biomarker and as a surrogate indicator of chemotherapy effectiveness in advanced NSCLC patients, with the additional value of analyzing other “objects” such as apoptotic CTC or CK fragments to guide the clinical management of these patients.

Evaluation of Circulating Tumor Cells and Related Events as Prognostic Factors and Surrogate Biomarkers in Advanced NSCLC Patients Receiving First-Line Systemic Treatment

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Muinelo-Romay, Laura; Vieito, Maria; Abalo, Alicia; Alonso Nocelo, Marta; Barón, Francisco; Anido, Urbano; Brozos, Elena; Vázquez, Francisca; Aguín, Santiago; Abal, Miguel; López López, Rafael, E-mail: rafael.lopez.lopez@sergas.es [Translational Medical Oncology, Health Research Institute of Santiago (IDIS), Complexo Hospitalario Universitario de Santiago de Compostela (SERGAS), Trav. Choupana s/n 15706 Santiago de Compostela (Spain)

2014-01-21

In the present study we investigated the prognostic value of Circulating Tumour Cells (CTC) and their utility for therapy monitoring in non-small cell lung cancer (NSCLC). A total of 43 patients newly diagnosed with NSCLC were prospectively enrolled. Blood samples were obtained before the 1st, 2nd and 5th cycles of chemotherapy and analyzed using CellSearch technology. Both CTC and CTC-related objects (not morphological standard or broken epithelial cells) were counted. At baseline 18 (41.9%) patients were positive for intact CTC count and 10 (23.2%) of them had ≥5 CTC, while CK positive events were found in 79.1% of patients. The group of patients with CTC ≥5 at baseline presented worse PFS and OS than those with <5 CTC (p = 0.034 and p = 0.008, respectively). Additionally, high levels of total CK positive events were associated with poor prognosis in the group of patients with <5 CTC. Regarding therapy monitoring, patients presenting increased levels of CTC during the treatment demonstrated lower OS and PFS rates. All these data supported the value of CTC as a prognostic biomarker and as a surrogate indicator of chemotherapy effectiveness in advanced NSCLC patients, with the additional value of analyzing other “objects” such as apoptotic CTC or CK fragments to guide the clinical management of these patients.

Intravenous or oral administration of vinorelbine in adjuvant chemotherapy with cisplatin and vinorelbine for resected NSCLC

DEFF Research Database (Denmark)

Sorensen, Steffen Filskov; Carus, Andreas; Meldgaard, Peter

2015-01-01

OBJECTIVES: Cisplatin and vinorelbine given intravenously is a well-established adjuvant chemotherapy regimen after surgery for early-stage NSCLC. Vinorelbine can also be administered orally. However, the efficacy of orally administrated vinorelbine in adjuvant treatment of NSCLC is unknown. We...... University Hospital (Denmark) from 2005 to 2012 for adjuvant chemotherapy after surgery for NSCLC. RESULTS AND CONCLUSION: Of the 265 patients included in this study, 126 patients received i.v. and 139 received p.o. vinorelbine/cisplatin. The two groups were comparable with respect to important baseline....... In conclusion we observed that intravenous or oral administration of vinorelbine in combination with cisplatin after surgery for NSCLC appear equally effective in terms of overall and disease-free survival....

Blood group antigen A type 3 expression is a favorable prognostic factor in advanced NSCLC.

Science.gov (United States)

Schmidt, L H; Kuemmel, A; Schliemann, C; Schulze, A; Humberg, J; Mohr, M; Görlich, D; Hartmann, W; Bröckling, S; Marra, A; Hillejan, L; Goletz, S; Karsten, U; Berdel, W E; Spieker, T; Wiewrodt, R

2016-02-01

Several blood group-related carbohydrate antigens are prognosis-relevant markers of tumor tissues. A type 3 (repetitive A) is a blood group antigen specific for A1 erythrocytes. Its potential expression in tumor tissues has so far not been examined. We have evaluated its expression in normal lung and in lung cancer using a novel antibody (A69-A/E8). For comparison an anti-A antibody specific to A types 1 and 2 was used, because its expression on lung cancer tissue has been previously reported to be of prognostic relevance. Resected tissue samples of 398 NSCLC patients were analyzed in immunohistochemistry using tissue microarrays. Expression of A type 3 was not observed in non-malignant lung tissues. A type 3 was expressed on tumor cells of around half of NSCLC patients of blood group A1 (ptype 1/2 antigen was observed (p=0.562), the expression of A type 3 by tumor cells indicated a highly significant favorable prognosis among advanced NSCLC patients (p=0.011) and in NSCLC patients with lymphatic spread (p=0.014). Univariate prognostic results were confirmed in a Cox proportional hazards model. In this study we present for the first time prognostic data for A type 3 antigen expression in lung cancer patients. Prospective studies should be performed to confirm the prognostic value of A type 3 expression for an improved risk stratification in NSCLC patients. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

P13.10 Intracranial response to nivolumab in NSCLC patients with untreated or progressing CNS metastases

Science.gov (United States)

Yust-Katz, S.; Dudnik, E.; Perlov, E.; Zer, A.; Flex, D.; Peled, N.; Siegal, T.

2016-01-01

Abstract Background: Central nervous system (CNS) metastases occur in about 30% of patients (pts) with advanced non-small cell lung cancer (NSCLC). Local treatment strategies (e.g., radiotherapy or surgery) result in delays in systemic therapy administration and are frequently associated with neurocognitive impairment. Nivolumab is an anti-PD1 immune check-point inhibitor which has been recently approved by the FDA as a second line treatment of NSCLC. Data regarding its intracranial activity is lacking. Methods: We retrospectively reviewed efficacy and safety of nivolumab administered intravenously at a dose of 3mg/kg q2 weeks in five pts with advanced NSCLC and new or progressing intracranial metastases which were diagnosed before or within 1 month after starting the treatment. Results: Pt baseline characteristics were as follows: median age 78y (range, 52–84); 2 males; 4 smokers; ECOG PS 0/1/2 - 2 pts/1 pt/2 pts; histological subtype: adenocarcinoma/ squamous-cell carcinoma/NSCLC NOS 3 pts /1 pt/1 pt; EGFR WT/ALK neg/KRAS M all/all/2 pts. Four pts had parenchymal brain metastases, three pts had leptomeningeal disease. All pts were asymptomatic and did not require corticosteroids or immediate brain irradiation. Dramatic response in the brain was observed in two pts (including 1 pt with leptomeningeal spread demonstrating a complete response in the CNS); time-to-response comprised 5 weeks and 9 weeks; all responses are still ongoing at the time of the report (18+ weeks, 19+ weeks). In one pt stabilization of leptomeningeal carcinomatosis for 10 weeks was achieved. Systemic responses and intracranial responses were largely concordant. No treatment-related or CNS-metastases related grade ≥ 3 adverse events were observed. Conclusions: Nivolumab has a promising intracranial activity and favorable safety profile in pts with NSCLC and untreated/progressing CNS metastases. Nivolumab CNS activity warrants further evaluation.

Feasibility of accelerated radiotherapy (AR) using a concomitant boost for the treatment of unresectable non-small cell lung cancer (NSCLC): a phase II study

International Nuclear Information System (INIS)

Kumar, Parvesh; Wan, Jim; Paig, Camilo U.; Kun, Larry E.; Niell, H. Barry

1996-01-01

Purpose/Objective: The feasibility of AR using a concomitant boost in the treatment of unresectable NSCLC was prospectively tested in a phase II study. Materials and Methods: Twenty patients were enrolled to the protocol between 11/90 and 5/93. Stage distribution was as follows: Medically inoperable stage I = 5 (T 1 = 1, T 2 = 4), stage IIIA = 1, and stage IIIA(N 2 ) = 14. Planned AR delivered a total dose of 65 Gy in 45 fractions over five weeks using a 'field within a field technique'. The large field (day 1, a.m.) encompassed the primary lesion and adjacent lymph nodes to 45 Gy at 1.8 Gy/fraction (fx). A CT planned small field (day 8, >6 hours apart in p.m.) included only the primary lesion and overt nodal disease to 20 Gy at 1.0 Gy/fx. Doses were not corrected for lung inhomogeneity. Results: Median age of the 20 male enrolled patients was 68 years (range = 42-80 years). Eighteen (90%) of 20 patients completed the planned AR without any interruptions in therapy. One patient experienced a 4 day interruption due to tumor related obstructive pneumonia while the other patient missed 2 days secondary to non-treatment related small bowel obstruction. No incidence of grade ≥3 esophagitis was observed. One patient experienced pneumonitis within the radiation portal 1 month post-RT which response d to corticosteroid therapy; otherwise, no late sequelae were observed. The median total delivered dose was 65 Gy (range 64.0-65.4). At a minimum follow-up interval of 30 months, the 2-year Kaplan-Meier and median survival are 15% and 13.4 months, respectively for all 20 patients. Conclusion: AR using a concomitant boost to 65 Gy in 5 weeks for unresectable NSCLC is feasible with minimal acute or long term toxicity. Median survival in our study was similar to the chemo radiation arms of CALGB 8433 and RTOG 8808 protocols. Protocols which combine AR with chemotherapy should be explored for unresectable NSCLC

Next-generation sequencing in NSCLC and melanoma patients: a cost and budget impact analysis

Science.gov (United States)

van Amerongen, Rosa A; Retèl, Valesca P; Coupé, Veerle MH; Nederlof, Petra M; Vogel, Maartje J; van Harten, Wim H

2016-01-01

Next-generation sequencing (NGS) has reached the molecular diagnostic laboratories. Although the NGS technology aims to improve the effectiveness of therapies by selecting the most promising therapy, concerns are that NGS testing is expensive and that the ‘benefits’ are not yet in relation to these costs. In this study, we give an estimation of the costs and an institutional and national budget impact of various types of NGS tests in non-small-cell lung cancer (NSCLC) and melanoma patients within The Netherlands. First, an activity-based costing (ABC) analysis has been conducted on the costs of two examples of NGS panels (small- and medium-targeted gene panel (TGP)) based on data of The Netherlands Cancer Institute (NKI). Second, we performed a budget impact analysis (BIA) to estimate the current (2015) and future (2020) budget impact of NGS on molecular diagnostics for NSCLC and melanoma patients in The Netherlands. Literature, expert opinions, and a data set of patients within the NKI (n = 172) have been included in the BIA. Based on our analysis, we expect that the NGS test cost concerns will be limited. In the current situation, NGS can indeed result in higher diagnostic test costs, which is mainly related to required additional tests besides the small TGP. However, in the future, we expect that the use of whole-genome sequencing (WGS) will increase, for which it is expected that additional tests can be (partly) avoided. Although the current clinical benefits are expected to be limited, the research potentials of NGS are already an important advantage. PMID:27899957

SU-F-J-64: Comparison of Dosimetric Robustness Between Proton Therapy and IMRT Plans Following Tumor Regression for Locally Advanced Non-Small Cell Lung Cancer (NSCLC)

Energy Technology Data Exchange (ETDEWEB)

Teng, C; Ainsley, C; Teo, B; Burgdorf, B; Berman, A; Levin, W; Xiao, Y; Lin, L; Simone, C; Solberg, T [University of Pennsylvania, Philadelphia, PA (United States); Janssens, G [IBA, Louvain-la-Neuve (Belgium)

2016-06-15

Purpose: In the light of tumor regression and normal tissue changes, dose distributions can deviate undesirably from what was planned. As a consequence, replanning is sometimes necessary during treatment to ensure continued tumor coverage or to avoid overdosing organs at risk (OARs). Proton plans are generally thought to be less robust than photon plans because of the proton beam’s higher sensitivity to changes in tissue composition, suggesting also a higher likely replanning rate due to tumor regression. The purpose of this study is to compare dosimetric deviations between forward-calculated double scattering (DS) proton plans with IMRT plans upon tumor regression, and assesses their impact on clinical replanning decisions. Methods: Ten consecutive locally advanced NSCLC patients whose tumors shrank > 50% in volume and who received four or more CT scans during radiotherapy were analyzed. All the patients received proton radiotherapy (6660 cGy, 180 cGy/fx). Dosimetric robustness during therapy was characterized by changes in the planning objective metrics as well as by point-by-point root-mean-squared differences for the entire PTV, ITV, and OARs (heart, cord, esophagus, brachial plexus and lungs) DVHs. Results: Sixty-four pairs of DVHs were reviewed by three clinicians, who requested a replanning rate of 16.7% and 18.6% for DS and IMRT plans, respectively, with a high agreement between providers. Robustness of clinical indicators was found to depend on the beam orientation and dose level on the DVH curve. Proton dose increased most in OARs distal to the PTV along the beam path, but these changes were primarily in the mid to low dose levels. In contrast, the variation in IMRT plans occurred primarily in the high dose region. Conclusion: Robustness of clinical indicators depends where on the DVH curves comparisons are made. Similar replanning rates were observed for DS and IMRT plans upon large tumor regression.

Systemic treatment in EGFR-ALK NSCLC patients: second line therapy and beyond

International Nuclear Information System (INIS)

Karachaliou, Niki; Rosell, Rafael

2014-01-01

Lung cancer is the most frequently diagnosed cancer and a leading cause of cancer mortality worldwide, with adenocarcinoma being the most common histological subtype. Deeper understanding of the pathobiology of non-small cell lung cancer (NSCLC) has led to the development of small molecules that target genetic mutations known to play critical roles in progression to metastatic disease and to influence response to targeted therapies. The principle goal of precision medicine is to define those patient populations most likely to respond to targeted therapies. However, the cancer genome landscape is composed of relatively few “mountains” [representing the most commonly mutated genes like KRAS, epidermal growth factor (EGFR), and anaplastic lymphoma kinase (ALK)] and a vast number of “hills” (representing low frequency but potentially actionable mutations). Low-frequency lesions that affect a druggable gene product allow a relatively small population of cancer patients for targeted therapy to be selected

Improved progression free survival for patients with diabetes and locally advanced non-small cell lung cancer (NSCLC) using metformin during concurrent chemoradiotherapy

NARCIS (Netherlands)

Wink, Krista C. J.; Belderbos, José S. A.; Dieleman, Edith M. T.; Rossi, Maddalena; Rasch, Coen R. N.; Damhuis, Ronald A. M.; Houben, Ruud M. A.; Troost, Esther G. C.

2016-01-01

The aim was to investigate whether the use of metformin during concurrent chemoradiotherapy (cCRT) for locally advanced non-small cell lung cancer (NSCLC) improved treatment outcome. A total of 682 patients were included in this retrospective cohort study (59 metformin users, 623 control patients).

GAS5 modulated autophagy is a mechanism modulating cisplatin sensitivity in NSCLC cells.

Science.gov (United States)

Zhang, N; Yang, G-Q; Shao, X-M; Wei, L

2016-06-01

In this study, we investigated the association between lncRNA GAS5 and cisplatin (DDP) resistance in NSCLC and further studied the regulative effect of GAS5 on autophagy and DDP resistance. GAS5 expression in cancerous and adjacent normal tissues from 15 NSCLC patients received neoadjuvant chemotherapy and the following surgery were measured using qRT-PCR analysis. GAS5 gain-and-loss study was performed using A549 and A549/DDP cells as an in-vitro model to investigate the effect of GAS5 on autophagy and cisplatin sensitivity. NSCLC tissues had a substantially lower expression of GAS5 than adjacent normal tissues. The NSCLC tissues from patients with progressive disease (PD) had even lower GAS5 expression. GAS5 knockdown increased DDP IC50 of A549 cells, while GAS5 overexpression decreased DDP IC50 of A549/DDP cells. A549/DDP cells had significantly higher basal autophagy than A549 cells. GAS5 knockdown resulted in decreased autophagy in A549 cells, while GAS5 overexpression led to increased autophagy in A549/DDP cells. Treatment with 3-MA, an autophagy inhibitor, significantly decreased DDP IC50 and promoted DDP-induced cell apoptosis in A549 cells. In addition, 3-MA also partly reversed the effect of GAS5 knockdown. In A549/DDP cells, GAS5 showed the similar effect as 3-MA in reducing DPP IC50 and promoting DDP-induced apoptosis and also presented synergic effect with 3-MA. GAS5 downregulation is associated with cisplatin resistance in NSCLC. GAS5 can inhibit autophagy and therefore enhance cisplatin sensitivity in NSCLC cells.

Economic impact of tissue testing and treatments of metastatic NSCLC in the era of personalized medicine.

Directory of Open Access Journals (Sweden)

Donna Marie Graham

2014-09-01

Full Text Available A paradigm-shift in the management of non-small cell lung cancer (NSCLC has resulted in many new therapies becoming available for patients with advanced disease. Stratification of treatment by histologic and molecular subtype is recommended in order to obtain the greatest clinical benefit for patients while minimizing adverse effects of treatment. However, these advances in diagnosis and treatment of NSCLC have come at a financial cost. This review highlights the economic impact of screening for molecular abnormalities and targeted treatment for advanced NSCLC. Major determinants of cost are drug acquisition and molecular testing. As technologies advance, molecular testing costs may reduce. However, we must collaborate with payers and manufacturers to ensure that high drug costs do not limit patient accessibility to potentially beneficial treatment.

Emerging treatments and combinations in the management of NSCLC

DEFF Research Database (Denmark)

Reck, Martin; Mellemgaard, Anders

2015-01-01

There remains an unmet need for effective, well-tolerated treatment options in advanced non-small cell lung cancer (NSCLC) to alleviate the disease burden for a broad selection of patients. Nintedanib is a potent, oral, triple angiokinase inhibitor of vascular endothelial growth factor, fibroblast...

Cost-effectiveness analysis of EGFR mutation testing in patients with non-small cell lung cancer (NSCLC) with gefitinib or carboplatin-paclitaxel.

Science.gov (United States)

Arrieta, Oscar; Anaya, Pablo; Morales-Oyarvide, Vicente; Ramírez-Tirado, Laura Alejandra; Polanco, Ana C

2016-09-01

Assess the cost-effectiveness of an EGFR-mutation testing strategy for advanced NSCLC in first-line therapy with either gefitinib or carboplatin-paclitaxel in Mexican institutions. Cost-effectiveness analysis using a discrete event simulation (DES) model to simulate two therapeutic strategies in patients with advanced NSCLC. Strategy one included patients tested for EGFR-mutation and therapy given accordingly. Strategy two included chemotherapy for all patients without testing. All results are presented in 2014 US dollars. The analysis was made with data from the Mexican frequency of EGFR-mutation. A univariate sensitivity analysis was conducted on EGFR prevalence. Progression-free survival (PFS) transition probabilities were estimated on data from the IPASS and simulated with a Weibull distribution, run with parallel trials to calculate a probabilistic sensitivity analysis. PFS of patients in the testing strategy was 6.76 months (95 % CI 6.10-7.44) vs 5.85 months (95 % CI 5.43-6.29) in the non-testing group. The one-way sensitivity analysis showed that PFS has a direct relationship with EGFR-mutation prevalence, while the ICER and testing cost have an inverse relationship with EGFR-mutation prevalence. The probabilistic sensitivity analysis showed that all iterations had incremental costs and incremental PFS for strategy 1 in comparison with strategy 2. There is a direct relationship between the ICER and the cost of EGFR testing, with an inverse relationship with the prevalence of EGFR-mutation. When prevalence is >10 % ICER remains constant. This study could impact Mexican and Latin American health policies regarding mutation detection testing and treatment for advanced NSCLC.

Evaluation of elastix-based propagated align algorithm for VOI- and voxel-based analysis of longitudinal F-18-FDG PET/CT data from patients with non-small cell lung cancer (NSCLC)

OpenAIRE

Kerner, Gerald S. M. A.; Fischer, Alexander; Koole, Michel J. B.; Pruim, Jan; Groen, Harry J. M.

2015-01-01

Background: Deformable image registration allows volume of interest (VOI)- and voxel-based analysis of longitudinal changes in fluorodeoxyglucose (FDG) tumor uptake in patients with non-small cell lung cancer (NSCLC). This study evaluates the performance of the elastix toolbox deformable image registration algorithm for VOI and voxel-wise assessment of longitudinal variations in FDG tumor uptake in NSCLC patients. Methods: Evaluation of the elastix toolbox was performed using F-18-FDG PET/CT ...

Stereotactic body radiotherapy for centrally located stage I NSCLC. A multicenter analysis

Energy Technology Data Exchange (ETDEWEB)

Schanne, Daniel H.; Nestle, Ursula; Grosu, Anca L. [Universitaetsklinik Freiburg, Klinik fuer Strahlenheilkunde, Freiburg (Germany); Allgaeuer, Michael [Barmherzige Brueder, Klinik fuer Strahlentherapie, Regensburg (Germany); Andratschke, Nicolaus; Molls, Michael [TU Muenchen, Klinik und Poliklinik fuer Strahlentherapie und Radiologische Onkologie, Muenchen (Germany); Appold, Steffen [Universitaetsklinikum Dresden, Klinik und Poliklinik fuer Strahlentherapie und Radioonkologie, Dresden (Germany); Dieckmann, Ute [Allgemeines Krankenhaus Wien, Univ. Klinik fuer Strahlentherapie, Wien (Austria); Ernst, Iris [Universitaetsklinikum Muenster, Klinik fuer Strahlentherapie, Muenster (Germany); Ganswindt, Ute [LMU Muenchen, Klinik und Poliklinik fuer Strahlentherapie und Radioonkologie, Muenchen (Germany); Holy, Richard [Universitaetsklinikum Aachen, Klinik fuer Strahlentherapie, Aachen (Germany); Nevinny-Stickel, Meinhard [Medizinischen Universitaet Innsbruck, Univ. Klinik fuer Strahlentherapie und Radioonkologie, Innsbruck (Austria); Semrau, Sabine [Universitaetsklinikum Erlangen, Strahlenklinik Erlangen, Erlangen (Germany); Sterzing, Florian [Universitaetsklinikum Heidelberg, Klinik fuer Radioonkologie und Strahlentherapie, Heidelberg (Germany); Wittig, Andrea [Philipps-Universitaet Marburg, Klinik fuer Strahlentherapie und Radioonkologie, Marburg (Germany); Guckenberger, Matthias [Universitaet Wuerzburg, Klinik und Poliklinik fuer Strahlentherapie, Wuerzburg (Germany)

2014-08-27

The purpose of this work is to analyze patterns of care and outcome after stereotactic body radiotherapy (SBRT) for centrally located, early-stage, non-small cell lung cancer (NSCLC) and to address the question of potential risk for increased toxicity in this entity. A total of 90 patients with centrally located NSCLC were identified among 613 cases in a database of 13 German and Austrian academic radiotherapy centers. The outcome of centrally located NSCLC was compared to that of cases with peripheral tumor location from the same database. Patients with central tumors most commonly presented with UICC stage IB (50 %), while the majority of peripheral lesions were stage IA (56 %). Average tumor diameters were 3.3 cm (central) and 2.8 cm (peripheral). Staging PET/CT was available for 73 and 74 % of peripheral and central tumors, respectively. Biopsy was performed in 84 % (peripheral) and 88 % (central) of cases. Doses varied significantly between central and peripheral lesions with a median BED{sub 10} of 72 Gy and 84 Gy, respectively (p < 0.001). Fractionation differed as well with medians of 5 (central) and 3 (peripheral) fractions (p < 0.001). In the Kaplan-Meier analysis, 3-year actuarial overall survival was 29 % (central) and 51 % (peripheral; p = 0.004) and freedom from local progression was 52 % (central) and 84 % (peripheral; p < 0.001). Toxicity after treatment of central tumors was low with no grade III/IV and one grade V event. Mortality rates were 0 and 1 % after 30 and 60 days, respectively. Local tumor control in patients treated with SBRT for centrally located, early-stage NSCLC was favorable, provided ablative radiation doses were prescribed. This was, however, not the case in the majority of patients, possibly due to concerns about treatment-related toxicity. Reported toxicity was low, but prospective trials are needed to resolve the existing uncertainties and to establish safe high-dose regimens for this cohort of patients. (orig.) [German] Ziel

An Evidence-Based Approach to the Use of Predictive Biomarkers in the Treatment of Non- Small Cell Lung Cancer (NSCLC)

International Nuclear Information System (INIS)

Quinton, Cindy; Ellis, Peter M.

2011-01-01

Recent advances in the treatment of non-small cell lung cancer (NSCLC) have led to improvements in patient survival and quality of life. It is unclear whether molecular abnormalities associated with NSCLC cell survival, growth and proliferation are useful in predicting treatment benefit. We conducted a systematic review to establish which biomarkers contribute meaningfully to the management of NSCLC. A team of researchers searched PubMed and conference proceedings (ASCO, ESMO, IASLC, USCAP) using MESH terms for NSCLC and randomized trials (RCT), plus keywords for variables of interest. Evidence from multiple RCTs confirmed that histologic subtype is prognostic for survival and predictive of treatment efficacy and/or toxicity in NSCLC. Likewise, activating mutations of the epidermal growth factor receptor (EGFR) are associated with benefit from EGFR tyrosine kinase inhibitors in patients with advanced non-squamous NSCLC and should be assessed routinely. No biomarkers to date reliably predict response to anti-Vascular Endothelial Growth Factor (VEGF) therapies. There are inconsistent data on the role of ERCC1, BRCA, Beta tubulin III, RRM1, K-RAS, or TP-53 in treatment decisions. These tests should not be routinely used in selecting treatment at this time, whereas EML4/ALK translocations predict responses to specific targeted agents, the optimal assessment of this molecular abnormality has yet to be established. Personalized care of patients with NSCLC based on biomarkers is increasingly important to both clinical practice and research

Prediction of residual metabolic activity after treatment in NSCLC patients

International Nuclear Information System (INIS)

Rios Velazquez, Emmanuel; Aerts, Hugo J.W.L.; Oberije, Cary; Ruysscher, Dirk De; Lambin, Philippe

2010-01-01

Purpose. Metabolic response assessment is often used as a surrogate of local failure and survival. Early identification of patients with residual metabolic activity is essential as this enables selection of patients who could potentially benefit from additional therapy. We report on the development of a pre-treatment prediction model for metabolic response using patient, tumor and treatment factors. Methods. One hundred and one patients with inoperable NSCLC (stage I-IV), treated with 3D conformal radical (chemo)-radiotherapy were retrospectively included in this study. All patients received a pre and post-radiotherapy fluorodeoxyglucose positron emission tomography-computed tomography FDG-PET-CT scan. The electronic medical record system and the medical patient charts were reviewed to obtain demographic, clinical, tumor and treatment data. Primary outcome measure was examined using a metabolic response assessment on a post-radiotherapy FDG-PET-CT scan. Radiotherapy was delivered in fractions of 1.8 Gy, twice a day, with a median prescribed dose of 60 Gy. Results. Overall survival was worse in patients with residual metabolic active areas compared with the patients with a complete metabolic response (p=0.0001). In univariate analysis, three variables were significantly associated with residual disease: larger primary gross tumor volume (GTVprimary, p=0.002), higher pre-treatment maximum standardized uptake value (SUV max , p=0.0005) in the primary tumor and shorter overall treatment time (OTT, p=0.046). A multivariate model including GTVprimary, SUV max , equivalent radiation dose at 2 Gy corrected for time (EQD2, T) and OTT yielded an area under the curve assessed by the leave-one-out cross validation of 0.71 (95% CI, 0.65-0.76). Conclusion. Our results confirmed the validity of metabolic response assessment as a surrogate of survival. We developed a multivariate model that is able to identify patients at risk of residual disease. These patients may benefit from

Combined effects of EGFR tyrosine kinase inhibitors and vATPase inhibitors in NSCLC cells

Energy Technology Data Exchange (ETDEWEB)

Jin, Hyeon-Ok [KIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of); Hong, Sung-Eun [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of); Kim, Chang Soon [Department of Microbiological Engineering, Kon-Kuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 143–701 (Korea, Republic of); Park, Jin-Ah; Kim, Jin-Hee; Kim, Ji-Young; Kim, Bora [KIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of); Chang, Yoon Hwan; Hong, Seok-Il; Hong, Young Jun [Department of Laboratory Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of); Park, In-Chul, E-mail: parkic@kirams.re.kr [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of); Lee, Jin Kyung, E-mail: jklee@kirams.re.kr [KIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of); Department of Laboratory Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of)

2015-08-15

Despite excellent initial clinical responses of non-small cell lung cancer (NSCLC) patients to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), many patients eventually develop resistance. According to a recent report, vacuolar H + ATPase (vATPase) is overexpressed and is associated with chemotherapy drug resistance in NSCLC. We investigated the combined effects of EGFR TKIs and vATPase inhibitors and their underlying mechanisms in the regulation of NSCLC cell death. We found that combined treatment with EGFR TKIs (erlotinib, gefitinib, or lapatinib) and vATPase inhibitors (bafilomycin A1 or concanamycin A) enhanced synergistic cell death compared to treatments with each drug alone. Treatment with bafilomycin A1 or concanamycin A led to the induction of Bnip3 expression in an Hif-1α dependent manner. Knock-down of Hif-1α or Bnip3 by siRNA further enhanced cell death induced by bafilomycin A1, suggesting that Hif-1α/Bnip3 induction promoted resistance to cell death induced by the vATPase inhibitors. EGFR TKIs suppressed Hif-1α and Bnip3 expression induced by the vATPase inhibitors, suggesting that they enhanced the sensitivity of the cells to these inhibitors by decreasing Hif-1α/Bnip3 expression. Taken together, we conclude that EGFR TKIs enhance the sensitivity of NSCLC cells to vATPase inhibitors by decreasing Hif-1α/Bnip3 expression. We suggest that combined treatment with EGFR TKIs and vATPase inhibitors is potentially effective for the treatment of NSCLC. - Highlights: • Co-treatment with EGFR TKIs and vATPase inhibitors induces synergistic cell death • EGFR TKIs enhance cell sensitivity to vATPase inhibitors via Hif-1α downregulation • Co-treatment of these inhibitors is potentially effective for the treatment of NSCLC.

[Significance and mechanism of MSCT perfusion scan on differentiation of NSCLC].

Science.gov (United States)

Liu, Jin-Kang; Hu, Cheng-Ping; Zhou, Mo-Ling; Zhou, Hui; Xiong, Zeng; Xia, Yu; Chen, Wei

2009-06-01

To determine the significance of MSCT perfusion scan on differentiation of NSCLC and to investigate its possible mechanisms. Forty four NSCLC patients underwent CT perfusion scan by MSCT. Among them, 22 cases were selected to detected the two-dimensional tumor microvascular architecture phenotype (2D-TMAP), the relationships between CT perfusion parameters (BF, BV, PEI, TIP), and the differentiation of NSCLC were analysed by using the correlation analysis and trend test. Spearman correlation analysis was used to study the relationships between CT perfusion parameters, differentiation, and 2D-TMAP. The total BF, BV and PEI decreased with decreasing differentiation of NSCLC (P<0.05). The total PEI showed a positive correlation with the total MVD (P<0.05). There were negative correlations between the surrounding area BF, the total BF, BV, and PEI, the uncomplete lumen of the surrounding area MVD, and expression of PCNA, respectively (P<0.05). There were positive correlations between degree of differentiation and the uncomplete lumen of the surrounding area MVD (P<0.05). It was the same as degree of differentiation and expression of PCNA, VEGF, respectively. There were positive correlations between the uncomplete lumen of the surrounding area MVD and expression of VEGF, ephrinB2, EphB4, and PCNA, respectively (P<0.05). Perfusion parameters reflect the difference of density of vassels with mature functional lumen. Careful evaluation of the differences of blood flow pattern in pulmonary space-occupying lesions by MSCT perfusion scan can be used to identify the degree of NSCLC differentiation.

Developing and Validating a Survival Prediction Model for NSCLC Patients Through Distributed Learning Across 3 Countries.

Science.gov (United States)

Jochems, Arthur; Deist, Timo M; El Naqa, Issam; Kessler, Marc; Mayo, Chuck; Reeves, Jackson; Jolly, Shruti; Matuszak, Martha; Ten Haken, Randall; van Soest, Johan; Oberije, Cary; Faivre-Finn, Corinne; Price, Gareth; de Ruysscher, Dirk; Lambin, Philippe; Dekker, Andre

2017-10-01

Tools for survival prediction for non-small cell lung cancer (NSCLC) patients treated with chemoradiation or radiation therapy are of limited quality. In this work, we developed a predictive model of survival at 2 years. The model is based on a large volume of historical patient data and serves as a proof of concept to demonstrate the distributed learning approach. Clinical data from 698 lung cancer patients, treated with curative intent with chemoradiation or radiation therapy alone, were collected and stored at 2 different cancer institutes (559 patients at Maastro clinic (Netherlands) and 139 at Michigan university [United States]). The model was further validated on 196 patients originating from The Christie (United Kingdon). A Bayesian network model was adapted for distributed learning (the animation can be viewed at https://www.youtube.com/watch?v=ZDJFOxpwqEA). Two-year posttreatment survival was chosen as the endpoint. The Maastro clinic cohort data are publicly available at https://www.cancerdata.org/publication/developing-and-validating-survival-prediction-model-nsclc-patients-through-distributed, and the developed models can be found at www.predictcancer.org. Variables included in the final model were T and N category, age, performance status, and total tumor dose. The model has an area under the curve (AUC) of 0.66 on the external validation set and an AUC of 0.62 on a 5-fold cross validation. A model based on the T and N category performed with an AUC of 0.47 on the validation set, significantly worse than our model (PLearning the model in a centralized or distributed fashion yields a minor difference on the probabilities of the conditional probability tables (0.6%); the discriminative performance of the models on the validation set is similar (P=.26). Distributed learning from federated databases allows learning of predictive models on data originating from multiple institutions while avoiding many of the data-sharing barriers. We believe that

Clinical features and treatment outcome of non-small cell lung cancer (NSCLC) patients with uncommon or complex epidermal growth factor receptor (EGFR) mutations

Science.gov (United States)

Fassan, Matteo; Indraccolo, Stefano; Calabrese, Fiorella; Favaretto, Adolfo; Bonanno, Laura; Polo, Valentina; Zago, Giulia; Lunardi, Francesca; Attili, Ilaria; Pavan, Alberto; Rugge, Massimo; Guarneri, Valentina; Conte, PierFranco; Pasello, Giulia

2017-01-01

Introduction Tyrosine-kinase inhibitors (TKIs) represent the best treatment for advanced non-small cell lung cancer (NSCLC) with common exon 19 deletion or exon 21 epidermal growth factor receptor mutation (EGFRm). This is an observational study investigating epidemiology, clinical features and treatment outcome of NSCLC cases harbouring rare/complex EGFRm. Results Among 764 non-squamous NSCLC cases with known EGFRm status, 26(3.4%) harboured rare/complex EGFRm. Patients receiving first-line TKIs (N = 17) achieved median Progression Free Survival (PFS) and Overall Survival (OS) of 53 (IC 95%, 2–105) and 84 (CI 95%, 27–141) weeks respectively, without significant covariate impact. Response Rate and Disease Control Rate (DCR) were 47% and 65%, respectively. Uncommon exon 19 mutations achieved longer OS and PFS and higher DCR compared with exon 18 and 20 mutations. No additional gene mutation was discovered by MassARRAY analysis. TKIs were globally well tolerated. Materials and methods A retrospective review of advanced non-squamous NSCLC harbouring rare/complex EGFRm referred to our Center between 2010 and 2015 was performed. Additional molecular pathways disregulation was explored in selected cases, through MassARRAY analysis. Conclusions Peculiar clinical features and lower TKIs sensitivity of uncommon/complex compared with common EGFRm were shown. Exon 19 EGFRm achieved the best TKIs treatment outcome, while the optimal treatment of exon 18 and 20 mutations should be further clarified. PMID:28427238

Second-Line Therapy for Advanced NSCLC.

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Weiss, Jared M; Stinchcombe, Thomas E

2013-01-01

Most patients with lung cancer have non-small cell lung cancer (NSCLC) subtype and have advanced disease at the time of diagnosis. Improvements in both first-line and subsequent therapies are allowing longer survival and enhanced quality of life for these patients. The median overall survival observed in many second-line trials is approximately 9 months, and many patients receive further therapy after second-line therapy. The cytotoxic agents pemetrexed and docetaxel and the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib are standard second-line therapies. For patients with EGFR mutation, a TKI is the favored second-line therapy if not already used in first-line therapy. For patients without the EGFR mutation, TKIs are an option, but many oncologists favor cytotoxic therapy. The inhibitor of the EML4/ALK fusion protein, crizotinib, has recently become a standard second-line treatment for patients with the gene rearrangement and has promise for patients with the ROS1 rearrangement.

Metabolic tumor burden as marker of outcome in advanced EGFR wild-type NSCLC patients treated with erlotinib

DEFF Research Database (Denmark)

Winther-Larsen, Anne; Fledelius, Joan; Sorensen, Boe Sandahl

2016-01-01

OBJECTIVES: Accurate estimation of the prognosis of advanced non-small cell lung cancer (NSCLC) patients is essential before initiation of palliative treatment; especially in the second and third-line setting. This study was conducted in order to evaluate tumor burden measured on an 2'-deoxy-2...... a prospectively collected cohort. An F-18-FDG-PET/CT scan was conducted prior to erlotinib treatment and tumor burden was measured in terms of metabolic tumor volume (MTV) and total lesion glycolysis (TLG). Median values of MTV and TLG were used for dichotomization of patients. Survival outcome was compared...... between groups.RESULTS: MTV and TLG could be measured in 49 patients. High values of MTV and TLG were significantly correlated with shorter PFS (p

Promoter methylation of APC and RAR-β genes as prognostic markers in non-small cell lung cancer (NSCLC).

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Feng, Hongxiang; Zhang, Zhenrong; Qing, Xin; Wang, Xiaowei; Liang, Chaoyang; Liu, Deruo

2016-02-01

Aberrant promoter hypermethylations of tumor suppressor genes are promising markers for lung cancer diagnosis and prognosis. The purpose of this study was to determine methylation status at APC and RAR-β promoters in primary NSCLC, and whether they have any relationship with survival. APC and RAR-β promoter methylation status were determined in 41 NSCLC patients using methylation specific PCR. APC promoter methylation was detectable in 9 (22.0%) tumor samples and 6 (14.6%) corresponding non-tumor samples (P=0.391). RAR-β promoter methylation was detectable in 13 (31.7%) tumor samples and 4 (9.8%) corresponding non-tumor samples (P=0.049) in the NSCLC patients. APC promoter methylation was found to be associated with T stage (P=0.046) and nodal status (P=0.019) in non-tumor samples, and with smoking (P=0.004) in tumor samples. RAR-β promoter methylation was found associated with age (P=0.031) in non-tumor samples and with primary tumor site in tumor samples. Patients with APC promoter methylation in tumor samples showed significantly longer survival than patients without it (Log-rank P=0.014). In a multivariate analysis of prognostic factors, APC methylation in tumor samples was an independent prognostic factor (P=0.012), as were N1 positive lymph node number (P=0.025) and N2 positive lymph node number (P=0.06). Our study shows that RAR-β methylation detected in lung tissue may be used as a predictive marker for NSCLC diagnosis and that APC methylation in tumor sample may be a useful marker for superior survival in NSCLC patients. Copyright © 2015. Published by Elsevier Inc.

Systematic mediastinal lymphadenectomy or mediastinal lymph node sampling in patients with pathological stage I NSCLC: a meta-analysis.

Science.gov (United States)

Dong, Siyuan; Du, Jiang; Li, Wenya; Zhang, Shuguang; Zhong, Xinwen; Zhang, Lin

2015-02-01

To evaluate the evidence comparing systematic mediastinal lymphadenectomy (SML) and mediastinal lymph node sampling (MLS) in the treatment of pathological stage I NSCLC using meta-analytical techniques. A literature search was undertaken until January 2014 to identify the comparative studies evaluating 1-, 3-, and 5-year survival rates. The pooled odds ratios (OR) and the 95 % confidence intervals (95 % CI) were calculated with either the fixed or random effect models. One RCT study and four retrospective studies were included in our meta-analysis. These studies included a total of 711 patients: 317 treated with SML, and 394 treated with MLS. The SML and the MLS did not demonstrate a significant difference in the 1-year survival rate. There were significant statistical differences between the 3-year (P = 0.03) and 5-year survival rates (P = 0.004), which favored SML. This meta-analysis suggests that in pathological stage I NSCLC, the MLS can get the similar outcome to the SML in terms of 1-year survival rate. However, the SML is superior to MLS in terms of 3- and 5-year survival rates.

Radiotherapy treatment planning for patients with non-small cell lung cancer using positron emission tomography (PET)

International Nuclear Information System (INIS)

Erdi, Yusuf E.; Rosenzweig, Kenneth; Erdi, Alev K.; Macapinlac, Homer A.; Hu, Yu-Chi; Braban, Louise E.; Humm, John L.; Squire, Olivia D.; Chui, Chen-Shou; Larson, Steven M.; Yorke, Ellen D.

2002-01-01

Purpose: Many patients with non-small cell lung cancer (NSCLC) receive external beam radiation therapy as part of their treatment. Three-dimensional conformal radiation therapy (3DCRT) commonly uses computed tomography (CT) to accurately delineate the target lesion and normal tissues. Clinical studies, however, indicate that positron emission tomography (PET) has higher sensitivity than CT in detecting and staging of mediastinal metastases. Imaging with fluoro-2-deoxyglucose (FDG) PET in conjunction with CT, therefore, can improve the accuracy of lesion definition. In this pilot study, we investigated the potential benefits of incorporating PET data into the conventional treatment planning of NSCLC. Case-by-case, we prospectively analyzed planning target volume (PTV) and lung toxicity changes for a cohort of patients. Materials and methods: We have included 11 patients in this study. They were immobilized in the treatment position and CT simulation was performed. Following CT simulation, PET scanning was performed in the treatment position using the same body cast that was produced for CT simulation and treatment. The PTV, along with the gross target volume (GTV) and normal organs, was first delineated using the CT data set. The CT and PET transmission images were then registered in the treatment planning system using either manual or automated methods, leading to consequent registration of the CT and emission images. The PTV was then modified using the registered PET emission images. The modified PTV is seen simultaneously on both CT and PET images, allowing the physician to define the PTV utilizing the information from both data sets. Dose-volume histograms (DVHs) for lesion and normal organs were generated using both CT-based and PET+CT-based treatment plans. Results: For all patients, there was a change in PTV outline based on CT images versus CT/PET fused images. In seven out of 11 cases, we found an increase in PTV volume (average increase of 19%) to

The incorporation of SPECT functional lung imaging into inverse radiotherapy planning for non-small cell lung cancer

International Nuclear Information System (INIS)

Christian, Judith A.; Partridge, Mike; Nioutsikou, Elena; Cook, Gary; McNair, Helen A.; Cronin, Bernadette; Courbon, Frederic; Bedford, James L.; Brada, Michael

2005-01-01

Background and purpose: Patients with non-small cell lung cancer (NSCLC) often have inhomogeneous lung perfusion. Radiotherapy planning computed tomography (CT) scans have been accurately co-registered with lung perfusion single photon emission computed tomography (SPECT) scans to design radiotherapy treatments which limit dose to healthy 'perfused' lung. Patients and methods: Patients with localised NSCLC had CT and SPECT scans accurately co-registered in the planning system. The SPECT images were used to define a volume of perfused 'functioning' lung (FL). Inverse planning software was used to create 3D-conformal plans, the planning objective being either to minimise the dose to whole lungs (WL) or to minimise the dose to FL. Results: Four plans were created for each of six patients. The mean difference in volume between WL and FL was 1011.7 cm 3 (range 596.2-1581.1 cm 3 ). One patient with bilateral upper lobe perfusion deficits had a 16% reduction in FLV 2 (the percentage volume of functioning lung receiving ≥20 Gy). The remaining patients had inhomogeneous perfusion deficits such that inverse planning was not able to sufficiently optimise beam angles to avoid functioning lung. Conclusion: SPECT perfusion images can be accurately co-registered with radiotherapy planning CT scans and may be helpful in creating treatment plans for patients with large perfusion deficits

Superiority of conventional intensity-modulated radiotherapy over helical tomotherapy in locally advanced non-small cell lung cancer. A comparative plan analysis

Energy Technology Data Exchange (ETDEWEB)

Song, C. [National Cancer Center, Research Institute and Hospital, Goyang (Korea, Republic of). Proton Therapy Center; Seoul National Univ. College of Medicine (Korea, Republic of). Dept. of Radiation Oncology; Pyo, H.; Kim, J. [Sungkyunkwan Univ. School of Medicine, Samsung Medical Center, Seoul (Korea, Republic of). Dept. of Radiation Oncology; Lim, Y.K.; Kim, D.W.; Cho, K.H. [National Cancer Center, Research Institute and Hospital, Goyang (Korea, Republic of). Proton Therapy Center; Kim, W.C. [Inha Univ. School of Medicine, Incheon (Korea, Republic of). Dept. of Radiation Oncology; Kim, H.J. [Seoul National Univ. College of Medicine (Korea, Republic of). Dept. of Radiation Oncology

2012-10-15

Purpose: To compare helical tomotherapy (HT) and conventional intensity-modulated radiotherapy (IMRT) using a variety of dosimetric and radiobiologic indexes in patients with locally advanced non-small cell lung cancer (LA-NSCLC). Patients and methods: A total of 20 patients with LA-NSCLC were enrolled. IMRT plans with 4-6 coplanar beams and HT plans were generated for each patient. Dose distributions and dosimetric indexes for the tumors and critical structures were computed for both plans and compared. Results: Both modalities created highly conformal plans. They did not differ in the volumes of lung exposed to > 20 Gy of radiation. The average mean lung dose, volume receiving {>=} 30 Gy, and volume receiving {>=} 10 Gy in HT planning were 18.3 Gy, 18.5%, and 57.1%, respectively, compared to 19.4 Gy, 25.4%, and 48.9%, respectively, with IMRT (p = 0.004, p < 0.001, and p < 0.001). The differences between HT and IMRT in lung volume receiving {>=} 10-20 Gy increased significantly as the planning target volume (PTV) increased. For 6 patients who had PTV greater than 700 cm{sup 3}, IMRT was superior to HT for 5 patients in terms of lung volume receiving {>=} 5-20 Gy. The integral dose to the entire thorax in HT plans was significantly higher than in IMRT plans. Conclusion: HT gave significantly better control of mean lung dose and volume receiving {>=} 30-40 Gy, whereas IMRT provided better control of the lung volume receiving {>=} 5-15 Gy and the integral dose to entire thorax. In most patients with PTV greater than 700 cm{sup 3}, IMRT was superior to HT in terms of lung volume receiving {>=} 5-20 Gy. It is therefore advised that caution should be exercised when planning LA-NSCLC using HT. (orig.)

Impact of 18FDG-PET/CT on biological target volume (BTV) definition for treatment planning for non-small cell lung cancer patients

International Nuclear Information System (INIS)

Devic, Slobodan; Tomic, Nada; Faria, Sergio; Dean, Geoffrey; Lisbona, Robert; Parker, William; Kaufman, Chris; Podgorsak, Ervin B.

2007-01-01

This work represents our effort to test feasibility of FDG-based PET/CT on target volume delineation in radiotherapy treatment planning of NSCLC patients. Different methods have been developed to enable more precise target outlining using PET: Qualitative Visual Method, CTV=2.5 SUV units, linear SUV threshold function method, and CTV=40% Iso of Maximum Uptake Value. We are proposing reconstruction of three biological target volumes: necrotic BTV (same as PTV created by radiation oncologist using CT data), proliferating BTV (based on PET signal to background ratio 1:3) and hypoxic BTV (based on PET signal to background ratio of 1:19). Two IMRT plans were created and compared to the conventional treatment plan: 'conservative' IMRT plan delivers 52.5 Gy to the necrotic BTV and 65 Gy to the hypoxic BTV; 'radical' IMRT plan delivers 30 Gy to necrotic BTV, 52.5 Gy to proliferating BTV and 65 Gy to hypoxic BTV. Use of BTVs in IMRT plans is attractive because it increases dose to targets considered to need higher doses. It reduces considerably dose to heart and spinal cord, organs considered to limit dose escalation approaches in NSCLC treatment. 'Conservative' IMRT approach can be understood as a PET/CT-based concomitant boost to the tumor expressing the highest FDG uptake. 'Radical' plan implies deviation from the traditional uniform dose target coverage approach, with the intention of achieving better surrounding tissue sparing and ultimately allowing for dose escalation protocols relying on biologically based treatment planning

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

Multicenter Phase II Study Evaluating Two Cycles of Docetaxel, Cisplatin and Cetuximab as Induction Regimen Prior to Surgery in Chemotherapy-Naive Patients with NSCLC Stage IB-IIIA (INN06-Study.

Directory of Open Access Journals (Sweden)

Wolfgang Hilbe

Full Text Available Different strategies for neoadjuvant chemotherapy in patients with early stage NSCLC have already been evaluated. The aim of this study was to evaluate the tolerability and efficacy of a chemoimmunotherapy when limited to two cycles.Between 01/2007 and 03/2010 41 patients with primarily resectable NSCLC stage IB to IIIA were included. Treatment consisted of two cycles cisplatin (40 mg/m2 d1+2 and docetaxel (75 mg/m2 d1 q3 weeks, accompanied by the administration of cetuximab (400 mg/m2 d1, then 250 mg weekly. The primary endpoint was radiological response according to RECIST.40 patients were evaluable for toxicity, 39 for response. The main grade 3/4 toxicities were: neutropenia 25%, leucopenia 11%, febrile neutropenia 6%, nausea 8% and rash 8%. 20 patients achieved a partial response, 17 a stable disease, 2 were not evaluable. 37 patients (95% underwent surgery and in three of them a complete pathological response was achieved. At a median follow-up of 44.2 months, 41% of the patients had died, median progression-free survival was 22.5 months.Two cycles of cisplatin/ docetaxel/ cetuximab showed promising efficacy in the neoadjuvant treatment of early-stage NSCLC and rapid operation was possible in 95% of patients. Toxicities were manageable and as expected.EU Clinical Trials Register; Eudract-Nr: 2006-004639-31.

Loss of tumour-specific ATM protein expression is an independent prognostic factor in early resected NSCLC.

Science.gov (United States)

Petersen, Lars F; Klimowicz, Alexander C; Otsuka, Shannon; Elegbede, Anifat A; Petrillo, Stephanie K; Williamson, Tyler; Williamson, Chris T; Konno, Mie; Lees-Miller, Susan P; Hao, Desiree; Morris, Don; Magliocco, Anthony M; Bebb, D Gwyn

2017-06-13

Ataxia-telangiectasia mutated (ATM) is critical in maintaining genomic integrity. In response to DNA double-strand breaks, ATM phosphorylates downstream proteins involved in cell-cycle checkpoint arrest, DNA repair, and apoptosis. Here we investigate the frequency, and influence of ATM deficiency on outcome, in early-resected non-small cell lung cancer (NSCLC). Tissue microarrays, containing 165 formalin-fixed, paraffin-embedded resected NSCLC tumours from patients diagnosed at the Tom Baker Cancer Centre, Calgary, Canada, between 2003 and 2006, were analyzed for ATM expression using quantitative fluorescence immunohistochemistry. Both malignant cell-specific ATM expression and the ratio of ATM expression within malignant tumour cells compared to that in the surrounding tumour stroma, defined as the ATM expression index (ATM-EI), were measured and correlated with clinical outcome. ATM loss was identified in 21.8% of patients, and was unaffected by clinical pathological variables. Patients with low ATM-EI tumours had worse survival outcomes compared to those with high ATM-EI (p ATM-deficient patients may derive greater benefit from guideline-recommended adjuvant chemotherapy following surgical resection. Taken together, these results indicate that ATM loss seems to be an early event in NSCLC carcinogenesis and is an independent prognostic factor associated with worse survival in stage II/III patients.

Prognostic value and molecular correlates of a CT image-based quantitative pleural contact index in early stage NSCLC

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Lee, Juheon; Cui, Yi; Li, Bailiang; Wu, Jia; Gensheimer, Michael F. [Stanford University School of Medicine, Department of Radiation Oncology, Stanford, CA (United States); Sun, Xiaoli [First Affiliated Hospital of Zhejiang University, Radiotherapy Department, Hangzhou, Zhejiang (China); Li, Dengwang [Stanford University School of Medicine, Department of Radiation Oncology, Stanford, CA (United States); Shandong Normal University, Shandong Province Key Laboratory of Medical Physics and Image Processing Technology, Institute of Biomedical Sciences, School of Physics and Electronics, Jinan Shi (China); Loo, Billy W.; Li, Ruijiang [Stanford University School of Medicine, Department of Radiation Oncology, Stanford, CA (United States); Stanford University School of Medicine, Stanford Cancer Institute, Stanford, CA (United States); Diehn, Maximilian [Stanford University School of Medicine, Department of Radiation Oncology, Stanford, CA (United States); Stanford University School of Medicine, Stanford Cancer Institute, Stanford, CA (United States); Stanford University School of Medicine, Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA (United States)

2018-02-15

To evaluate the prognostic value and molecular basis of a CT-derived pleural contact index (PCI) in early stage non-small cell lung cancer (NSCLC). We retrospectively analysed seven NSCLC cohorts. A quantitative PCI was defined on CT as the length of tumour-pleura interface normalised by tumour diameter. We evaluated the prognostic value of PCI in a discovery cohort (n = 117) and tested in an external cohort (n = 88) of stage I NSCLC. Additionally, we identified the molecular correlates and built a gene expression-based surrogate of PCI using another cohort of 89 patients. To further evaluate the prognostic relevance, we used four datasets totalling 775 stage I patients with publically available gene expression data and linked survival information. At a cutoff of 0.8, PCI stratified patients for overall survival in both imaging cohorts (log-rank p = 0.0076, 0.0304). Extracellular matrix (ECM) remodelling was enriched among genes associated with PCI (p = 0.0003). The genomic surrogate of PCI remained an independent predictor of overall survival in the gene expression cohorts (hazard ratio: 1.46, p = 0.0007) adjusting for age, gender, and tumour stage. CT-derived pleural contact index is associated with ECM remodelling and may serve as a noninvasive prognostic marker in early stage NSCLC. (orig.)

A single-arm, multicenter, safety-monitoring, phase IV study of icotinib in treating advanced non-small cell lung cancer (NSCLC).

Science.gov (United States)

Hu, Xingsheng; Han, Baohui; Gu, Aiqin; Zhang, Yiping; Jiao, Shun Chang; Wang, Chang-Li; He, Jintao; Jia, Xueke; Zhang, Li; Peng, Jiewen; Wu, Meina; Ying, Kejing; Wang, Junye; Ma, Kewei; Zhang, Shucai; You, Changxuan; Tan, Fenlai; Wang, Yinxiang; Ding, Lieming; Sun, Yan

2014-11-01

The phase 3 ICOGEN trial established the non-inferiority of icotinib to gefitinib in terms of progression-free survival (PFS) in non-small cell lung cancer (NSCLC) patients, and this led to the approval of icotinib for NSCLC by the China Food and Drug Administration. A phase 4 study was conducted to assess the safety and efficacy of icotinib in a broad range of patients with advanced NSCLC across China. This study retrospectively analyzed data from unresectable, recurrent, and/or advanced NSCLC patients who received oral icotinib 125 mg three times per day. The primary endpoint was safety. The secondary endpoints included objective response rate (ORR) and disease control rate (DCR), which were investigated overall and in subgroups such as patients with an EGFR mutation and elderly patients. Between August, 2011 and August, 2012, a total of 6087 advanced NSCLC patients were registered in this study, of which 5549 were evaluable for safety and tumor response. The median age was 63 years (range 21-95 years), and 1571 (28.3%) patients were over the age of 70. The majority of patients were non-smokers, and had adenocarcinoma and stage IV disease. The overall incidence of adverse drug reactions (ADRs) of any grade was 31.5%. The most common ADRs included rash (17.4%) and diarrhea (8.5%), and three patients experienced interstitial lung disease (ILD). The ORR and DCR were 30.0% and 80.6%, respectively, for the overall population, and 33.4% and 81.2%, 30.3% and 80.3%, and 30.4% and 89.3%, for first-line, second-line, and third-line or multiple line subsets, respectively. In 665 EGFR-mutated patients who were evaluable for tumor response, the ORR and DCR were 49.2% (327/665) and 92.3% (614/665), respectively. The data from over 6000 patients was consistent with the results of the ICOGEN study. Icotinib demonstrated a favorable toxicity profile and efficacy in the routine clinical setting. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

FDG PET evaluation of therapeutic response and toxicity after radiotherapy for NSCLC

International Nuclear Information System (INIS)

Hicks, R.J.; MacManus, M.P.; Matthews, J.P.; Rischin, D.; Binns, D.; McKenzie, A.F.; Ball, D.L.

2002-01-01

Full text: Positron emission tomography (PET) using F-18 fluorodeoxyglucose (FDG) is recognised for staging and therapeutic planning of patients with non-small cell carcinoma of the lung (NSCLC). The potential for this technique to be used in the assessment of therapeutic response has also been highlighted but may be limited by false positive results due to inflammatory response, particularly early after radiotherapy (RT). To evaluate the utility of FEX PET for therapeutic monitoring early (<12 weeks) after completion of radical RT we prospectively evaluated metabolic response and radiation toxicity using a standardised scoring system in 73 consecutive patients. All 73 had evaluable PET scans but 6 of the CT scan results were considered non-evaluable for therapeutic response using WHO criteria. PET therapeutic response category differed from that by CT in 40/67 (60%) cases and in 80% of such cases suggested a more marked response than suggested by CT (p 0.0002). Multifactor analysis including PET response, CT response, performance status, weight loss and stage revealed that PET response was the only significant predictor of survival (p 0.0001). Radiation toxicity scores were inversely related to therapeutic response on both PET (p = 0.022) and CT (p =0.029). In particular, more severe (grade 2 or 3) radiotoxicity scores on PET were associated with a greater proportion of partial or complete responses on both PET and CT than were lower (grade 0 and 1) scores (p =0.0044 and 0.041 respectively) consistent with the known relationship between the radiosensitivity of normal host and tumoral tissues. Early after completion of radiotherapy for NSCLC, PET response provides better prognostic stratification than CT response. PET can also identify typical radiation toxicity changes which are associated with response to treatment. Copyright (2002) The Australian and New Zealand Society of Nuclear Medicine Inc

SU-F-T-451: Doses to Organs-At-Risk in the Presence and Absence of a 1.5 T Magnetic Field for NSCLC Patients Undergoing SABR

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Al-Ward, S; Kim, A; McCann, C; Ruschin, M; Cheung, P; Sahgal, A; Keller, B [Sunnybrook Health Sciences Centre, Toronto, Ontario (Canada)

2016-06-15

Purpose: To determine whether the electron return effect (ERE) has deleterious effects on lung SABR plans optimized in the presence of an orthogonal 1.5 T magnetic field. Methods: Data from five NSCLC-SABR patients were used. The Dose was modeled with a 2.5 mm dose grid in the presence and absence of a magnetic field using the Monaco (Elekta) TPS with the Monte Carlo GPUMCD (v5.1) algorithm. For each patient, two plans were generated, one using our conventional Elekta Agility linac beam model and another using the Elekta MRI Linac (MRL) model. Both plans were generated on the average CT using similar dose constraints and a 5 mm PTV. The optimization was performed using our clinic’s planning criteria, with normalization of the targets such that their V99% was equal to 99%. The OAR DVHs were compared for each patient. Results: The DVH plots revealed that there were limited differences when optimizing plans in the presence or absence of the magnetic field. The mean of the absolute differences, between the two planning types, in the equivalent uniform doses (EUDs) for the OARs were: 0.3 Gy (range of 0.0 - 1.0 Gy) for the esophagus, 0.6 Gy (range of 0.1 – 1.9 Gy) for the heart, 0.5 Gy (range of 0.2 – 0.8 Gy) for the lungs, and 0.6 Gy (range of 0.2 – 1.5 Gy) for the spinal canal. Regarding the maximum doses to the serial organs, the mean of the differences were 3.0 Gy (esophagus) and 0.9 Gy (spinal canal). No trends in the differences were observed. Conclusion: This study has demonstrated that there were no major differences between plans optimized using a conventional linac and those optimized using an MRI linac with an orthogonal 1.5 T magnetic field. This is attributed to the consideration of the ERE in the optimization. This project was made possible with the financial support of Elekta.

Open-label, randomized study of individualized, pharmacokinetically (PK)-guided dosing of paclitaxel combined with carboplatin or cisplatin in patients with advanced non-small-cell lung cancer (NSCLC).

Science.gov (United States)

Joerger, M; von Pawel, J; Kraff, S; Fischer, J R; Eberhardt, W; Gauler, T C; Mueller, L; Reinmuth, N; Reck, M; Kimmich, M; Mayer, F; Kopp, H-G; Behringer, D M; Ko, Y-D; Hilger, R A; Roessler, M; Kloft, C; Henrich, A; Moritz, B; Miller, M C; Salamone, S J; Jaehde, U

2016-10-01

Variable chemotherapy exposure may cause toxicity or lack of efficacy. This study was initiated to validate pharmacokinetically (PK)-guided paclitaxel dosing in patients with advanced non-small-cell lung cancer (NSCLC) to avoid supra- or subtherapeutic exposure. Patients with newly diagnosed, advanced NSCLC were randomly assigned to receive up to 6 cycles of 3-weekly carboplatin AUC 6 or cisplatin 80 mg/m(2) either with standard paclitaxel at 200 mg/m(2) (arm A) or PK-guided dosing of paclitaxel (arm B). In arm B, initial paclitaxel dose was adjusted to body surface area, age, sex, and subsequent doses were guided by neutropenia and previous-cycle paclitaxel exposure [time above a plasma concentration of 0.05 µM (Tc>0.05)] determined from a single blood sample on day 2. The primary end point was grade 4 neutropenia; secondary end points included neuropathy, radiological response, progression-free survival (PFS) and overall survival (OS). Among 365 patients randomly assigned, grade 4 neutropenia was similar in both arms (19% versus 16%; P = 0.10). Neuropathy grade ≥2 (38% versus 23%, P PK-guided dosing of paclitaxel does not improve severe neutropenia, but reduces paclitaxel-associated neuropathy and thereby improves the benefit-risk profile in patients with advanced NSCLC. NCT01326767 (https://clinicaltrials.gov/ct2/show/NCT01326767). © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Efficacy of sorafenib in BRAF-mutated non-small-cell lung cancer (NSCLC) and no response in synchronous BRAF wild type-hepatocellular carcinoma: a case report

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Casadei Gardini, Andrea; Chiadini, Elisa; Faloppi, Luca; Marisi, Giorgia; Delmonte, Angelo; Scartozzi, Mario; Loretelli, Cristian; Lucchesi, Alessandro; Oboldi, Devil; Dubini, Alessandra; Frassineti, Giovanni Luca; Ulivi, Paola

2016-01-01

Sorafenib is a multi-targeted kinase inhibitor with a demonstrated activity in renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC), and it is currently used for the treatment of these pathologies. Ongoing clinical trials are studying its activity in other malignancies, such as non-small-cell lung cancer (NSCLC). However, no biological marker is known to define either the sensitivity or resistance to the drug. Here we report a case of a patient with two synchronous tumors, HCC and NSCLC, with metastases in the contralateral lung and bone. The patient was treated with gemcitabine as first line, with a resulting progressive disease after two months, and then with sorafenib at standard dosage in the second line setting. After 6 months of treatment CT scan showed a partial response in the primary lesion of the lung, complete response of the metastasis in the contralateral lung, and stability of HCC. The patient had progression in the lung, liver and bone after 13 months of therapy. A molecular characterization of NSCLC and HCC lesions was performed, revealing a BRAF exon 11 mutation (G469V) only in NSCLC. We hypothesize that the response observed in NSCLC lesions could be due to the presence of BRAF mutation, and that this alteration could be responsible in determining sorafenib sensitivity. Results observed in this case encourage further research on the activity of sorafenib in both HCC and NSCLC, based on the presence of BRAF mutation. This could lead to a selection of HCC patients to be treated with this drug, and could help identify a novel treatment strategy for BRAF-mutated NSCLC patients

Detection of EGFR somatic mutations in non-small cell lung cancer (NSCLC) using a novel mutant-enriched liquidchip (MEL) technology.

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Zhang, Li; Yang, Huiyi; Zhao, Yanwei; Liu, Wenchao; Wu, Shiyang; He, Jiaying; Luo, Xiaodi; Zhu, Zeyao; Xu, Jiasen; Zhou, Qinghua; Ren-Heidenreich, Lifen

2012-09-01

We have developed and standardized a novel technology, mutant-enriched liquidchip (MEL), for clinical detection of EGFR mutations. The MEL integrates a mutant-enriched PCR procedure with liquidchip technology for detections of EGFR exon 19 deletions and L858R mutation on both formalin-fixed and paraffin-embedded (FFPE) slides and plasma samples from patients with non-small cell lung cancer (NSCLC). The detection sensitivity was 0.1% of mutant DNA in the presence of its wild-type DNA. The cross-reaction rate was lower than 5%. To evaluate the MEL platform, the EGFR mutation status of 59 patients with advanced NSCLC treated with EGFRTKIs (Tyrosine Kinase Inhibitors) were tested on their FFPE samples. EGFR exon 19 deletions and L858R were detected in 21 patients (21/59) and 76.2% (16/21) of them had partial response to the EGFR-TKIs, while by sequencing method, only 4 (4/59) mutations were detected. Plasma samples from 627 patients with various stages of NSCLC were examined with the MEL and 22% of EGFR exon 19 deletions and L858R were detected. Furthermore, in patients with advanced disease there are more mutations detected in plasma samples than in patients with less advanced disease. In conclusion, the MEL is a sensitive, stable, and robust technology for detecting EGFR DNA mutations from both FFPE and plasma samples from patients with NSCLC and is now routinely used for clinical diagnosis.

Evaluation of NGS and RT-PCR methods for ALK rearrangement in European NSCLC patients

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Letovanec, Igor; Finn, Stephen; Zygoura, Panagiota

2018-01-01

INTRODUCTION: The reported prevalence of ALK rearrangement in NSCLC ranges from 2%-7%. The primary standard diagnostic method is fluorescence in situ hybridization (FISH). Recently, immunohistochemistry (IHC) has also proven to be a reproducible and sensitive technique. Reverse transcriptase...

Does the IMRT technique allow improvement of treatment plans (e.g. lung sparing) for lung cancer patients with small lung volume: a planning study

International Nuclear Information System (INIS)

Komosinska, K.; Kepka, L.; Gizynska, M.; Zawadzka, A.

2008-01-01

Aim: We evaluated whether intensity-modulated radiation therapy (IMRT) may offer any advantages in comparison with three-dimensional conformal radiotherapy (3D-CRT) for patients with small lung volume (SLV). Methods: Treatment planning was performed for 10 NSCLC patients with the smallest lung volume (mean: 2241 cc) among 200 patients from our database. For each patient 3D-CRT and IMRT plans were prepared. The goal was to deliver 66 Gy/33 fractions, with dose constraints: mean lung dose (MLD) < 20 Gy, V20 < 35%; spinal cord - Dmax < 45 Gy. When the plan could not meet these criteria, total dose was reduced. The 3D-CRT and IMRT plans were compared. We investigated: prescribed dose, coverage and conformity indices, MLD, V5-V65 in the lung. Results: In 4 out of 10 plans, 3D-CRT did not allow 66 Gy to be delivered, because of predicted pulmonary toxicity. These 4 cases included 3 for which we did not reach 66 Gy with IMRT; still, for these 3 plans the total dose was increased by an average of 9 Gy with IMRT in comparison with 3D-CRT. Coverage indices were similar for both techniques. Conformity indices were better for IMRT plans. MLD was lower in five IMRT and two 3D-CRT plans if equal doses were delivered. The decrease in MLD was seen for cases with large PTV and high PTV/lung volume ratio. Lung V5 was lower for all 3D-CRT plans, 47% vs. 57% for IMRT; V15 and above were larger for 3D-CRT Conclusion: In the planning study, IMRT seems to be a promising technique for cases with SLV, especially when associated with large PT V. (authors)

Incidental Prophylactic Nodal Irradiation and Patterns of Nodal Relapse in Inoperable Early Stage NSCLC Patients Treated With SBRT: A Case-Matched Analysis

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Lao, Louis [Department of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario (Canada); Department of Radiation Oncology, Auckland City Hospital, Auckland (New Zealand); Hope, Andrew J. [Department of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario (Canada); Maganti, Manjula [Department of Biostatistics, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario (Canada); Brade, Anthony; Bezjak, Andrea; Saibishkumar, Elantholi P.; Giuliani, Meredith; Sun, Alexander [Department of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario (Canada); Cho, B. C. John, E-mail: john.cho@rmp.uhn.on.ca [Department of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario (Canada)

2014-09-01

Purpose: Reported rates of non-small cell lung cancer (NSCLC) nodal failure following stereotactic body radiation therapy (SBRT) are lower than those reported in the surgical series when matched for stage. We hypothesized that this effect was due to incidental prophylactic nodal irradiation. Methods and Materials: A prospectively collected group of medically inoperable early stage NSCLC patients from 2004 to 2010 was used to identify cases with nodal relapses. Controls were matched to cases, 2:1, controlling for tumor volume (ie, same or greater) and tumor location (ie, same lobe). Reference (normalized to equivalent dose for 2-Gy fractions [EQD2]) point doses at the ipsilateral hilum and carina, demographic data, and clinical outcomes were extracted from the medical records. Univariate conditional logistical regression analyses were performed with variables of interest. Results: Cases and controls were well matched except for size. The controls, as expected, had larger gross tumor volumes (P=.02). The mean ipsilateral hilar doses were 9.6 Gy and 22.4 Gy for cases and controls, respectively (P=.014). The mean carinal doses were 7.0 Gy and 9.2 Gy, respectively (P=.13). Mediastinal nodal relapses, with and without ipsilateral hilar relapse, were associated with mean ipsilateral hilar doses of 3.6 Gy and 19.8 Gy, respectively (P=.01). The conditional density plot appears to demonstrate an inverse dose-effect relationship between ipsilateral hilar normalized total dose and risk of ipsilateral hilar relapse. Conclusions: Incidental hilar dose greater than 20 Gy is significantly associated with fewer ipsilateral hilar relapses in inoperable early stage NSCLC patients treated with SBRT.

Incidental Prophylactic Nodal Irradiation and Patterns of Nodal Relapse in Inoperable Early Stage NSCLC Patients Treated With SBRT: A Case-Matched Analysis

International Nuclear Information System (INIS)

Lao, Louis; Hope, Andrew J.; Maganti, Manjula; Brade, Anthony; Bezjak, Andrea; Saibishkumar, Elantholi P.; Giuliani, Meredith; Sun, Alexander; Cho, B. C. John

2014-01-01

Purpose: Reported rates of non-small cell lung cancer (NSCLC) nodal failure following stereotactic body radiation therapy (SBRT) are lower than those reported in the surgical series when matched for stage. We hypothesized that this effect was due to incidental prophylactic nodal irradiation. Methods and Materials: A prospectively collected group of medically inoperable early stage NSCLC patients from 2004 to 2010 was used to identify cases with nodal relapses. Controls were matched to cases, 2:1, controlling for tumor volume (ie, same or greater) and tumor location (ie, same lobe). Reference (normalized to equivalent dose for 2-Gy fractions [EQD2]) point doses at the ipsilateral hilum and carina, demographic data, and clinical outcomes were extracted from the medical records. Univariate conditional logistical regression analyses were performed with variables of interest. Results: Cases and controls were well matched except for size. The controls, as expected, had larger gross tumor volumes (P=.02). The mean ipsilateral hilar doses were 9.6 Gy and 22.4 Gy for cases and controls, respectively (P=.014). The mean carinal doses were 7.0 Gy and 9.2 Gy, respectively (P=.13). Mediastinal nodal relapses, with and without ipsilateral hilar relapse, were associated with mean ipsilateral hilar doses of 3.6 Gy and 19.8 Gy, respectively (P=.01). The conditional density plot appears to demonstrate an inverse dose-effect relationship between ipsilateral hilar normalized total dose and risk of ipsilateral hilar relapse. Conclusions: Incidental hilar dose greater than 20 Gy is significantly associated with fewer ipsilateral hilar relapses in inoperable early stage NSCLC patients treated with SBRT

Stereotactic hypofractionated radiotherapy in stage I (T1-2 N0 M0) non-small-cell lung cancer (NSCLC)

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Zimmermann, Frank B.; Geinitz, Hans; Schill, Sabine; Thamm, Reinhard; Nieder, Carsten; Schratzenstaller, Ulrich; Molls, Michael [Technical Univ., Klinikum rechts der Isar, Munich (Germany). Dept. of Radiation Oncology

2006-09-15

Stereotactic Radiotherapy has the potential to produce high local control rates with low risk of severe lung toxicity. From December 2000 to January 2006, 68 inoperable patients (median age 76 years) with stage I NSCLC received definitive hSRT. A mean total dose of 37.5 Gy (24-40 Gy; 60%-isodose) in 3-5 fractions was applied. Immobilisation was carried out by means of a vacuum couch and low pressure foil (Medical Intelligence, Schwab Muenchen, Germany). Staging procedures were thoracic and abdominal CT-scan, FDG-PET and CT or MRI of the brain in all patients. Clinical target volume was the tumor as seen in lung windowing of CT and in FDG-PET. Organ movements (6-22 mm) and patient positioning in the couch (3-12 mm) were added as safety margin for the definition of the planning target volume (PTV), that was enclosed by the 60%-isodose. We observed four (6%) local tumor recurrences, resulting in an actuarial local tumor control rate of 96%, 88% and 88% after 1, 2 and 3 year follow-up. Nineteen patients died, with eight patients due to cancer (12%), two to local tumor progression alone. Cancer-specific survival is 96%, 82% and 73% at 1, 2 and 3 years. Eleven patients died from comorbidities, making a 53% overall 3-year survival. Fifty five percent of the patients were affected by mild acute and subacute side effects, with only 3% experiencing pneumonitis III. Late effects were pneumonitis III in 1%, rib fractures in 3%, and benign pleural effusion in 2 patients. Hypofractionated SRT is safe even in elderly patients with stage I NSCLC and significantly reduced lung capacity. It leads to high local control rates and should be offered to patients not amenable for curative resection.

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) Signaling Capacity and the Epithelial-Mesenchymal Transition in Non-Small Cell Lung Cancer (NSCLC): Implications for Use of 1,25(OH)2D3 in NSCLC Treatment

International Nuclear Information System (INIS)

Upadhyay, Santosh Kumar; Verone, Alissa; Shoemaker, Suzanne; Qin, Maochun; Liu, Song; Campbell, Moray; Hershberger, Pamela A.

2013-01-01

1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) exerts anti-proliferative activity by binding to the vitamin D receptor (VDR) and regulating gene expression. We previously reported that non-small cell lung cancer (NSCLC) cells which harbor epidermal growth factor receptor (EGFR) mutations display elevated VDR expression (VDR high ) and are vitamin D-sensitive. Conversely, those with K-ras mutations are VDR low and vitamin D-refractory. Because EGFR mutations are found predominately in NSCLC cells with an epithelial phenotype and K-ras mutations are more common in cells with a mesenchymal phenotype, we investigated the relationship between vitamin D signaling capacity and the epithelial mesenchymal transition (EMT). Using NSCLC cell lines and publically available lung cancer cell line microarray data, we identified a relationship between VDR expression, 1,25(OH) 2 D 3 sensitivity, and EMT phenotype. Further, we discovered that 1,25(OH) 2 D 3 induces E-cadherin and decreases EMT-related molecules SNAIL, ZEB1, and vimentin in NSCLC cells. 1,25(OH) 2 D 3 -mediated changes in gene expression are associated with a significant decrease in cell migration and maintenance of epithelial morphology. These data indicate that 1,25(OH) 2 D 3 opposes EMT in NSCLC cells. Because EMT is associated with increased migration, invasion, and chemoresistance, our data imply that 1,25(OH) 2 D 3 may prevent lung cancer progression in a molecularly defined subset of NSCLC patients

Phase II trial of second-line erlotinib and digoxin for nonsmall cell lung cancer (NSCLC

Directory of Open Access Journals (Sweden)

Fadi Kayali

2011-02-01

Full Text Available Fadi Kayali, Muhamad A Janjua, Damian A Laber, Donald Miller, Goetz H KloeckerUniversity of Louisville, James Graham Brown Cancer Center, Louisville, KY, USABackground: In vitro digoxin sensitizes cancer cells to the induction of apoptosis by chemotherapy. Inhibition of the Na/K-ATPase enzyme by ouabain disturbs the intracellular ion composition of cancer cells, altering cellular homeostasis. This suggests that inhibition of the Na/K pump results in cellular sensitization of malignant but not benign cells to the induction of apoptosis. Epidemiologic studies have also shown beneficial effects of digitalis in breast cancer incidence. At ASCO (American Society of Clinical Oncology 2007 our group presented a Phase II study showing encouraging results by adding digoxin to biochemotherapy for melanoma. Erlotinib is one of the standard second-line treatments for nonsmall cell lung cancer (NSCLC, with a response rate (RR of 10%. This study's hypothesis was that adding digoxin to erlotinib will improve the RR and time to progression (TTP in NSCLC.Methods: Patients with progressive disease (PD after chemotherapy were enrolled if they had an ECOG (Eastern Cooperative Oncology Group score from 0 to 2 and good organ function. Daily erlotinib 150 mg and digoxin 0.25 mg were taken by mouth. The digoxin dose was adjusted to keep levels between 1 and 2 ng/mL. Computed tomography scans were done every 6 weeks. Treatment continued until PD or significant toxicity occurred.Results: Patient accrual lasted from March 2006 until August 2008 and was stopped early at the time of interim analysis. Twenty-eight patients were enrolled, and 24 who completed at least 6 weeks of therapy are presented here. All patients had unresectable NSCLC stage III/IV at diagnosis. Median age was 61 (34–78, 14 were female, 17 had prior radiation (not involving the target lesions, 23 had one prior chemotherapy, and one subject had two. Only one patient was a never-smoker. Histologies were

Prevalence and clinical association of MET gene overexpression and amplification in patients with NSCLC: Results from the European Thoracic Oncology Platform (ETOP) Lungscape project.

Science.gov (United States)

Bubendorf, Lukas; Dafni, Urania; Schöbel, Martin; Finn, Stephen P; Tischler, Verena; Sejda, Aleksandra; Marchetti, Antonio; Thunnissen, Erik; Verbeken, Eric K; Warth, Arne; Sansano, Irene; Cheney, Richard; Speel, Ernst Jan M; Nonaka, Daisuke; Monkhorst, Kim; Hager, Henrik; Martorell, Miguel; Savic, Spasenija; Kerr, Keith M; Tan, Qiang; Tsourti, Zoi; Geiger, Thomas R; Kammler, Roswitha; Schulze, Katja; Das-Gupta, Ashis; Shames, David; Peters, Solange; Stahel, Rolf A

2017-09-01

In a well-defined NSCLC cohort of the ETOP Lungscape program, we explored the epidemiology of IHC MET overexpression and amplification, their inter-correlation, and their association to outcome. Resected NSCLC were assessed for MET gene copy number (GCN) and expression using silver in-situ hybridization (SISH) and immunohistochemistry (IHC) on TMAs in a multicenter setting. MET amplification was defined as MET/centromere ratio≥2 (with average MET GCN≥4), high MET GCN as CGN≥5 and MET IHC+ as ≥2+ intensity in ≥50% of tumor cells. A total of 182 MET IHC+ and EGFR/KRAS WT tumors were analyzed for METex14 skipping mutation. MET IHC+ was found in 23.8% of 2432 patients, significantly associated with female gender, small tumor size, and adenocarcinoma histology. We observed a high inter-laboratory variability in IHC and SISH analysis. MET amplification prevailed in 4.6% and MET GCN≥5 in 4.1% of 1572 patients. MET amplification and MET GCN≥5 were not significantly associated with any tumor characteristics or stage. Both were significantly associated with IHC MET positivity (poverexpression, SISH MET amplification or high MET GCN was found with OS, RFS or TTR. MET overexpression is found in 23.8% of surgically resected NSCLC. MET amplification prevails in 4.6% and is associated with MET overexpression. Both have no influence on prognosis. The large inter-laboratory variability in IHC highlights the challenge of MET IHC analysis in routine practice. Copyright © 2017 Elsevier B.V. All rights reserved.

The value of physical performance measurements alongside assessment of sarcopenia in predicting receipt and completion of planned treatment in non-small cell lung cancer: an observational exploratory study.

Science.gov (United States)

Collins, Jemima T; Noble, Simon; Chester, John; Davies, Helen E; Evans, William D; Farewell, Daniel; Lester, Jason F; Parry, Diane; Pettit, Rebecca; Byrne, Anthony

2018-01-01

The presence of muscle mass depletion is associated with poor outcomes and survival in cancer. Alongside muscle mass, assessment of muscle strength or physical performance is essential for the diagnosis of sarcopenia. Non-small cell lung cancer (NSCLC) is a prevalent form of cancer with high mortality, and Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) is commonly used to assess patients' suitability for treatment. However, a significant proportion of patients with good PS are unable to complete multidisciplinary team (MDT)-planned treatment. Little is known about the ability of objective measurements of physical performance in predicting patients' ability to complete MDT-planned treatment and outcomes in NSCLC. We sought to establish whether physical performance, utilising the short physical performance battery (SPPB), alongside muscle mass measurements, was able to predict receipt and completion of MDT-planned treatment, with a focus on chemotherapy in NSCLC. Participants with NSCLC treated through a single lung cancer MDT and ECOG PS 0-2 were recruited and the following assessed: body composition [bioelectrical impedance (BIA) and whole body dual-energy X-ray absorptiometry (DXA) in a subset], physical performance (SPPB), PS and nutritional status. We recorded receipt and completion of chemotherapy, as well as any adverse effects, hospitalisations, and treatment delays. We included a total of 62 participants with NSCLC, and in 26 of these, the MDT-planned treatment was chemotherapy. Participants with earlier stage disease and weight loss of performance by SPPB is quick and simple to do in clinical settings and may give better indication of likely chemotherapy treatment course completion than muscle mass alone and ECOG PS. In turn, this may identify specific targets for early functional intervention and impact on MDT decision-making and prudent use of resources.

COMPARATIVE ANALYSIS OF THE RADIATION EXPOSURE ON THE TARGET AND CRITICAL ORGANS WITH 2D AND 3D PLANNING OF RADIATION THERAPY FOR LUNG CANCER

Directory of Open Access Journals (Sweden)

I. A. Gulidov

2015-01-01

Full Text Available Background and purpose. The purpose of this investigation was to evaluate feasibility, safety and efficacy of radiotherapy for inoperable non-small-cell lung cancer (NSCLC. Various radiotherapy planning methods have been proposed to decrease normal tissue toxicity. We compared 2D-RT with 3D-RT for NSCLC. Parameters assessed included dose to PTV and organ-at-risk (OAR, multiple conformity and homogeneity indices. Material and methods. Initial and re-simulation CT images from 52 consecutive patients with IIB – IIIB NSCLC were used to quantify dosimetric differences between 2D and 3D conformal radiotherapy. Contouring was performed on both CTs, and plans (n=104 plans and dose-volume histograms were generated. Results. All plans provided comparable PTV coverage. Compared with 2D-RT, 3D-RT significantly reduced the maximum dose to heart (p<0.01, spinal cord (p<0.01, whole lung (p<0.01, esophagus (p<0.02 – Wilcoxon test.

Phase I/II trial of vorinostat (SAHA) and erlotinib for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations after erlotinib progression.

Science.gov (United States)

Reguart, Noemi; Rosell, Rafael; Cardenal, Felipe; Cardona, Andres F; Isla, Dolores; Palmero, Ramon; Moran, Teresa; Rolfo, Christian; Pallarès, M Cinta; Insa, Amelia; Carcereny, Enric; Majem, Margarita; De Castro, Javier; Queralt, Cristina; Molina, Miguel A; Taron, Miquel

2014-05-01

Vorinostat or suberoylanilide hydroxamic acid (SAHA) is a novel histone deacetylase inhibitor with demonstrated antiproliferative effects due to drug-induced accumulation of acetylated proteins, including the heat shock protein 90. We prospectively studied the activity of vorinostat plus erlotinib in EGFR-mutated NSCLC patients with progression to tyrosine kinase inhibitors. We conducted this prospective, non-randomized, multicenter, phase I/II trial to evaluate the maximum tolerated dose, toxicity profile and efficacy of erlotinib and vorinostat. Patients with advanced NSCLC harboring EGFR mutations and progressive disease after a minimum of 12 weeks on erlotinib were included. The maximum tolerated dose of vorinostat plus erlotinib was used as recommended dose for the phase II (RDP2) to assess the efficacy of the combination. The primary end point was progression-free-survival rate at 12 weeks (PFSR12w). Pre-treatment plasma samples were required to assess T790M resistant mutation. A total of 33 patients were enrolled in the phase I-II trial. The maximum tolerated dose was erlotinib 150 mg p.o., QD, and 400mg p.o., QD, on days 1-7 and 15-21 in a 28-day cycle. Among the 25 patients treated at the RDP2, the most common toxicities included anemia, fatigue and diarrhea. No responses were observed. PFSR12w was 28% (IC 95%: 18.0-37.2); median progression-free survival (PFS) was 8 weeks (IC 95%: 7.43-8.45) and overall survival (OS) 10.3 months (95% CI: 2.4-18.1). Full dose of continuous erlotinib with vorinostat 400mg p.o., QD on alternative weeks can be safely administered. Still, the combination has no meaningful activity in EGFR-mutated NSCLC patients after TKI progression. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

ERCC1, toxicity and quality of life in advanced NSCLC patients randomized in a large multicentre phase III trial

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Vilmar, Adam Christian; Santoni-Rugiu, Eric; Sørensen, Jens Benn

2010-01-01

Excision repair cross complementation group 1 (ERCC1) is a promising biomarker in advanced non-small cell lung cancer (NSCLC). However, current evidence regarding the impact of ERCC1 on toxicity and quality of life (QOL) is limited.......Excision repair cross complementation group 1 (ERCC1) is a promising biomarker in advanced non-small cell lung cancer (NSCLC). However, current evidence regarding the impact of ERCC1 on toxicity and quality of life (QOL) is limited....

Association of BIM Deletion Polymorphism and BIM-γ RNA Expression in NSCLC with EGFR Mutation.

Science.gov (United States)

Isobe, Kazutoshi; Kakimoto, Atsushi; Mikami, Tetsuo; Kaburaki, Kyohei; Kobayashi, Hiroshi; Yoshizawa, Takahiro; Makino, Takashi; Otsuka, Hajime; Sano, G O; Sugino, Keishi; Sakamoto, Susumu; Takai, Yujiro; Tochigi, Naobumi; Iyoda, Akira; Homma, Sakae

This pilot study assessed the association of BIM deletion polymorphism and BIM RNA isoform in patients with EGFR-positive non-small cell lung cancer (NSCLC). The study included 33 patients with EGFR-positive NSCLC treated with gefitinib. BIM deletion polymorphism and BIM RNA isoform (EL/L/S/γ) were determined by polymerase chain reaction (PCR). BIM-γ expression was significantly higher in patients with BIM deletion polymorphism than among those without BIM deletion polymorphism inside tumors (p=0.038) and around tumors (p=0.0024). Relative BIM-γ expression was significantly higher in patients with BIM deletion polymorphism than among those without BIM deletion polymorphism (p=0.0017). Patients with BIM-γ had significantly shorter progression-free survival than those without BIM-γ (median: 304 vs. 732 days; p=0.023). Expression of BIM-γ mRNA and BIM deletion polymorphism were strongly associated. BIM-γ overexpression may have a role in apoptosis related to EGFR-tyrosine kinase inhibitor. Copyright© 2016, International Institute of Anticancer Research (Dr. John G. Delinasios), All rights reserved.

Effectiveness of accelerated radiotherapy for patients with inoperable non-small cell lung cancer (NSCLC) and borderline prognostic factors without distant metastasis: a retrospective review

International Nuclear Information System (INIS)

Nguyen, Linh N.; Komaki, Ritsuko; Allen, Pamela; Schea, Randi A.; Milas, Luka

1999-01-01

Purpose: The standard treatment for patients with unresectable or medically inoperable non-small cell lung cancer (NSCLC) and good prognostic factors (e.g., weight loss [WL] ≤5% and Karnofsky performance status [KPS] ≥70) is induction chemotherapy followed by definitive radiotherapy to the primary site at 1.8-2.0 Gy per fraction with a total dose of 60-63 Gy to the target volume. Patients with poor prognostic factors usually receive radiotherapy alone, but the fractionation schedule and total dose have not been standardized. To attempt to optimize irradiation doses and schedule, we compared the effectiveness of accelerated radiotherapy (ACRT) alone to 45 Gy at 3 Gy per fraction with standard radiation therapy (STRT) of 60-66 Gy at 2 Gy per fraction in regard to tumor response, local control, distant metastasis, toxicity, and survival. Methods and Materials: Fifty-five patients treated with radiation for NSCLC at The University of Texas M. D. Anderson Cancer Center between 1990 and 1994 were identified. All 55 patients had node-positive, and no distant metastasis (N+, M0) of NSCLC. Two cohorts were identified. One cohort (26 patients) had borderline poor prognostic factors (KPS less than 70 but higher than 50, and/or WL of more than 5%) and was treated with radiotherapy alone to 45 Gy over 3 weeks at 3 Gy/fraction (ACRT). The second cohort (29 patients) had significantly better prognostic factors (KPS ≥70 and WL ≤5%) and was treated to 60-66 Gy over 6 to 6((1)/(2)) weeks at 2 Gy per fraction (STRT) during the same period. Results: In the first cohort treated by ACRT, the distribution of patients by AJCC stage was IIB 8%, IIIA 19%, and IIIB 73%. Sixty-two percent had KPS 5%. The maximum response rate as determined by chest X-ray was 60% among 45 of 55 patients who were evaluable for response: combined complete responses (20%) and partial responses (40%). Overall survival in these patients was 13% at 2 and 5 years, with a locoregional control rate of 42% and a

Severe late esophagus toxicity in NSCLC patients treated with IMRT and concurrent chemotherapy

International Nuclear Information System (INIS)

Chen, Chun; Uyterlinde, Wilma; Sonke, Jan-Jakob; Bois, Josien de; Heuvel, Michel van den; Belderbos, José

2013-01-01

Background and purpose: We reported the incidence of severe late esophagus toxicity (LET) in locally advanced NSCLC patients treated with intensity-modulated radiation therapy (IMRT) and concurrent chemotherapy. Acute esophagus toxicity (AET) and the dose to the esophagus were analyzed for their associations with severe LET. Material and methods: Two hundred and thirty-one patients treated from 2008 to 2011 with hypofractionated IMRT (66 Gy/24 fx) and concurrent daily low dose cisplatin were included. The association between AET and severe LET (grade ⩾3 RTOG/EORTC) was tested through Cox-proportional-hazards model. Equivalent uniform dose (EUD) to the esophagus and the volume percentage receiving more than x Gy (V x ) were applied by Lyman–Kutcher–Burman (LKB) model. Results: A total of 171 patients were eligible for this study. Severe LET was observed in 6% patients. Both the maximum grade and the recovery rate of AET were significantly associated with severe LET. In the EUD n -LKB model, the fitted values and 95% confidence intervals (CIs) were TD 50 = 76.1 Gy (73.2–78.6), m = 0.03 (0.02–0.06) and n = 0.03 (0–0.08). In the V x -LKB model, the fitted values and 95% CIs were Tx 50 = 23.5% (16.4–46.6), m = 0.44 (0.32–0.60) and x = 76.7 Gy (74.7–77.5). Conclusions: Severe AET, EUD (n = 0.03) and V76.7 to the esophagus were significantly associated with severe LET. An independent validation study is required

Vinorelbine/carboplatin vs gemcitabine/carboplatin in advanced NSCLC shows similar efficacy, but different impact of toxicity

DEFF Research Database (Denmark)

Helbekkmo, N; Sundstrøm, S H; Aasebø, U

2007-01-01

This randomised phase III study in advanced non-small cell lung cancer (NSCLC) patients was conducted to compare vinorelbine/carboplatin (VC) and gemcitabine/carboplatin (GC) regarding efficacy, health-related quality of life (HRQOL) and toxicity. Chemonaive patients with NSCLC stage IIIB....../IV and WHO performance status 0-2 were eligible. No upper age limit was defined. Patients received vinorelbine 25 mg m(-2) or gemcitabine 1000 mg m(-2) on days 1 and 8 and carboplatin AUC4 on day 1 and three courses with 3-week cycles. HRQOL questionnaires were completed at baseline, before chemotherapy...... and every 8 weeks until 49 weeks. During 14 months, 432 patients were included (VC, n=218; GC, n=214). Median survival was 7.3 vs 6.4 months, 1-year survival 28 vs 30% and 2-year survival 7 vs 7% in the VC and GC arm, respectively (P=0.89). HRQOL, represented by global QOL, nausea/vomiting, dyspnoea...

Is IMRT Superior or Inferior to 3DCRT in Radiotherapy for NSCLC? A Meta-Analysis.

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Xingsheng Hu

Full Text Available There are no adequate data to determine whether intensity-modulated radiotherapy (IMRT is superior to three-dimensional conformal radiotherapy (3DCRT in the treatment of non-small cell lung cancer (NSCLC. This meta-analysis was conducted to compare the clinical outcomes of IMRT and 3DCRT in the treatment of NSCLC.No exclusions were made based on types of study design. We performed a literature search in PubMed, EMBASE and the Cochrane library databases from their inceptions to April 30, 2015. The overall survival (OS and relative risk (RR of radiation pneumonitis and radiation oesophagitis were evaluated. Two authors independently assessed the methodological quality and extracted data. Publication bias was evaluated by funnel plot using Egger's test results.From the literature search, 10 retrospective studies were collected, and of those, 5 (12,896 patients were selected for OS analysis, 4 (981 patients were selected for radiation pneumonitis analysis, and 4 (1339 patients were selected for radiation oesophagitis analysis. Cox multivariate proportional hazards models revealed that 3DCRT and IMRT had similar OS (HR = 0.96, P = 0.477 but that IMRT reduced the incidence of grade 2 radiation pneumonitis (RR = 0.74, P = 0.009 and increased the incidence of grade 3 radiation oesophagitis (RR = 2.47, P = 0.000.OS of IMRT for NSCLC is not inferior to that of 3DCRT, but IMRT significantly reduces the risk of radiation pneumonitis and increases the risk of radiation oesophagitis compared to 3DCRT.

Partial response to carboplatin in an RRx-001 pretreated patient with EGFR-inhibitor-resistance and T790M-negative NSCLC.

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Carter, Corey A; Oronsky, Bryan; Caroen, Scott; Scicinski, Jan; Cabrales, Pedro; Degesys, Aiste; Brzezniak, Christina

2016-01-01

Few therapeutic options are available for T790M-negative non-small cell lung cancer (NSCLC) after failure of primary epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and chemotherapy. This report presents the case of a 71-year-old Asian female never smoker with EGFR mutated T790M negative non squamous cell lung cancer (NSCLC) pre-treated with the experimental epi-immunotherapeutic agent, RRx-001, that re-responded to single agent carboplatin after failure of platinum doublets, TKIs, pemetrexed and nivolumab. The management of advanced EGFR mutation-positive NSCLC is briefly reviewed herein and the emerging paradigm of episensitization, which contradicts the long-standing and widely accepted tenet about the immutability of resistance and the futility of therapeutic rechallenge, is introduced as a strategy to avert treatment failure and thereby stave off deterioration and death.

A comparison of QuantStudio™ 3D Digital PCR and ARMS-PCR for measuring plasma EGFR T790M mutations of NSCLC patients.

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Feng, Qin; Gai, Fei; Sang, Yaxiong; Zhang, Jie; Wang, Ping; Wang, Yue; Liu, Bing; Lin, Dongmei; Yu, Yang; Fang, Jian

2018-01-01

The AURA3 clinical trial has shown that advanced non-small cell lung cancer (NSCLC) patients with EGFR T790M mutations in circulating tumor DNA (ctDNA) could benefit from osimertinib. The aim of this study was to assess the usefulness of QuantStudio™ 3D Digital PCR System platform for the detection of plasma EGFR T790M mutations in NSCLC patients, and compare the performances of 3D Digital PCR and ARMS-PCR. A total of 119 Chinese patients were enrolled in this study. Mutant allele frequency of plasma EGFR T790M was detected by 3D Digital PCR, then 25 selected samples were verified by ARMS-PCR and four of them were verified by next generation sequencing (NGS). In total, 52.94% (69/119) had EGFR T790M mutations detected by 3D Digital PCR. In 69 positive samples, the median mutant allele frequency (AF) was 1.09% and three cases presented low concentration (AF Digital PCR) was identified as T790M- by ARMS-PCR. Four samples were identified as T790M+ by both NGS and 3D Digital PCR, and typically three samples (3/4) presented at a low ratio (AF Digital PCR is a novel method with high sensitivity and specificity to detect EGFR T790M mutation in plasma.

(18)F-FDG PET-CT simulation for non-small-cell lung cancer: effect in patients already staged by PET-CT.

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Hanna, Gerard G; McAleese, Jonathan; Carson, Kathryn J; Stewart, David P; Cosgrove, Vivian P; Eakin, Ruth L; Zatari, Ashraf; Lynch, Tom; Jarritt, Peter H; Young, V A Linda; O'Sullivan, Joe M; Hounsell, Alan R

2010-05-01

Positron emission tomography (PET), in addition to computed tomography (CT), has an effect in target volume definition for radical radiotherapy (RT) for non-small-cell lung cancer (NSCLC). In previously PET-CT staged patients with NSCLC, we assessed the effect of using an additional planning PET-CT scan for gross tumor volume (GTV) definition. A total of 28 patients with Stage IA-IIIB NSCLC were enrolled. All patients had undergone staging PET-CT to ensure suitability for radical RT. Of the 28 patients, 14 received induction chemotherapy. In place of a RT planning CT scan, patients underwent scanning on a PET-CT scanner. In a virtual planning study, four oncologists independently delineated the GTV on the CT scan alone and then on the PET-CT scan. Intraobserver and interobserver variability were assessed using the concordance index (CI), and the results were compared using the Wilcoxon signed ranks test. PET-CT improved the CI between observers when defining the GTV using the PET-CT images compared with using CT alone for matched cases (median CI, 0.57 for CT and 0.64 for PET-CT, p = .032). The median of the mean percentage of volume change from GTV(CT) to GTV(FUSED) was -5.21% for the induction chemotherapy group and 18.88% for the RT-alone group. Using the Mann-Whitney U test, this was significantly different (p = .001). PET-CT RT planning scan, in addition to a staging PET-CT scan, reduces interobserver variability in GTV definition for NSCLC. The GTV size with PET-CT compared with CT in the RT-alone group increased and was reduced in the induction chemotherapy group.

18F-FDG PET-CT Simulation for Non-Small-Cell Lung Cancer: Effect in Patients Already Staged by PET-CT

International Nuclear Information System (INIS)

Hanna, Gerard G.; McAleese, Jonathan; Carson, Kathryn J.; Stewart, David P.; Cosgrove, Vivian P.; Eakin, Ruth L.; Zatari, Ashraf; Lynch, Tom; Jarritt, Peter H.; Young, V.A. Linda D.C.R.; O'Sullivan, Joe M.

2010-01-01

Purpose: Positron emission tomography (PET), in addition to computed tomography (CT), has an effect in target volume definition for radical radiotherapy (RT) for non-small-cell lung cancer (NSCLC). In previously PET-CT staged patients with NSCLC, we assessed the effect of using an additional planning PET-CT scan for gross tumor volume (GTV) definition. Methods and Materials: A total of 28 patients with Stage IA-IIIB NSCLC were enrolled. All patients had undergone staging PET-CT to ensure suitability for radical RT. Of the 28 patients, 14 received induction chemotherapy. In place of a RT planning CT scan, patients underwent scanning on a PET-CT scanner. In a virtual planning study, four oncologists independently delineated the GTV on the CT scan alone and then on the PET-CT scan. Intraobserver and interobserver variability were assessed using the concordance index (CI), and the results were compared using the Wilcoxon signed ranks test. Results: PET-CT improved the CI between observers when defining the GTV using the PET-CT images compared with using CT alone for matched cases (median CI, 0.57 for CT and 0.64 for PET-CT, p = .032). The median of the mean percentage of volume change from GTV CT to GTV FUSED was -5.21% for the induction chemotherapy group and 18.88% for the RT-alone group. Using the Mann-Whitney U test, this was significantly different (p = .001). Conclusion: PET-CT RT planning scan, in addition to a staging PET-CT scan, reduces interobserver variability in GTV definition for NSCLC. The GTV size with PET-CT compared with CT in the RT-alone group increased and was reduced in the induction chemotherapy group.

Phase I study of icotinib hydrochloride (BPI-2009H), an oral EGFR tyrosine kinase inhibitor, in patients with advanced NSCLC and other solid tumors.

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Zhao, Qiong; Shentu, Jianzhong; Xu, Nong; Zhou, Jianya; Yang, Guangdie; Yao, Yinan; Tan, Fenlai; Liu, Dongyang; Wang, Yingxiang; Zhou, Jianying

2011-08-01

The goal of this study was to assess the safety and tolerability of icotinib hydrochloride (BPI-2009H), a new selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI), and to explore its pharmacokinetics (PK) and clinical activity in patients with advanced solid tumors, mainly those with non-small-cell lung cancer (NSCLC) after the failure of the prior platinum-based chemotherapy. Different doses of oral icotinib were administered once every 8 h (Q8H) for a 28-continuous-day cycle until disease progression and or undue toxicity was observed. PK studies of subjects' blood were performed during cycle one (day 1 through 28). Patients aged ≥18 and ≤70 years with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1 and adequate organ functions eligible for the study. Tumor responses were assessed by Response Evaluation Criteria in Solid Tumors (RECIST). K-ras and EGFR mutations in the extracted DNA of fourteen specimens were examined using PCR-based direct sequencing assay. Thirty-six patients were enrolled in the study. PK analysis demonstrated that the mean elimination half-life of icotinib was 6 h, and the T(max) was around 2 h. The steady-state concentration of icotinib administered at a dose of 125 mg once every 8 h (Q8H) was significantly higher than that achieved by a dose of 100mg Q8H. The most frequent treatment-related adverse events (TRAEs) were an acne-like (folliculitis) rash (16/36, 44.4%), diarrhea (8/36, 22.2%) and a decrease in white blood cells (4/36, 11.1%). The maximum-tolerated dose (MTD) was not reached. Among 33 patients with NSCLC, 7 patients exhibited a partial response, 7 showed stable disease at the 24 weeks. Among 14 patients undergoing DNA sequence for K-ras and EGFR mutations, 3 with K-ras mutation presented 2 stable disease (SD) and 1 partial response (PR), 5 with EGFR exon 19 or 21 mutation 2 PR and 3 SD within 4 weeks. Oral icotinib was generally well tolerated, with manageable and

Dosimetric comparison between helical tomotherapy and intensity-modulated radiation therapy plans for non-small cell lung cancer.

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Meng, Ling-Ling; Feng, Lin-Chun; Wang, Yun-Lai; Dai, Xiang-Kun; Xie, Chuan-Bin

2011-06-01

Helical tomotherapy (HT) is a new image-guided intensity-modulated radiation therapy (IMRT) technique. It is reported that HT plan for non-small-cell lung cancer (NSCLC) can give better dose uniformity, dose gradients, and protection for the lung than IMRT plan. We compared the dosimetric characteristics of HT for NSCLC with those of conventional IMRT to observe the superiority of HT. There was a comparative case series comprising 10 patients with NSCLC. Computed tomographic (CT) images of delineated targets were transferred to the PrecisePlan planning system (IMRT) and Tomo planning system (HT). The prescription doses were 70 Gy/33F for the gross tumor volume (GTV) and the visible lymph nodes (GTVnd), and 60 Gy/33F for the clinical target volume (CTV) and the clinical target volume of the visible lymph nodes (CTVnd). The dose restrictions for organs at risk were as follows: the maximum dose to spinal cord ≤ 45 Gy, V20 to the total lungs 0.05). The maximum doses to the spinal cord, heart, esophagus and trachea in the HT plan were lower than those in the IMRT plan, but the differences were not statistically significant. The HT plan provids better dose uniformity, dose gradients, and protection for the organs at risk. It can reduce the high-dose radiation volume for lung and the MLD, but may deliver a larger lung volume of low-dose radiation.

Loss of lung function after chemo-radiotherapy for NSCLC measured by perfusion SPECT/CT: Correlation with radiation dose and clinical morbidity

DEFF Research Database (Denmark)

Farr, Katherina P; Møller, Ditte S; Khalil, Azza A

2015-01-01

BACKGROUND: The purpose of the study was to assess dose and time dependence of radiotherapy (RT)-induced changes in regional lung function measured with single photon emission computed tomography (SPECT) of the lung and relate these changes to the symptomatic endpoint of radiation pneumonitis (RP......) in patients treated for non-small cell lung cancer (NSCLC). MATERIAL AND METHODS: NSCLC patients scheduled to receive curative RT of minimum 60 Gy were included prospectively in the study. Lung perfusion SPECT/CT was performed before and three months after RT. Reconstructed SPECT/CT data were registered...

Influence of Vitamins on Secondary Reactive Oxygen Species Production in Sera of Patients with Resectable NSCLC

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Thierry Patrice

2016-07-01

Full Text Available Background: Singlet oxygen (1O2 oxidizes targets through the production of secondary reactive oxygen species (SOS. Cancers induce oxidative stress changing with progression, the resulting antioxidant status differing from one patient to the other. The aim of this study was to determine the oxidative status of patients with resectable Non-Small cell lung cancers (NSCLC and the potential influence of antioxidants, compared to sera from healthy donors. Materials and Methods: Serum samples from 10 women and 28 men, 19 adenocarcinomas (ADK, 15 patients N1 or M1 were submitted to a photoreaction producing 1O2. Then, samples were supplemented with vitamins (Vit C, Vit E, or glutathione (GSH. Results: Squamous cell carcinomas (SCC and metastatic SCCs induced a lower SOS rate. While Vit C increased SOS in controls as in patients with metastases, Vit E or the combination of Vit E and C strongly reduced SOS. GSH alone lightly decreased SOS in controls but had no effect in patients either alone or combined with Vit C. Conclusion: In “early” lung cancers, SOS are comparable or lower than for healthy persons. The role of Vitamins varies with gender, cancer type, and metastases. This suggests that an eventual supplementation should be performed on a per-patient basis to evidence any effect.

Correlation of the apparent diffusion coefficient (ADC with the standardized uptake value (SUV in lymph node metastases of non-small cell lung cancer (NSCLC patients using hybrid 18F-FDG PET/MRI.

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Benedikt Michael Schaarschmidt

Full Text Available To compare the apparent diffusion coefficient (ADC in lymph node metastases of non-small cell lung cancer (NSCLC patients with standardized uptake values (SUV derived from combined 18F-fluoro-deoxy-glucose-positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI.38 patients with histopathologically proven NSCLC (mean age 60.1 ± 9.5 y received whole-body PET/CT (Siemens mCT™ 60 min after injection of a mean dose of 280 ± 50 MBq 18F-FDG and subsequent PET/MRI (mean time after tracer injection: 139 ± 26 min, Siemens Biograph mMR. During PET acquisition, simultaneous diffusion-weighted imaging (DWI, b values: 0, 500, 1000 s/mm² was performed. A maximum of 10 lymph nodes per patient suspicious for malignancy were analyzed. Regions of interest (ROI were drawn covering the entire lymph node on the attenuation-corrected PET-image and the monoexponential ADC-map. According to histopathology or radiological follow-up, lymph nodes were classified as benign or malignant. Pearson's correlation coefficients were calculated for all lymph node metastases correlating SUVmax and SUVmean with ADCmean.A total of 146 suspicious lymph nodes were found in 25 patients. One hundred lymph nodes were eligible for final analysis. Ninety-one lymph nodes were classified as malignant and 9 as benign according to the reference standard. In malignant lesions, mean SUVmax was 9.1 ± 3.8 and mean SUVmean was 6.0 ± 2.5 while mean ADCmean was 877.0 ± 128.6 x10(-5 mm²/s in PET/MRI. For all malignant lymph nodes, a weak, inverse correlation between SUVmax and ADCmean as well as SUVmean and ADCmean (r = -0.30, p<0.05 and r = -0.36, p<0.05 existed.The present data show a weak inverse correlation between increased glucose-metabolism and cellularity in lymph node metastases of NSCLC patients. 18F-FDG-PET and DWI thus may offer complementary information for the evaluation of treatment response in lymph node metastases of NSCLC.

Optimised Pre-Analytical Methods Improve KRAS Mutation Detection in Circulating Tumour DNA (ctDNA) from Patients with Non-Small Cell Lung Cancer (NSCLC)

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Sherwood, James L.; Corcoran, Claire; Brown, Helen; Sharpe, Alan D.; Musilova, Milena; Kohlmann, Alexander

2016-01-01

Introduction Non-invasive mutation testing using circulating tumour DNA (ctDNA) is an attractive premise. This could enable patients without available tumour sample to access more treatment options. Materials & Methods Peripheral blood and matched tumours were analysed from 45 NSCLC patients. We investigated the impact of pre-analytical variables on DNA yield and/or KRAS mutation detection: sample collection tube type, incubation time, centrifugation steps, plasma input volume and DNA extraction kits. Results 2 hr incubation time and double plasma centrifugation (2000 x g) reduced overall DNA yield resulting in lowered levels of contaminating genomic DNA (gDNA). Reduced “contamination” and increased KRAS mutation detection was observed using cell-free DNA Blood Collection Tubes (cfDNA BCT) (Streck), after 72 hrs following blood draw compared to EDTA tubes. Plasma input volume and use of different DNA extraction kits impacted DNA yield. Conclusion This study demonstrated that successful ctDNA recovery for mutation detection in NSCLC is dependent on pre-analytical steps. Development of standardised methods for the detection of KRAS mutations from ctDNA specimens is recommended to minimise the impact of pre-analytical steps on mutation detection rates. Where rapid sample processing is not possible the use of cfDNA BCT tubes would be advantageous. PMID:26918901

Optimised Pre-Analytical Methods Improve KRAS Mutation Detection in Circulating Tumour DNA (ctDNA from Patients with Non-Small Cell Lung Cancer (NSCLC.

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James L Sherwood

Full Text Available Non-invasive mutation testing using circulating tumour DNA (ctDNA is an attractive premise. This could enable patients without available tumour sample to access more treatment options.Peripheral blood and matched tumours were analysed from 45 NSCLC patients. We investigated the impact of pre-analytical variables on DNA yield and/or KRAS mutation detection: sample collection tube type, incubation time, centrifugation steps, plasma input volume and DNA extraction kits.2 hr incubation time and double plasma centrifugation (2000 x g reduced overall DNA yield resulting in lowered levels of contaminating genomic DNA (gDNA. Reduced "contamination" and increased KRAS mutation detection was observed using cell-free DNA Blood Collection Tubes (cfDNA BCT (Streck, after 72 hrs following blood draw compared to EDTA tubes. Plasma input volume and use of different DNA extraction kits impacted DNA yield.This study demonstrated that successful ctDNA recovery for mutation detection in NSCLC is dependent on pre-analytical steps. Development of standardised methods for the detection of KRAS mutations from ctDNA specimens is recommended to minimise the impact of pre-analytical steps on mutation detection rates. Where rapid sample processing is not possible the use of cfDNA BCT tubes would be advantageous.

Preoperative Pulmonary Function Tests (PFTs) and Outcomes from Resected Early Stage Non-small Cell Lung Cancer (NSCLC).

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Almquist, Daniel; Khanal, Nabin; Smith, Lynette; Ganti, Apar Kishor

2018-05-01

Preoperative pulmonary function tests (PFTs) predict operative morbidity and mortality after resection in lung cancer. However, the impact of preoperative PFTs on overall outcomes in surgically-resected stage I and II non-small cell lung cancer (NSCLC) has not been well studied. This is a retrospective study of 149 patients who underwent surgical resection as first-line treatment for stage I and II NSCLC at a single center between 2003 and 2014. PFTs [forced expiratory volume in 1 sec (FEV1), Diffusing Capacity (DLCO)], both absolute values and percent predicted values were categorized into quartiles. The Kaplan-Meier method and Cox regression analysis were used to determine whether PFTs predicted for overall survival (OS). Logistic regression was used to estimate the risk of postoperative complications and length of stay (LOS) greater than 10 days based on the results of PFTs. The median age of the cohort was 68 years. The cohort was predominantly males (98.6%), current or ex-smokers (98%), with stage I NSCLC (82.76%). The majority of patients underwent a lobectomy (n=121, 81.21%). The predominant tumor histology was adenocarcinoma (n=70, 47%) followed by squamous cell carcinoma (n=61, 41%). The median follow-up of surviving patients was 53.2 months. DLCO was found to be a significant predictor of OS (HR=0.93, 95% CI=0.87-0.99; p=0.03) on univariate analysis. Although PFTs did not predict for postoperative complications, worse PFTs were significant predictors of length of stay >10 days. Preoperative PFTs did not predict for survival from resected early-stage NSCLC, but did predict for prolonged hospital stay following surgery. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Inhibitory effect and molecular mechanism of mesenchymal stem cells on NSCLC cells.

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Pan, Mengwu; Hou, Lingling; Zhang, Jingsi; Zhao, Diandian; Hua, Jilei; Wang, Ziling; He, Jinsheng; Jiang, Hong; Hu, Honggang; Zhang, Lishu

2018-04-01

Non-small-cell lung cancer (NSCLC) is still the main threat of cancer-associated death. Current treatment of NSCLC has limited effectiveness, and unfortunately, the prognosis of NSCLC remains poor. Therefore, a novel strategy for cancer therapy is urgently needed. Stem cell therapy has significant potential for cancer treatment. Mesenchymal stem cells (MSCs) with capacity for self-renewal and differentiation into various cells types exhibit the feature of homing to tumor site and immunosuppression, have been explored as a new treatment for various cancers. Studies revealed that the broad repertoire of trophic factors secreted by MSCs extensively involved in the interplay between MSCs and tumor cells. In this study, we confirmed that MSCs do have the paracrine effect on proliferation and migration of NSCLC cells (A549, NCI-H460, and SK-MES-1). Co-culture system and conditioned medium experiments results showed that soluble factors secreted by MSCs inhibited the proliferation of NSCLC cells in vitro. The scratch assay showed that conditioned medium of MSCs could suppress the migration of NSCLC cells in vitro. Western blot results showed that the expression of proteins relevant to cell proliferation, anti-apoptosis, and migration was remarkably decreased via MAPK/eIF4E signaling pathway. We speculated that soluble factors secreted by MSCs might be responsible for inhibitory mechanism of NSCLC cells. By Human Gene Expression Microarray Assay and recombinant Vascular Endothelial Growth Factor 165 (VEGF165) neutralizing experiment, we verified that VEGF might be responsible for the down-regulation of proteins related to cell proliferation, anti-apoptosis, and migration by suppressing translation initiation factor eIF4E via MAPK signaling pathway. Taken together, our study demonstrated that a possible trophic factor secreted by MSCs could manipulate translation initiation of NSCLC cells via MAPK signaling pathway, and significantly affect the fate of tumor cells, which

1,25-Dihydroxyvitamin D{sub 3} (1,25(OH){sub 2}D{sub 3}) Signaling Capacity and the Epithelial-Mesenchymal Transition in Non-Small Cell Lung Cancer (NSCLC): Implications for Use of 1,25(OH){sub 2}D{sub 3} in NSCLC Treatment

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Upadhyay, Santosh Kumar; Verone, Alissa; Shoemaker, Suzanne [Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263 (United States); Qin, Maochun; Liu, Song [Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263 (United States); Campbell, Moray; Hershberger, Pamela A., E-mail: pamela.hershberger@roswellpark.org [Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263 (United States)

2013-11-08

1,25-dihydroxyvitamin D{sub 3} (1,25(OH){sub 2}D{sub 3}) exerts anti-proliferative activity by binding to the vitamin D receptor (VDR) and regulating gene expression. We previously reported that non-small cell lung cancer (NSCLC) cells which harbor epidermal growth factor receptor (EGFR) mutations display elevated VDR expression (VDR{sup high}) and are vitamin D-sensitive. Conversely, those with K-ras mutations are VDR{sup low} and vitamin D-refractory. Because EGFR mutations are found predominately in NSCLC cells with an epithelial phenotype and K-ras mutations are more common in cells with a mesenchymal phenotype, we investigated the relationship between vitamin D signaling capacity and the epithelial mesenchymal transition (EMT). Using NSCLC cell lines and publically available lung cancer cell line microarray data, we identified a relationship between VDR expression, 1,25(OH){sub 2}D{sub 3} sensitivity, and EMT phenotype. Further, we discovered that 1,25(OH){sub 2}D{sub 3} induces E-cadherin and decreases EMT-related molecules SNAIL, ZEB1, and vimentin in NSCLC cells. 1,25(OH){sub 2}D{sub 3}-mediated changes in gene expression are associated with a significant decrease in cell migration and maintenance of epithelial morphology. These data indicate that 1,25(OH){sub 2}D{sub 3} opposes EMT in NSCLC cells. Because EMT is associated with increased migration, invasion, and chemoresistance, our data imply that 1,25(OH){sub 2}D{sub 3} may prevent lung cancer progression in a molecularly defined subset of NSCLC patients.

Validation and comparison of two NGS assays for the detection of EGFR T790M resistance mutation in liquid biopsies of NSCLC patients.

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Vollbrecht, Claudia; Lehmann, Annika; Lenze, Dido; Hummel, Michael

2018-04-06

Analysis of circulating cell-free DNA (cfDNA) derived from peripheral blood ("liquid biopsy") is an attractive alternative to identify non-small cell lung cancer (NSCLC) patients with the EGFR T790M mutation eligible for 3rd generation tyrosine kinase inhibitor therapy. We evaluated two PCR-based next generation sequencing (NGS) approaches, one including unique molecular identifiers (UMI), with focus on highly sensitive EGFR T790M mutation detection. Therefore, we extracted and sequenced cfDNA from synthetic plasma samples spiked with mutated DNA at decreasing allele frequencies and from 21 diagnostic NSCLC patients. Data evaluation was performed to determine the limit of detection (LoD), accuracy, specificity and sensitivity of both assays. Considering all tested reference dilutions and mutations the UMI assay performed best in terms of LoD (1% vs. 5%), sensitivity (95.8% vs. 81.3%), specificity (100% vs. 93.8%) and accuracy (96.9% vs. 84.4%). Comparing mutation status of diagnostic samples with both assays showed 81.3% concordance with primary mutation verifiable in 52% of cases. EGFR T790M was detected concordantly in 6/7 patients with allele frequencies from 0.1% to 27%. In one patient, the T790M mutation was exclusively detectable with the UMI assay. Our data demonstrate that both assays are applicable as multi-biomarker NGS tools enabling the simultaneous detection of primary EGFR driver and resistance mutations. However, for mutations with low allelic frequencies the use of NGS panels with UMI facilitates a more sensitive and reliable detection.

Correlation of metabolic information on FDG-PET with tissue expression of immune markers in patients with non-small cell lung cancer (NSCLC) who are candidates for upfront surgery

Energy Technology Data Exchange (ETDEWEB)

Lopci, Egesta; Olivari, Laura [Humanitas Clinical and Research Hospital, Nuclear Medicine Department, Rozzano, MI (Italy); Toschi, Luca; Marchetti, Silvia; Pistillo, Daniela [Humanitas Clinical and Research Hospital, Oncology, Rozzano, Milan (Italy); Grizzi, Fabio; Castino, Giovanni Francesco; Cortese, Nina; Qehajaj, Dorina [Humanitas Clinical and Research Hospital, Department of Immunology and Inflammation, Rozzano, Milan (Italy); Rahal, Daoud [Humanitas Clinical and Research Hospital, Department of Pathology, Rozzano, Milan (Italy); Alloisio, Marco [Humanitas Clinical and Research Hospital, Thoracic Surgery, Rozzano, Milan (Italy); Roncalli, Massimo [Humanitas Clinical and Research Hospital, Department of Pathology, Rozzano, Milan (Italy); Humanitas University, Rozzano, Milan (Italy); Allavena, Paola [Humanitas University, Rozzano, Milan (Italy); Santoro, Armando [Humanitas Clinical and Research Hospital, Oncology, Rozzano, Milan (Italy); Humanitas University, Rozzano, Milan (Italy); Marchesi, Federica [Humanitas Clinical and Research Hospital, Department of Immunology and Inflammation, Rozzano, Milan (Italy); University of Milan, Department of Medical Biotechnologies and Translational Medicine, Milan (Italy); Chiti, Arturo [Humanitas Clinical and Research Hospital, Nuclear Medicine Department, Rozzano, MI (Italy); Humanitas University, Rozzano, Milan (Italy)

2016-10-15

Eliciting antitumor T-cell response by targeting the PD-1/PD-L1 axis with checkpoint inhibitors has emerged as a novel therapeutic strategy in non-small cell lung cancer (NSCLC). The identification of predictors for sensitivity or resistance to these agents is, therefore, needed. Herein, we investigate the correlation of metabolic information on FDG-PET with tissue expression of immune-checkpoints and other markers of tumor-related immunity in resected NSCLC patients. All patients referred to our institution for upfront surgical resection of NSCLC, who were investigated with FDG-PET prior to surgery, were consecutively included in the study. From January 2010 to May 2014, 55 patients (stage IA-IIIB; M:F = 42:13; mean age 68.9 years) were investigated. Sampled surgical tumor specimens were analyzed by immunohistochemistry (IHC) for CD68-TAMs (tumor-associated macrophages), CD8-TILs (tumor infiltrating lymphocytes), PD-1-TILs, and PD-L1 tumor expression. Immunoreactivity was evaluated, and scores were compared with imaging findings. FDG-PET images were analyzed to define semi-quantitative parameters: SUVmax and SUVmean. Metabolic information on FDG-PET was correlated with tissue markers expression and disease-free survival (DFS) considering a median follow-up of 16.2 months. Thirty-six adenocarcinomas (ADC), 18 squamous cell carcinomas (SCC), and one sarcomatoid carcinoma were analyzed. All tumors resulted positive at FDG-PET: median SUVmax 11.3 (range: 2.3-32.5) and SUVmean 6.4 (range: 1.5-13) both resulted significantly higher in SCC compared to other NSCLC histotypes (p = 0.007 and 0.048, respectively). IHC demonstrated a median immunoreactive surface covered by CD68-TAMs of 5.41 % (range: 0.84-14.01 %), CD8-TILs of 2.9 % (range: 0.11-11.92 %), PD-1 of 0.65 % (range: 0.02-5.87 %), and PD-L1 of 0.7 % (range: 0.03-10.29 %). We found a statistically significant correlation between SUVmax and SUVmean with the expression of CD8 TILs (rho = 0.31; p = 0.027) and PD-1

Correlation of metabolic information on FDG-PET with tissue expression of immune markers in patients with non-small cell lung cancer (NSCLC) who are candidates for upfront surgery

International Nuclear Information System (INIS)

Lopci, Egesta; Olivari, Laura; Toschi, Luca; Marchetti, Silvia; Pistillo, Daniela; Grizzi, Fabio; Castino, Giovanni Francesco; Cortese, Nina; Qehajaj, Dorina; Rahal, Daoud; Alloisio, Marco; Roncalli, Massimo; Allavena, Paola; Santoro, Armando; Marchesi, Federica; Chiti, Arturo

2016-01-01

Eliciting antitumor T-cell response by targeting the PD-1/PD-L1 axis with checkpoint inhibitors has emerged as a novel therapeutic strategy in non-small cell lung cancer (NSCLC). The identification of predictors for sensitivity or resistance to these agents is, therefore, needed. Herein, we investigate the correlation of metabolic information on FDG-PET with tissue expression of immune-checkpoints and other markers of tumor-related immunity in resected NSCLC patients. All patients referred to our institution for upfront surgical resection of NSCLC, who were investigated with FDG-PET prior to surgery, were consecutively included in the study. From January 2010 to May 2014, 55 patients (stage IA-IIIB; M:F = 42:13; mean age 68.9 years) were investigated. Sampled surgical tumor specimens were analyzed by immunohistochemistry (IHC) for CD68-TAMs (tumor-associated macrophages), CD8-TILs (tumor infiltrating lymphocytes), PD-1-TILs, and PD-L1 tumor expression. Immunoreactivity was evaluated, and scores were compared with imaging findings. FDG-PET images were analyzed to define semi-quantitative parameters: SUVmax and SUVmean. Metabolic information on FDG-PET was correlated with tissue markers expression and disease-free survival (DFS) considering a median follow-up of 16.2 months. Thirty-six adenocarcinomas (ADC), 18 squamous cell carcinomas (SCC), and one sarcomatoid carcinoma were analyzed. All tumors resulted positive at FDG-PET: median SUVmax 11.3 (range: 2.3-32.5) and SUVmean 6.4 (range: 1.5-13) both resulted significantly higher in SCC compared to other NSCLC histotypes (p = 0.007 and 0.048, respectively). IHC demonstrated a median immunoreactive surface covered by CD68-TAMs of 5.41 % (range: 0.84-14.01 %), CD8-TILs of 2.9 % (range: 0.11-11.92 %), PD-1 of 0.65 % (range: 0.02-5.87 %), and PD-L1 of 0.7 % (range: 0.03-10.29 %). We found a statistically significant correlation between SUVmax and SUVmean with the expression of CD8 TILs (rho = 0.31; p = 0.027) and PD-1

An exploratory study of volumetric analysis for assessing tumor response with (18)F-FAZA PET/CT in patients with advanced non-small-cell lung cancer (NSCLC).

Science.gov (United States)

Kerner, Gerald S M A; Bollineni, Vikram R; Hiltermann, Thijo J N; Sijtsema, Nanna M; Fischer, Alexander; Bongaerts, Alphons H H; Pruim, Jan; Groen, Harry J M

2016-12-01

Hypoxia is associated with resistance to chemotherapy and radiotherapy and is randomly distributed within malignancies. Characterization of changes in intratumoral hypoxic regions is possible with specially developed PET tracers such as (18)F-fluoroazomycin arabinoside ((18)F-FAZA) while tumor metabolism can be measured with 2-deoxy-2-[(18)F]fluoro-D-glucose ((18)F-FDG). The purpose of this study was to study the effects of chemotherapy on (18)F-FAZA and (18)F-FDG uptake simultaneously in non-small-cell lung cancer (NSCLC) patients At baseline and after the second chemotherapy cycle, both PET/CT with (18)F-FDG and (18)F-FAZA was performed in seven patients with metastasized NSCLC. (18)F-FAZA and (18)F-FDG scans were aligned with deformable image registration using Mirada DBx. The primary tumors were contoured, and on the (18)F-FDG scan, volumes of interest (VOI) were drawn using a 41 % adaptive threshold technique. Subsequently, the resulting VOI was transferred to the (18)F-FAZA scan. (18)F-FAZA maximum tumor-to-background (T/Bgmax) ratio and the fractional hypoxic volume (FHV) were assessed. Measurements were corrected for partial volume effects. Finally, a voxel-by-voxel analysis of the primary tumor was performed to assess regional uptake differences. In the primary tumor of all seven patients, median (18)F-FDG standard uptake value (SUVmax) decreased significantly (p = 0.03). There was no significant decrease in (18)F-FAZA uptake as measured with T/Bgmax (p = 0.24) or the FHV (p = 0.35). Additionally, volumetric voxel-by-voxel analysis showed that low hypoxic tumors did not significantly change in hypoxic status between baseline and two cycles of chemotherapy, whereas highly hypoxic tumors did. Individualized volumetric voxel-by-voxel analysis revealed that hypoxia and metabolism were not associated before and after 2 cycles of chemotherapy. Tumor hypoxia and metabolism are independent dynamic events as measured by (18)F-FAZA PET and (18)F

Evaluation of elastix-based propagated align algorithm for VOI- and voxel-based analysis of longitudinal F-18-FDG PET/CT data from patients with non-small cell lung cancer (NSCLC)

NARCIS (Netherlands)

Kerner, Gerald S. M. A.; Fischer, Alexander; Koole, Michel J. B.; Pruim, Jan; Groen, Harry J. M.

2015-01-01

Background: Deformable image registration allows volume of interest (VOI)- and voxel-based analysis of longitudinal changes in fluorodeoxyglucose (FDG) tumor uptake in patients with non-small cell lung cancer (NSCLC). This study evaluates the performance of the elastix toolbox deformable image

SU-E-J-244: Development and Validation of a Knowledge Based Planning Model for External Beam Radiation Therapy of Locally Advanced Non-Small Cell Lung Cancer

Energy Technology Data Exchange (ETDEWEB)

Liu, Z; Kennedy, A [Sarah Cannon, Nashville, TN (United States); Larsen, E; Hayes, C; Grow, A [North Florida Cancer Center, Gainesville, FL (United States); Bahamondes, S.; Zheng, Y; Wu, X [JFK Comprehensive Cancer Institute, Lake Worth, FL (United States); Choi, M; Pai, S [Good Samaritan Hospital, Los Gatos, CA (United States); Li, J [Doctors Hospital of Augusta, Augusta, GA (United States); Cranford, K [Trident Medical Center, Charleston, SC (United States)

2015-06-15

Purpose: The study aims to develop and validate a knowledge based planning (KBP) model for external beam radiation therapy of locally advanced non-small cell lung cancer (LA-NSCLC). Methods: RapidPlan™ technology was used to develop a lung KBP model. Plans from 65 patients with LA-NSCLC were used to train the model. 25 patients were treated with VMAT, and the other patients were treated with IMRT. Organs-at-risk (OARs) included right lung, left lung, heart, esophagus, and spinal cord. DVH and geometric distribution DVH were extracted from the treated plans. The model was trained using principal component analysis and step-wise multiple regression. Box plot and regression plot tools were used to identify geometric outliers and dosimetry outliers and help fine-tune the model. The validation was performed by (a) comparing predicted DVH boundaries to actual DVHs of 63 patients and (b) using an independent set of treatment planning data. Results: 63 out of 65 plans were included in the final KBP model with PTV volume ranging from 102.5cc to 1450.2cc. Total treatment dose prescription varied from 50Gy to 70Gy based on institutional guidelines. One patient was excluded due to geometric outlier where 2.18cc of spinal cord was included in PTV. The other patient was excluded due to dosimetric outlier where the dose sparing to spinal cord was heavily enforced in the clinical plan. Target volume, OAR volume, OAR overlap volume percentage to target, and OAR out-of-field volume were included in the trained model. Lungs and heart had two principal component scores of GEDVH, whereas spinal cord and esophagus had three in the final model. Predicted DVH band (mean ±1 standard deviation) represented 66.2±3.6% of all DVHs. Conclusion: A KBP model was developed and validated for radiotherapy of LA-NSCLC in a commercial treatment planning system. The clinical implementation may improve the consistency of IMRT/VMAT planning.

MO19390 (SAiL): bleeding events in a phase IV study of first-line bevacizumab with chemotherapy in patients with advanced non-squamous NSCLC.

Science.gov (United States)

Dansin, Eric; Cinieri, Saverio; Garrido, Pilar; Griesinger, Frank; Isla, Dolores; Koehler, Manfred; Kohlhaeufl, Martin

2012-06-01

The clinical benefit and safety profile associated with first-line bevacizumab with doublet chemotherapy in patients with advanced non-squamous non-small cell lung cancer (NSCLC) was established in two large phase III studies, E4599 and AVAiL. SAiL, a single-arm phase IV study, was conducted to evaluate bevacizumab with a range of first-line chemotherapy regimens in a routine oncology practice setting. This analysis of the SAiL data was undertaken to specifically evaluate bleeding adverse events (AEs) in this study, and to explore potential associations between bleeding and baseline patient and disease characteristics. In total, 2212 patients were evaluated. Bleeding AEs (any grade) occurred in 38.2% of patients (grade ≥ 3 bleeding AEs: 3.6%). Grade ≥ 3 pulmonary hemorrhage and central nervous system bleeding events were observed in 0.7% and 0.1% of patients, respectively. The incidence of grade ≥ 3 bleeding AEs was comparable across patient subgroups defined by central tumor location, tumor cavitation, histology, concomitant anticoagulation therapy and age. The majority (88.6%) of bleeding events resolved or improved, 10.2% persisted and 1.3% led to death; 10.2% of bleeding events required bevacizumab interruption or discontinuation. This analysis from the SAiL trial reaffirms a comparable incidence of clinically significant bleeding associated with first-line bevacizumab and chemotherapy as previous phase III studies in NSCLC patients despite less stringent first-line selection criteria. Grade ≥ 3 bleeding appears to be comparable when analyzed for patient and tumor characteristics, including tumor cavitation and concomitant anticoagulation therapy. Most bleeding events resolved or improved, and interruption/discontinuation of bevacizumab was infrequent in a standard oncology practice setting. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Acute esophagitis for patients with Local-regional Advanced NSCLC treated with concurrent chemoradiotherapy

DEFF Research Database (Denmark)

Pan, Y.; Brink, C.; Knap, M.

2015-01-01

Purpose/Objective: Esophagitis are one of the acute treatment related toxicities to definitive radiotherapy for NSCLC. Most current researches about the risk factors for acute esophagitis are based on 3DCRT. The purpose of this study was to estimate the dose-effect relationship between esophagitis...... though multivariable logistic regression. The optimal dose metrics were chosen using Akaike Information Criterion (AIC). All models included one dose position parameter, one dosimetric parameter, gender, and institution. Dose position was defined as the average relative position (zero at start...

Changes in pulmonary function after definitive radiotherapy for NSCLC

DEFF Research Database (Denmark)

Schytte, Tine; Bentzen, Søren M; Brink, Carsten

2015-01-01

a negative impact on FVC. Long-term FEV1 and FVC were analyzed using linear regression. Treatment year and V60 had a significant impact on loss of FEV1. V60 had a significant impact on FVC changes. CONCLUSION: In this study, early PF change reached a plateau at 6months after the start of radiotherapy......INTRODUCTION: The objective of this study was to identify factors associated with early and long-term pulmonary function (PF) changes after definitive radiotherapy for NSCLC patients. PF was measured by spirometry i.e. forced expiratory volume in 1s (FEV1), and forced vital capacity (FVC...

Age dependent prognosis in concurrent chemo-radiation of locally advanced NSCLC

DEFF Research Database (Denmark)

Hansen, Olfred; Schytte, Tine; Nielsen, Morten

2015-01-01

. Material and methods. Altogether, 478 patients completed radical radiotherapy in doses of 60-66 Gy/30-33 fractions from 1995 to June 2012; 137 of the patients had concurrent chemotherapy. The data was analyzed in age groups ... specific survival the hazard ratio was related to the use of concurrent chemotherapy was 0.49 (95% CI 0.29; 0.82), 0.68 (95% CI 0.48; 0.98) and 1.01 (95% CI 0.67; 1.51) for the age groups ..., the results might be due to selection bias, thus reports from a cohort of consecutively treated patients are warranted. The current single institution study reports on the influence of age on survival of locally advanced NSCLC patients treated with radiotherapy combined with or without concurrent chemotherapy...

Ablative dose proton beam therapy for stage I and recurrent non-small cell lung carcinomas. Ablative dose PBT for NSCLC

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Lee, Sung Uk; Cho, Kwan Ho; Kim, Joo Young; Kim, Dae Yong; Kim, Tae Hyun; Suh, Yang-Gun; Kim, Yeon-Joo [Research Institute and Hospital, National Cancer Center, Proton Therapy Center, Goyang (Korea, Republic of); Moon, Sung Ho [Research Institute and Hospital, National Cancer Center, Proton Therapy Center, Goyang (Korea, Republic of); Research Institute and Hospital, National Cancer Center, Center for Lung Cancer, Goyang (Korea, Republic of); Research Institute and Hospital, National Cancer Center, Proton Therapy Center, Ilsandong-gu, Goyang-si, Gyeonggi-do, 410-769 (Korea, Republic of); Pyo, Hong Ryull [Samsung Medical Center, Sungkyunkwan University School of Medicine, Department of Radiation Oncology, Seoul (Korea, Republic of)

2016-09-15

To evaluate the efficacy and safety of ablative dose hypofractionated proton beam therapy (PBT) for patients with stage I and recurrent non-small cell lung carcinoma (NSCLC). A total of 55 patients with stage I (n = 42) and recurrent (n = 13) NSCLC underwent hypofractionated PBT and were retrospectively reviewed. A total dose of 50-72 CGE (cobalt gray equivalent) in 5-12 fractions was delivered. The median follow-up duration was 29 months (range 4-95 months). There were 24 deaths (43.6%) during the follow-up period: 11 died of disease progression and 13 from other causes. Kaplan-Meier overall survival rate (OS) at 3 years was 54.9% and the median OS was 48.6 months (range 4-95 months). Local progression was observed in 7 patients and the median time to local progression was 9.3 months (range 5-14 months). Cumulative actuarial local control rate (LCR), lymph node metastasis-free survival, and distant metastasis-free survival rates at 3 years were 85.4, 78.4, and 76.5%, respectively. Larger tumor diameter was significantly associated with poorer LCR (3-year: 94% for ≤3 cm vs. 65% for >3 cm, p = 0.006) on univariate analysis and also an independent prognostic factor for LCR (HR 6.9, 95% CI = 1.3-37.8, p = 0.026) on multivariate analysis. No grade 3 or 4 treatment-related toxicities developed. One grade 5 treatment-related adverse event occurred in a patient with symptomatic idiopathic pulmonary fibrosis. Ablative dose hypofractionated PBT was safe and promising for stage I and recurrent NSCLC. (orig.) [German] Beurteilung von Wirksamkeit und Sicherheit hypofraktionierter Protonentherapie (PBT) mit ablativen Dosen fuer nichtkleinzellige Lungenkarzinome (NSCLC) im Stadium I und rekurrierende NSCLC. Retrospektiv wurden insgesamt 55 NSCLC-Patienten (Stadium I: n = 42; rekurrierender Tumor: n = 13), analysiert. Sie waren mit einer Gesamtdosis von 50-72 CGE (''cobalt gray equivalent'') in 5-12 Fraktionen behandelt worden. Der Median der Follow

The impact of induction chemotherapy on the dosimetric parameters of subsequent radiotherapy: an investigation of 30 consecutive patients with locally-advanced non-small cell lung cancer and modern radiation planning techniques

International Nuclear Information System (INIS)

Grant, Jonathan D; Sobremonte, Angela; Hillebrandt, Evangeline; Allen, Pamela K; Gomez, Daniel R

2015-01-01

To investigate the influence of induction chemotherapy (ICT) on dosimetric outcomes in patients with inoperable non-small cell lung cancer (NSCLC) treated with definitive chemoradiation (CRT). 30 patients with inoperable stage II-III NSCLC treated with 2–4 cycles of ICT followed by definitive CRT to ≥ 60 Gy were selected. Tumor response to chemotherapy was scored by RECIST criteria. Treatment plans based on tumor extent prior to chemotherapy were generated based on equivalent planning constraints and techniques as the original post-chemotherapy plans. Dosimetric parameters predictive of toxicity for lung, esophagus, heart, and spinal cord were compared amongst the pre- and post-ICT plans. The majority of patients (70%) experienced an overall reduction in GTV size between the pre-ICT imaging and the time of simulation. Comparing pre-and post-ICT diagnostic imaging, 5 patients met the RECIST criteria for response, 23 were classified as stable, and 2 experienced disease progression on diagnostic imaging. Despite a significantly reduced GTV size in the post-ICT group, no systematic improvements in normal tissue doses were seen amongst the entire cohort. This result persisted amongst the subgroup of patients with larger pre-ICT GTV tumor volumes (>100 cc 3 ). Among patients with RECIST-defined response, a significant reduction in lung mean dose (1.9 Gy absolute, median 18.2 Gy to 16.4 Gy, p = 0.04) and V 20, the percentage of lung receiving 20 Gy (3.1% absolute, median 29.3% to 26.3%, p = 0.04) was observed. In the non-responding group of patients, an increased esophageal V 50 was found post-chemotherapy (median 28.9% vs 30.1%, p = 0.02). For patients classified as having a response by RECIST to ICT, modest improvements in V 20 and mean lung dose were found. However, these benefits were not realized for the cohort as a whole or for patients with larger tumors upfront. Given the variability of tumor response to ICT, the a priori impact of induction chemotherapy to

Revisiting the relationship between tumour volume and diameter in advanced NSCLC patients: An exercise to maximize the utility of each measure to assess response to therapy

International Nuclear Information System (INIS)

Nishino, M.; Jackman, D.M.; DiPiro, P.J.; Hatabu, H.; Jänne, P.A.; Johnson, B.E.

2014-01-01

Aim: To revisit the presumed relationship between tumour diameter and volume in advanced non-small-cell lung cancer (NSCLC) patients, and determine whether the measured volume using volume-analysis software and its proportional changes during therapy matches with the calculated volume obtained from the presumed relationship and results in concordant response assessment. Materials and methods: Twenty-three patients with stage IIIB/IV NSCLC with a total of 53 measurable lung lesions, treated in a phase II trial of erlotinib, were studied with institutional review board approval. Tumour volume and diameter were measured at baseline and at the first follow-up computed tomography (CT) examination using volume-analysis software. Using the measured diameter (2r) and the equation, calculated volume was obtained as (4/3)πr 3 at baseline and at the follow-up. Percent volume change was obtained by comparing to baseline for measured and calculated volumes, and response assessment was assigned. Results: The measured volume was significantly smaller than the calculated volume at baseline (median 11,488.9 mm 3 versus 17,148.6 mm 3 ; p < 0.0001), with a concordance correlation coefficient (CCC) of 0.7022. At follow-up, the measured volume was once again significantly smaller than the calculated volume (median 6573.5 mm 3 versus 9198.1 mm 3 ; p = 0.0022), with a CCC of 0.7408. Response assessment by calculated versus measured volume changes had only moderate agreement (weighted κ = 0.545), with discordant assessment results in 20% (8/40) of lesions. Conclusion: Calculated volume based on the presumed relationship significantly differed from the measured volume in advanced NSCLC patients, with only moderate concordance in response assessment, indicating the limitations of presumed relationship. - Highlights: • Response assessment by measured vs calculated values has only moderate agreement. • It is important to obtain the actual measured values for tumor response

Risk of intracranial hemorrhage and cerebrovascular accidents in non-small cell lung cancer brain metastasis patients.

Science.gov (United States)

Srivastava, Geetika; Rana, Vishal; Wallace, Suzy; Taylor, Sarah; Debnam, Matthew; Feng, Lei; Suki, Dima; Karp, Daniel; Stewart, David; Oh, Yun

2009-03-01

Brain metastases confer significant morbidity and a poorer survival in non-small cell lung cancer (NSCLC). Vascular endothelial growth factor-targeted antiangiogenic therapies (AAT) have demonstrated benefit for patients with metastatic NSCLC and are expected to directly inhibit the pathophysiology and morbidity of brain metastases, yet patients with brain metastases have been excluded from most clinical trials of AAT for fear of intracranial hemorrhage (ICH). The underlying risk of ICH from NSCLC brain metastases is low, but needs to be quantitated to plan clinical trials of AAT for NSCLC brain metastases. Data from MD Anderson Cancer Center Tumor Registry and electronic medical records from January 1998 to March 2006 was interrogated. Two thousand one hundred forty-three patients with metastatic NSCLC registering from January 1998 to September 2005 were followed till March 2006. Seven hundred seventy-six patients with and 1,367 patients without brain metastases were followed till death, date of ICH, or last date of study, whichever occurred first. The incidence of ICH seemed to be higher in those with brain metastasis compared with those without brain metastases, in whom they occurred as result of cerebrovascular accidents. However, the rates of symptomatic ICH were not significantly different. All ICH patients with brain metastasis had received radiation therapy for them and had been free of anticoagulation. Most of the brain metastasis-associated ICH's were asymptomatic, detected during increased radiologic surveillance. The rates of symptomatic ICH, or other cerebrovascular accidents in general were similar and not significantly different between the two groups. In metastatic NSCLC patients, the incidence of spontaneous ICH appeared to be higher in those with brain metastases compared with those without, but was very low in both groups without a statistically significant difference. These data suggest a minimal risk of clinically significant ICH for NSCLC

Maximal Oxygen Uptake--Risk Predictor of NSCLC Resection in Patients With Comorbid Emphysema: Lessons From NETT.

Science.gov (United States)

Makey, Ian; Berger, Robert L; Cabral, Howard J; Celli, Bartolome; Folch, Erik; Whyte, Richard I

2015-01-01

We compared VO2 max values from ACCP Guidelines and from NETT's homogenous NULPD surrogate for predicting operative mortalities. Estimated mid and long-term non-cancer related survival in NETT's subset was also obtained. NETT and ACCP Guideline VO2 max values were similar in the "low" and "mid" risk operative mortality categories but NETT's "high" risk subset showed lower mortality (14% vs. 26%). Estimated non-cancer related survival in NETT "low", "mid" and "high" risk VO2 max categories at two and eight years were 100%, 74%, 59% and 48%, 26%, 14%, respectively. The lower predicted risk in NETT's "high- risk" subset raises the possibility of extending indications for potential curative resection in selected patients. The NETT surrogate also provides hitherto unavailable estimate on long-term non-cancer related survival after potential curative resection of NSCLC and suggests that the operation does not shorten eight-year longevity. Copyright © 2015 Elsevier Inc. All rights reserved.

Time evolution of regional CT density changes in normal lung after IMRT for NSCLC

International Nuclear Information System (INIS)

Bernchou, Uffe; Schytte, Tine; Bertelsen, Anders; Bentzen, Søren M.; Hansen, Olfred; Brink, Carsten

2013-01-01

Purpose: This study investigates the clinical radiobiology of radiation induced lung disease in terms of regional computed tomography (CT) density changes following intensity modulated radiotherapy (IMRT) for non-small-cell lung cancer (NSCLC). Methods: A total of 387 follow-up CT scans in 131 NSCLC patients receiving IMRT to a prescribed dose of 60 or 66 Gy in 2 Gy fractions were analyzed. The dose-dependent temporal evolution of the density change was analyzed using a two-component model, a superposition of an early, transient component and a late, persistent component. Results: The CT density of healthy lung tissue was observed to increase significantly (p 12 months. Conclusions: The radiobiology of lung injury may be analyzed in terms of CT density change. The initial transient change in density is consistent with radiation pneumonitis, while the subsequent stabilization of the density is consistent with pulmonary fibrosis

Benefit-Risk Summary of Nivolumab for Patients With Metastatic Squamous Cell Lung Cancer After Platinum-Based Chemotherapy: A Report From the US Food and Drug Administration.

Science.gov (United States)

Kazandjian, Dickran; Khozin, Sean; Blumenthal, Gideon; Zhang, Lijun; Tang, Shenghui; Libeg, Meredith; Kluetz, Paul; Sridhara, Rajeshwari; Keegan, Patricia; Pazdur, Richard

2016-01-01

Metastatic squamous non-small-cell lung cancer (SQ NSCLC) is a serious and life-threatening malignant condition with unmet medical need. In late December 2014, the US Food and Drug Administration (FDA) obtained the data monitoring committee report of a planned interim analysis of a trial in second-line SQ NSCLC (CM017) that demonstrated an overall survival benefit for patients treated with nivolumab compared with docetaxel. In that trial, 272 patients with metastatic SQ NSCLC patients had been randomized to receive nivolumab (n = 135) or docetaxel (n = 137). Median overall survival was 9.2 months for patients randomized to nivolumab and 6.0 months for those randomized to docetaxel (hazard ratio, 0.59; 95% CI, 0.44-0.79; P chemotherapy. The approval provides an important treatment option for these patients, affecting routine care and clinical trials.

Chromosome 5p Region SNPs Are Associated with Risk of NSCLC among Women

International Nuclear Information System (INIS)

Dyke, A. L. V.

2009-01-01

In a population-based case-control study, we explored the associations between 42 polymorphisms in seven genes in this region and non-small cell lung cancer (NSCLC) risk among Caucasian (364 cases; 380 controls) and African American (95 cases; 103 controls) women. Two TERT region SNPs, rs2075786 and rs2853677, conferred an increased risk of developing NSCLC, especially among African American women, and TERT-rs2735940 was associated with a decreased risk of lung cancer among African Americans. Five of the 20 GHR polymorphisms and SEPP1-rs6413428 were associated with a marginally increased risk of NSCLC among Caucasians. Random forest analysis reinforced the importance of GHR among Caucasians and identified AMACR, TERT, and GHR among African Americans, which were also significant using gene-based risk scores. Smoking-SNP interactions were explored, and haplotype in TERT and GHR associated with NSCLC risk were identified. The roles of TERT, GHR, AMACR and SEPP1 genes in lung carcinogenesis warrant further exploration

ROMANA 3: a phase 3 safety extension study of anamorelin in advanced non-small-cell lung cancer (NSCLC) patients with cachexia.

Science.gov (United States)

Currow, D; Temel, J S; Abernethy, A; Milanowski, J; Friend, J; Fearon, K C

2017-08-01

Cancer anorexia-cachexia is a debilitating condition frequently observed in NSCLC patients, characterized by decreased body weight, reduced food intake, and impaired quality of life. Anamorelin, a novel selective ghrelin receptor agonist, has anabolic and appetite-enhancing activities. ROMANA 3 was a safety extension study of two phase 3, double-blind studies that assessed safety and efficacy of anamorelin in advanced NSCLC patients with cachexia. Patients with preserved Eastern Cooperative Oncology Group ≤2 after completing 12 weeks (w) on the ROMANA 1 or ROMANA 2 trials (0-12 weeks) could enroll in ROMANA 3 and continue to receive anamorelin 100 mg or placebo once daily for an additional 12w (12-24 weeks). The primary endpoint of ROMANA 3 was anamorelin safety/tolerability (12-24 weeks). Secondary endpoints included changes in body weight, handgrip strength (HGS), and symptom burden (0-24 weeks). Of the 703 patients who completed ROMANA 1 and ROMANA 2, 513 patients entered ROMANA 3 (anamorelin, N = 345, mean age 62.0 years; placebo, N = 168; mean age 62.2 years). During ROMANA 3, anamorelin and placebo groups had similar incidences of treatment-emergent adverse events (TEAEs; 52.2% versus 55.7%), grade ≥3 TEAEs (22.4% versus 21.6%), and serious TEAEs (12.8% versus 12.6%). There were 36 (10.5%) and 23 (13.8%) deaths in the anamorelin and placebo groups, respectively; none were drug-related. Improvements in body weight and anorexia-cachexia symptoms observed in the original trials were consistently maintained over 12-24 weeks. Anamorelin, versus placebo, significantly increased body weight from baseline of original trials at all time points (P cachexia symptoms at weeks 3, 6, 9, 12, and 16 (P < 0.05). No significant improvement in HGS was seen in either group. During the 12-24 weeks ROMANA 3 trial, anamorelin continued to be well tolerated. Over the entire 0-24w treatment period, body weight and symptom burden were improved

Impact of [18F]fluorodeoxyglucose PET-CT staging on treatment planning in radiotherapy incorporating elective nodal irradiation for non-small-cell lung cancer: a prospective study.

Science.gov (United States)

Kolodziejczyk, Milena; Kepka, Lucyna; Dziuk, Miroslaw; Zawadzka, Anna; Szalus, Norbert; Gizewska, Agnieszka; Bujko, Krzysztof

2011-07-15

To evaluate prospectively how positron emission tomography (PET) information changes treatment plans for non-small-cell lung cancer (NSCLC) patients receiving or not receiving elective nodal irradiation (ENI). One hundred consecutive patients referred for curative radiotherapy were included in the study. Treatment plans were carried out with CT data sets only. For stage III patients, mediastinal ENI was planned. Then, patients underwent PET-CT for diagnostic/planning purposes. PET/CT was fused with the CT data for final planning. New targets were delineated. For stage III patients with minimal N disease (N0-N1, single N2), the ENI was omitted in the new plans. Patients were treated according to the PET-based volumes and plans. The gross tumor volume (GTV)/planning tumor volume (PTV) and doses for critical structures were compared for both data sets. The doses for areas of potential geographical misses derived with the CT data set alone were compared in patients with and without initially planned ENI. In the 75 patients for whom the decision about curative radiotherapy was maintained after PET/CT, there would have been 20 cases (27%) with potential geographical misses by using the CT data set alone. Among them, 13 patients would receive ENI; of those patients, only 2 patients had the PET-based PTV covered by 90% isodose by using the plans based on CT alone, and the mean of the minimum dose within the missed GTV was 55% of the prescribed dose, while for 7 patients without ENI, it was 10% (p = 0.006). The lung, heart, and esophageal doses were significantly lower for plans with ENI omission than for plans with ENI use based on CT alone. PET/CT should be incorporated in the planning of radiotherapy for NSCLC, even in the setting of ENI. However, if PET/CT is unavailable, ENI may to some extent compensate for an inadequate dose coverage resulting from diagnostic uncertainties. Copyright © 2011 Elsevier Inc. All rights reserved.

Impact of [18F]Fluorodeoxyglucose PET-CT Staging on Treatment Planning in Radiotherapy Incorporating Elective Nodal Irradiation for Non-Small-Cell Lung Cancer: A Prospective Study

International Nuclear Information System (INIS)

Kolodziejczyk, Milena; Kepka, Lucyna; Dziuk, Miroslaw; Zawadzka, Anna; Szalus, Norbert; Gizewska, Agnieszka; Bujko, Krzysztof

2011-01-01

Purpose: To evaluate prospectively how positron emission tomography (PET) information changes treatment plans for non-small-cell lung cancer (NSCLC) patients receiving or not receiving elective nodal irradiation (ENI). Methods and Materials: One hundred consecutive patients referred for curative radiotherapy were included in the study. Treatment plans were carried out with CT data sets only. For stage III patients, mediastinal ENI was planned. Then, patients underwent PET-CT for diagnostic/planning purposes. PET/CT was fused with the CT data for final planning. New targets were delineated. For stage III patients with minimal N disease (N0-N1, single N2), the ENI was omitted in the new plans. Patients were treated according to the PET-based volumes and plans. The gross tumor volume (GTV)/planning tumor volume (PTV) and doses for critical structures were compared for both data sets. The doses for areas of potential geographical misses derived with the CT data set alone were compared in patients with and without initially planned ENI. Results: In the 75 patients for whom the decision about curative radiotherapy was maintained after PET/CT, there would have been 20 cases (27%) with potential geographical misses by using the CT data set alone. Among them, 13 patients would receive ENI; of those patients, only 2 patients had the PET-based PTV covered by 90% isodose by using the plans based on CT alone, and the mean of the minimum dose within the missed GTV was 55% of the prescribed dose, while for 7 patients without ENI, it was 10% (p = 0.006). The lung, heart, and esophageal doses were significantly lower for plans with ENI omission than for plans with ENI use based on CT alone. Conclusions: PET/CT should be incorporated in the planning of radiotherapy for NSCLC, even in the setting of ENI. However, if PET/CT is unavailable, ENI may to some extent compensate for an inadequate dose coverage resulting from diagnostic uncertainties.

Genetic association between polymorphism of mdm2 gene and symptoms and pathological types of NSCLC

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Liu Xiaolan; Wang Weili; Zhang Xueying; Hao Ming; Liu Linlin; Wu Zhenfeng; Jiang Hongwei

2008-01-01

Objective: To investigate the genetic association between polymorphism of mdm2 gene and symptoms and pathological types of non-small cell lung cancer (NSCLC). Methods: Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) was used to identify mdm2 genotypes. The Pearson Chi square test and Woolf statistic method were used to analyze the relative risk and 95% confidence interval (CI) in order to find the genetic association between polymorphism of mdm2 gene and symptoms and pathological types of NSCLC. Results: In the SNP rs1196337 (a G to A base change) AA genotype showed association with cough of NSCLC (P<0.05). Conclusion: The polymorphism of mdm2 gene may be associated with symptom as cough of NSCLC. (authors)

A retrospective analysis of RET translocation, gene copy number gain and expression in NSCLC patients treated with vandetanib in four randomized Phase III studies.

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Platt, Adam; Morten, John; Ji, Qunsheng; Elvin, Paul; Womack, Chris; Su, Xinying; Donald, Emma; Gray, Neil; Read, Jessica; Bigley, Graham; Blockley, Laura; Cresswell, Carl; Dale, Angela; Davies, Amanda; Zhang, Tianwei; Fan, Shuqiong; Fu, Haihua; Gladwin, Amanda; Harrod, Grace; Stevens, James; Williams, Victoria; Ye, Qingqing; Zheng, Li; de Boer, Richard; Herbst, Roy S; Lee, Jin-Soo; Vasselli, James

2015-03-23

To determine the prevalence of RET rearrangement genes, RET copy number gains and expression in tumor samples from four Phase III non-small-cell lung cancer (NSCLC) trials of vandetanib, a selective inhibitor of VEGFR, RET and EGFR signaling, and to determine any association with outcome to vandetanib treatment. Archival tumor samples from the ZODIAC ( NCT00312377 , vandetanib ± docetaxel), ZEAL ( NCT00418886 , vandetanib ± pemetrexed), ZEPHYR ( NCT00404924 , vandetanib vs placebo) and ZEST ( NCT00364351 , vandetanib vs erlotinib) studies were evaluated by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) in 944 and 1102 patients. The prevalence of RET rearrangements by FISH was 0.7% (95% CI 0.3-1.5%) among patients with a known result. Seven tumor samples were positive for RET rearrangements (vandetanib, n = 3; comparator, n = 4). 2.8% (n = 26) of samples had RET amplification (innumerable RET clusters, or ≥7 copies in > 10% of tumor cells), 8.1% (n = 76) had low RET gene copy number gain (4-6 copies in ≥40% of tumor cells) and 8.3% (n = 92) were RET expression positive (signal intensity ++ or +++ in >10% of tumor cells). Of RET-rearrangement-positive patients, none had an objective response in the vandetanib arm and one patient responded in the comparator arm. Radiologic evidence of tumor shrinkage was observed in two patients treated with vandetanib and one treated with comparator drug. The objective response rate was similar in the vandetanib and comparator arms for patients positive for RET copy number gains or RET protein expression. We have identified prevalence for three RET biomarkers in a population predominated by non-Asians and smokers. RET rearrangement prevalence was lower than previously reported. We found no evidence of a differential benefit for efficacy by IHC and RET gene copy number gains. The low prevalence of RET rearrangements (0.7%) prevents firm conclusions regarding association of vandetanib treatment with

Textural features in pre-treatment [F18]-FDG-PET/CT are correlated with risk of local recurrence and disease-specific survival in early stage NSCLC patients receiving primary stereotactic radiation therapy.

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Pyka, Thomas; Bundschuh, Ralph A; Andratschke, Nicolaus; Mayer, Benedikt; Specht, Hanno M; Papp, Laszló; Zsótér, Norbert; Essler, Markus

2015-04-22

Textural features in FDG-PET have been shown to provide prognostic information in a variety of tumor entities. Here we evaluate their predictive value for recurrence and prognosis in NSCLC patients receiving primary stereotactic radiation therapy (SBRT). 45 patients with early stage NSCLC (T1 or T2 tumor, no lymph node or distant metastases) were included in this retrospective study and followed over a median of 21.4 months (range 3.1-71.1). All patients were considered non-operable due to concomitant disease and referred to SBRT as the primary treatment modality. Pre-treatment FDG-PET/CT scans were obtained from all patients. SUV and volume-based analysis as well as extraction of textural features based on neighborhood gray-tone difference matrices (NGTDM) and gray-level co-occurence matrices (GLCM) were performed using InterView Fusion™ (Mediso Inc., Budapest). The ability to predict local recurrence (LR), lymph node (LN) and distant metastases (DM) was measured using the receiver operating characteristic (ROC). Univariate and multivariate analysis of overall and disease-specific survival were executed. 7 out of 45 patients (16%) experienced LR, 11 (24%) LN and 11 (24%) DM. ROC revealed a significant correlation of several textural parameters with LR with an AUC value for entropy of 0.872. While there was also a significant correlation of LR with tumor size in the overall cohort, only texture was predictive when examining T1 (tumor diameter 3 cm) subgroups. No correlation of the examined PET parameters with LN or DM was shown. In univariate survival analysis, both heterogeneity and tumor size were predictive for disease-specific survival, but only texture determined by entropy was determined as an independent factor in multivariate analysis (hazard ratio 7.48, p = .016). Overall survival was not significantly correlated to any examined parameter, most likely due to the high comorbidity in our cohort. Our study adds to the growing evidence that tumor

Textural features in pre-treatment [F18]-FDG-PET/CT are correlated with risk of local recurrence and disease-specific survival in early stage NSCLC patients receiving primary stereotactic radiation therapy

International Nuclear Information System (INIS)

Pyka, Thomas; Bundschuh, Ralph A; Andratschke, Nicolaus; Mayer, Benedikt; Specht, Hanno M; Papp, Laszló; Zsótér, Norbert; Essler, Markus

2015-01-01

Textural features in FDG-PET have been shown to provide prognostic information in a variety of tumor entities. Here we evaluate their predictive value for recurrence and prognosis in NSCLC patients receiving primary stereotactic radiation therapy (SBRT). 45 patients with early stage NSCLC (T1 or T2 tumor, no lymph node or distant metastases) were included in this retrospective study and followed over a median of 21.4 months (range 3.1–71.1). All patients were considered non-operable due to concomitant disease and referred to SBRT as the primary treatment modality. Pre-treatment FDG-PET/CT scans were obtained from all patients. SUV and volume-based analysis as well as extraction of textural features based on neighborhood gray-tone difference matrices (NGTDM) and gray-level co-occurence matrices (GLCM) were performed using InterView Fusion™ (Mediso Inc., Budapest). The ability to predict local recurrence (LR), lymph node (LN) and distant metastases (DM) was measured using the receiver operating characteristic (ROC). Univariate and multivariate analysis of overall and disease-specific survival were executed. 7 out of 45 patients (16%) experienced LR, 11 (24%) LN and 11 (24%) DM. ROC revealed a significant correlation of several textural parameters with LR with an AUC value for entropy of 0.872. While there was also a significant correlation of LR with tumor size in the overall cohort, only texture was predictive when examining T1 (tumor diameter < = 3 cm) and T2 (>3 cm) subgroups. No correlation of the examined PET parameters with LN or DM was shown. In univariate survival analysis, both heterogeneity and tumor size were predictive for disease-specific survival, but only texture determined by entropy was determined as an independent factor in multivariate analysis (hazard ratio 7.48, p = .016). Overall survival was not significantly correlated to any examined parameter, most likely due to the high comorbidity in our cohort. Our study adds to the growing evidence

Phosphorylated EGFR expression may predict outcome of EGFR-TKIs therapy for the advanced NSCLC patients with wild-type EGFR

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Wang Fen

2012-08-01

Full Text Available Abstract Background EGFR mutation is a strong predictive factor of EGFR-TKIs therapy. However, at least 10% of patients with EGFR wild-type are responsive to TKIs, suggesting that other determinants of outcome besides EGFR mutation might exist. We hypothesized that activation of phosphorylated EGFR could be a potential predictive biomarker to EGFR-TKIs treatment among patients in wild-type EGFR. Method Total of 205 stage IIIb and IV NSCLC patients, tissue samples of whom were available for molecular analysis, were enrolled in this study. The phosphorylation of EGFR at tyrosine 1068 (pTyr1068 and 1173 (pTyr1173 were assessed by immunohistochemistry, and EGFR mutations were detected by denaturing high performance liquid chromatograph (DHPLC. Results Among 205 patients assessable for EGFR mutation and phosphorylation analysis, 92 (44.9% were EGFR mutant and 165 patients (57.6% had pTyr1173 expression. Superior progression-free survival (PFS was seen after EGFR-TKIs therapy in patients with pTyr1068 expression compared to pTyr1068 negative ones (median PFS 7.0 months vs. 1.2 months, P P = 0.016. In subgroup of patients with wild-type EGFR, pTyr1068 expression positive ones had a significantly prolonged PFS (4.2 months vs.1.2 months P  Conclusion pTyr1068 may be a predictive biomarker for screening the population for clinical response to EGFR-TKIs treatment; especially for patients with wild-type EGFR.

Metastatic squamous cell non-small-cell lung cancer (NSCLC: disrupting the drug treatment paradigm with immunotherapies

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Sarah L Scarpace

2015-10-01

Full Text Available Lung cancer is the third most commonly diagnosed cancer and the leading cause of cancer-related death in the United States. Unlike non-squamous NSCLC, squamous NSCLC rarely harbor epidermal growth factor receptor (EGFR and anaplastic lymphoma kinase (ALK mutations for which there are directed therapies, and until the recent approval of immunotherapies for squamous NSCLC, a limited number of traditional cytotoxic chemotherapy drugs have been FDA-approved for use in the treatment of advanced and metastatic squamous NSCLC. Immunotherapies directed at the programmed cell death-1 receptor (PD-1 or its ligand (PD-L1 (nivolumab and pembrolizumab have demonstrated efficacy in both nonsquamous and squamous cell NSCLC. Because of their similar mechanism of action against the PD-L1/PD-1 pathway, both drugs have similar toxicity profiles related to immune-mediated adverse reactions that can generally be monitored and managed with oral corticosteroids. This paper provides an overview of drug therapy options for squamous cell NSCLC with a focus on the evidence and clinical application of the anti-PD1 therapies. A comparison of the dosing, administration, indications, and differences in the measurement of PD-L1 expression in the clinical trials of nivolumab and pembrolizumab is also provided.

Adaptive/Nonadaptive Proton Radiation Planning and Outcomes in a Phase II Trial for Locally Advanced Non-small Cell Lung Cancer

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Koay, Eugene J.; Lege, David [Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Mohan, Radhe [Department of Radiation Physics, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Komaki, Ritsuko; Cox, James D. [Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Chang, Joe Y., E-mail: jychang@mdanderson.org [Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (United States)

2012-12-01

Purpose: To analyze dosimetric variables and outcomes after adaptive replanning of radiation therapy during concurrent high-dose protons and chemotherapy for locally advanced non-small cell lung cancer (NSCLC). Methods and Materials: Nine of 44 patients with stage III NSCLC in a prospective phase II trial of concurrent paclitaxel/carboplatin with proton radiation [74 Gy(RBE) in 37 fractions] had modifications to their original treatment plans after re-evaluation revealed changes that would compromise coverage of the target volume or violate dose constraints; plans for the other 35 patients were not changed. We compared patients with adaptive plans with those with nonadaptive plans in terms of dosimetry and outcomes. Results: At a median follow-up of 21.2 months (median overall survival, 29.6 months), no differences were found in local, regional, or distant failure or overall survival between groups. Adaptive planning was used more often for large tumors that shrank to a greater extent (median, 107.1 cm{sup 3} adaptive and 86.4 cm{sup 3} nonadaptive; median changes in volume, 25.3% adaptive and 1.2% nonadaptive; P<.01). The median number of fractions delivered using adaptive planning was 13 (range, 4-22). Adaptive planning generally improved sparing of the esophagus (median absolute decrease in V{sub 70}, 1.8%; range, 0%-22.9%) and spinal cord (median absolute change in maximum dose, 3.7 Gy; range, 0-13.8 Gy). Without adaptive replanning, target coverage would have been compromised in 2 cases (57% and 82% coverage without adaptation vs 100% for both with adaptation); neither patient experienced local failure. Radiation-related grade 3 toxicity rates were similar between groups. Conclusions: Adaptive planning can reduce normal tissue doses and prevent target misses, particularly for patients with large tumors that shrink substantially during therapy. Adaptive plans seem to have acceptable toxicity and achieve similar local, regional, and distant control and overall

Toxicity and dosimetric analysis of non-small cell lung cancer patients undergoing radiotherapy with 4DCT and image-guided intensity modulated radiotherapy: a regional centre's experience.

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Livingston, Gareth C; Last, Andrew J; Shakespeare, Thomas P; Dwyer, Patrick M; Westhuyzen, Justin; McKay, Michael J; Connors, Lisa; Leader, Stephanie; Greenham, Stuart

2016-09-01

For patients receiving radiotherapy for locally advance non-small cell lung cancer (NSCLC), the probability of experiencing severe radiation pneumonitis (RP) appears to rise with an increase in radiation received by the lungs. Intensity modulated radiotherapy (IMRT) provides the ability to reduce planned doses to healthy organs at risk (OAR) and can potentially reduce treatment-related side effects. This study reports toxicity outcomes and provides a dosimetric comparison with three-dimensional conformal radiotherapy (3DCRT). Thirty curative NSCLC patients received radiotherapy using four-dimensional computed tomography and five-field IMRT. All were assessed for early and late toxicity using common terminology criteria for adverse events. All plans were subsequently re-planned using 3DCRT to the same standard as the clinical plans. Dosimetric parameters for lungs, oesophagus, heart and conformity were recorded for comparison between the two techniques. IMRT plans achieved improved high-dose conformity and reduced OAR doses including lung volumes irradiated to 5-20 Gy. One case each of oesophagitis and erythema (3%) were the only Grade 3 toxicities. Rates of Grade 2 oesophagitis were 40%. No cases of Grade 3 RP were recorded and Grade 2 RP rates were as low as 3%. IMRT provides a dosimetric benefit when compared to 3DCRT. While the clinical benefit appears to increase with increasing target size and increasing complexity, IMRT appears preferential to 3DCRT in the treatment of NSCLC.

The Efficacy of Synchronous Combination of Chemotherapy and EGFR TKIs for the First-Line Treatment of NSCLC: A Systematic Analysis.

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Han Yan

Full Text Available The combination of chemotherapy and epidermal growth factor receptor (EGFR tyrosine kinase inhibitors (TKIs currently has become the hotspot issue in the treatment of non-small lung cancer (NSCLC. This systematic review was conducted to compare the efficacy and safety of the synchronous combination of these two treatments with EGFR TKIs or chemotherapy alone in advanced NSCLC.EMBASE, PubMed, the Central Registry of Controlled Trials in the Cochrane Library (CENTRAL, Chinese biomedical literature database (CNKI and meeting summaries were searched. The Phase II/III randomized controlled trials were selected by which patients with advanced NSCLC were randomized to receive a combination of EGFR TKIs and chemotherapy by synchronous mode vs. EGFR TKIs or chemotherapy alone.A total of six randomized controlled trials (RCTs including 4675 patients were enrolled in the systematic review. The meta-analysis demonstrated that the synchronous combination group of chemotherapy and EGFR TKIs did not reach satisfactory results; there was no significant difference in overall survival (OS, time to progression (TTP and objective response rate (ORR, compared with monotherapy (OS: HR = 1.05, 95%CI = 0.98-1.12; TTP: HR = 0.94, 95%CI = 0.89-1.00; ORR: RR = 1.07, 95%CI = 0.98-1.17, and no significant difference in OS and progression-free survival (PFS, compared with EGFR TKIs alone (OS: HR = 1.10, 95% CI = 0.83-1.46; PFS: HR = 0.86, 95% CI = 0.67-1.10. The patients who received synchronous combined therapy presented with increased incidences of grade 3/4 anemia (RR = 1.40, 95% CI = 1.10-1.79 and rash (RR = 7.43, 95% CI = 4.56-12.09, compared with chemotherapy, grade 3/4 anemia (RR = 6.71, 95% CI = 1.25-35.93 and fatigue (RR = 9.60, 95% CI = 2.28-40.86 compared with EGFR TKI monotherapy.The synchronous combination of chemotherapy and TKIs is not superior to chemotherapy or EGFR TKIs alone for the first-line treatment of NSCLC.

FDG-PET-Detected Extracranial Metastasis in Patients with Non-Small Cell Lung Cancer Undergoing Staging for Surgery or Radical Radiotherapy

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Macmanus, Michael P.; Hicks, Rodney; Fisher, Richard; Rischin, Danny; Michael, Michael; Wirth, Andrew; Ball, David L. [Peter MacCallum Cancer Inst., Melbourne (Australia). Dept. of Radiation Oncology

2003-03-01

The prognostic significance of extracranial distant metastasis detected by positron emission tomography (PET) was investigated in patients with non-small cell lung cancer (NSCLC). Forty-two patients staged with 18F-fluorodeoxyglucose-PET-detected distant metastasis before planned surgery (n=7) or radical radiotherapy (RT)/chemoradiotherapy (n=35) for NSCLC were identified from a prospective database. The influence of metastasis number and other prognostic factors was investigated using Cox's regression analysis. Treatment after PET included surgery (n=2), radical RT (n =5), palliative RT (n=25), chemotherapy (n=8) or supportive care (n=2). All but 4 patients had died by the last follow-up. Median survival was 9 months overall, 12 months for 27 patients with single PET-detected metastasis and 5 months for 15 patients with >1 metastasis (p=0.009). It was found that the Eastern Cooperative Oncology Group performance status (p=0.027) but not pre-PET stage, weight loss or metastasis site correlated with survival. PET-detected metastatic tumor burden appeared to influence survival and should be evaluated as a prognostic factor in NSCLC.

Monocarboxylate transporters 1-4 in NSCLC: MCT1 is an independent prognostic marker for survival.

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Marte Eilertsen

Full Text Available INTRODUCTION: Monocarboxylate transporters (MCTs 1-4 are lactate transporters crucial for cancers cells adaption to upregulated glycolysis. Herein, we aimed to explore their prognostic impact on disease-specific survival (DSS in both cancer and tumor stromal cells in NSCLC. METHODS: Tissue micro arrays (TMAs were constructed, representing both cancer and stromal tumor tissue from 335 unselected patients diagnosed with stage I-IIIA NSCLC. Immunohistochemistry was used to evaluate the expression of MCT1-4. RESULTS: In univariate analyses; ↓ MCT1 (P = 0.021 and ↑ MCT4 (P = 0.027 expression in cancer cells, and ↑ MCT1 (P = 0.003, ↓ MCT2 (P = 0.006, ↓ MCT3 (P = 0.020 expression in stromal cells correlated significantly with a poor DSS. In multivariate analyses; ↓ MCT1 expression in cancer cells (HR: 1.9, CI 95%: 1.3-2.8, P = 0.001, ↓ MCT2 (HR: 2.4, CI 95%: 1.5-3.9, P<0.001, ↓ MCT3 (HR: 1.9, CI 95%: 1.1-3.5, P = 0.031 and ↑ MCT1 expression in stromal cells (HR: 1.7, CI 95%: 1.1-2.7, P = 0.016 were significant independent poor prognostic markers for DSS. CONCLUSIONS: We provide novel information of MCT1 as a candidate marker for prognostic stratification in NSCLC. Interestingly, MCT1 shows diverging, independent prognostic impact in the cancer cell and stromal cell compartments.

Resistance gene expression determines the in vitro chemosensitivity of non-small cell lung cancer (NSCLC)

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Glaysher, Sharon; Modi, Paul; Rahamim, Joe; Smith, Mark E; Amer, Khalid; Addis, Bruce; Poole, Matthew; Narayanan, Ajit; Gulliford, Tim J; Andreotti, Peter E; Cree, Ian A; Yiannakis, Dennis; Gabriel, Francis G; Johnson, Penny; Polak, Marta E; Knight, Louise A; Goldthorpe, Zoe; Peregrin, Katharine; Gyi, Mya

2009-01-01

NSCLC exhibits considerable heterogeneity in its sensitivity to chemotherapy and similar heterogeneity is noted in vitro in a variety of model systems. This study has tested the hypothesis that the molecular basis of the observed in vitro chemosensitivity of NSCLC lies within the known resistance mechanisms inherent to these patients' tumors. The chemosensitivity of a series of 49 NSCLC tumors was assessed using the ATP-based tumor chemosensitivity assay (ATP-TCA) and compared with quantitative expression of resistance genes measured by RT-PCR in a Taqman Array™ following extraction of RNA from formalin-fixed paraffin-embedded (FFPE) tissue. There was considerable heterogeneity between tumors within the ATP-TCA, and while this showed no direct correlation with individual gene expression, there was strong correlation of multi-gene signatures for many of the single agents and combinations tested. For instance, docetaxel activity showed some dependence on the expression of drug pumps, while cisplatin activity showed some dependence on DNA repair enzyme expression. Activity of both drugs was influenced more strongly still by the expression of anti- and pro-apoptotic genes by the tumor for both docetaxel and cisplatin. The doublet combinations of cisplatin with gemcitabine and cisplatin with docetaxel showed gene expression signatures incorporating resistance mechanisms for both agents. Genes predicted to be involved in known mechanisms drug sensitivity and resistance correlate well with in vitro chemosensitivity and may allow the definition of predictive signatures to guide individualized chemotherapy in lung cancer

Analysis of esophageal-sparing treatment plans for patients with high-grade esophagitis.

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Niedzielski, Joshua; Bluett, Jaques B; Williamson, Ryan T; Liao, Zhongxing; Gomez, Daniel R; Court, Laurence E

2013-07-08

We retrospectively generated IMRT plans for 14 NSCLC patients who had experienced grade 2 or 3 esophagitis (CTCAE version 3.0). We generated 11-beam and reduced esophagus dose plan types to compare changes in the volume and length of esophagus receiving doses of 50, 55, 60, 65, and 70 Gy. Changes in planning target volume (PTV) dose coverage were also compared. If necessary, plans were renormalized to restore 95% PTV coverage. The critical organ doses examined were mean lung dose, mean heart dose, and volume of spinal cord receiving 50 Gy. The effect of interfractional motion was determined by applying a three-dimensional rigid shift to the dose grid. For the esophagus plan, the mean reduction in esophagus V50, V55, V60, V65, and V70 Gy was 2.8, 4.1, 5.9, 7.3, and 9.5 cm(3), respectively, compared with the clinical plan. The mean reductions in LE50, LE55, LE60, LE65, and LE70 Gy were 2.0, 3.0, 3.8, 4.0, and 4.6 cm, respectively. The mean heart and lung dose decreased 3.0 Gy and 2.4 Gy, respectively. The mean decreases in 90% and 95% PTV coverage were 1.7 Gy and 2.8 Gy, respectively. The normalized plans' mean reduction of esophagus V50, V55, V60, V65, and V70 Gy were 1.6, 2.0, 2.9, 3.9, and 5.5 cm(3), respectively, compared with the clinical plans. The normalized plans' mean reductions in LE50, LE55, LE60, LE65, and LE70 Gy were 4.9, 5.2, 5.4, 4.9, and 4.8 cm, respectively. The mean reduction in maximum esophagus dose with simulated interfractional motion was 3.0 Gy and 1.4 Gy for the clinical plan type and the esophagus plan type, respectively. In many cases, the esophagus dose can be greatly reduced while maintaining critical structure dose constraints. PTV coverage can be restored by increasing beam output, while still obtaining a dose reduction to the esophagus and maintaining dose constraints.

Combined use of anti-ErbB monoclonal antibodies and erlotinib enhances antibody-dependent cellular cytotoxicity of wild-type erlotinib-sensitive NSCLC cell lines

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Cavazzoni Andrea

2012-12-01

Full Text Available Abstract Background The epidermal growth factor receptor (EGFR is an established target for anti-cancer treatment in different tumour types. Two different strategies have been explored to inhibit this pivotal molecule in epithelial cancer development: small molecules TKIs and monoclonal antibodies. ErbB/HER-targeting by monoclonal antibodies such as cetuximab and trastuzumab or tyrosine-kinase inhibitors as gefitinib or erlotinib has been proven effective in the treatment of advanced NSCLC. Results In this study we explored the potential of combining either erlotinib with cetuximab or trastuzumab to improve the efficacy of EGFR targeted therapy in EGFR wild-type NSCLC cell lines. Erlotinib treatment was observed to increase EGFR and/or HER2 expression at the plasma membrane level only in NSCLC cell lines sensitive to the drug inducing protein stabilization. The combined treatment had marginal effect on cell proliferation but markedly increased antibody-dependent, NK mediated, cytotoxicity in vitro. Moreover, in the Calu-3 xenograft model, the combination significantly inhibited tumour growth when compared with erlotinib and cetuximab alone. Conclusion Our results indicate that erlotinib increases surface expression of EGFR and/or HER2 only in EGFR-TKI sensitive NSCLC cell lines and, in turns, leads to increased susceptibility to ADCC both in vitro and in a xenograft models. The combination of erlotinib with monoclonal antibodies represents a potential strategy to improve the treatment of wild-type EGFR NSCLC patients sensitive to erlotinib.

FDG-PET-based radiotherapy planning in lung cancer. Optimum breathing protocol and patient positioning - an intraindividual comparison; FDG-PET-basierte Bestrahlungsplanung von nicht kleinzelligen Bronchialkarzinomen. Optimales Atemprotokoll und Patientenpositionierung - ein intraindividueller Vergleich

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Grgic, A.; Schaefer-Schuler, A.; Kirsch, C.M.; Hellwig, D. [Universitaetsklinikum des Saarlandes, Homburg/Saar (Germany). Klinik fuer Nuklearmedizin; Nestle, U. [Universitaetsklinikum Freiburg (Germany). Klinik fuer Strahlenheilkunde; Kremp, S. [Universitaetsklinikum des Saarlandes, Homburg/Saar (Germany). Klinik fuer Strahlentherapie und Radioonkologie

2008-12-15

FDG-PET and PET / CT is increasingly used for radiotherapy (RT) planning in non-small-cell lung carcinoma (NSCLC). The planning process is often based on separately-acquired FDG-PET / CT and planning CT. We compared intraindividual differences between PET acquired in diagnostic and radiotherapy treatment position coregistered with planning CTs acquired using different breathing protocols. Sixteen patients with NSCLC underwent two PET acquisitions (diagnostic position-D-PET, radiotherapy position-RT-PET) and three planning-CT acquisitions (expiration-EXP, inspiration-INS, mid-breathhold-MID) on the same day. All scans were rigidly coregistered resulting in six fused datasets: D-INS, D-EXP, D-MID, RT-INS, RT-EXP and RT-MID. Fusion accuracy was assessed by three readers at eight anatomical landmarks: lung apices, aortic arch, heart, spine, sternum, carina, diaphragm and tumor using an alignment score ranging from 1 (no alignment) to 5 (exact alignment). RT-PET showed better alignment with any CT than D-PET (p < 0.001). With regard to breathing, RT-MID showed the best mean alignment score (3.7 {+-} 1.0) followed by RT-EXP (3.5 {+-} 0.9) and RT-INS (3.0 {+-} 0.8), all differences being significant (p < 0.001). Comparing the alignment scores with regard to anatomical landmarks, the largest deviations were found at diaphragm, heart and apices. Overall, there was a fair agreement (? = 0.48; p < 0.001) among the three readers. Significantly better fusion of PET and planning-CT can be reached with PET acquired in RT-position. The best intraindividual fusion results are obtained with the planning-CT performed during mid-breathhold. Our data justify the acquisition of a separate planning-PET in RT-treatment position if only a diagnostic PET-scan is available. (orig.)

Evaluation of elastix-based propagated align algorithm for VOI- and voxel-based analysis of longitudinal (18)F-FDG PET/CT data from patients with non-small cell lung cancer (NSCLC).

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Kerner, Gerald Sma; Fischer, Alexander; Koole, Michel Jb; Pruim, Jan; Groen, Harry Jm

2015-01-01

Deformable image registration allows volume of interest (VOI)- and voxel-based analysis of longitudinal changes in fluorodeoxyglucose (FDG) tumor uptake in patients with non-small cell lung cancer (NSCLC). This study evaluates the performance of the elastix toolbox deformable image registration algorithm for VOI and voxel-wise assessment of longitudinal variations in FDG tumor uptake in NSCLC patients. Evaluation of the elastix toolbox was performed using (18)F-FDG PET/CT at baseline and after 2 cycles of therapy (follow-up) data in advanced NSCLC patients. The elastix toolbox, an integrated part of the IMALYTICS workstation, was used to apply a CT-based non-linear image registration of follow-up PET/CT data using the baseline PET/CT data as reference. Lesion statistics were compared to assess the impact on therapy response assessment. Next, CT-based deformable image registration was performed anew on the deformed follow-up PET/CT data using the original follow-up PET/CT data as reference, yielding a realigned follow-up PET dataset. Performance was evaluated by determining the correlation coefficient between original and realigned follow-up PET datasets. The intra- and extra-thoracic tumors were automatically delineated on the original PET using a 41% of maximum standardized uptake value (SUVmax) adaptive threshold. Equivalence between reference and realigned images was tested (determining 95% range of the difference) and estimating the percentage of voxel values that fell within that range. Thirty-nine patients with 191 tumor lesions were included. In 37/39 and 12/39 patients, respectively, thoracic and non-thoracic lesions were evaluable for response assessment. Using the EORTC/SUVmax-based criteria, 5/37 patients had a discordant response of thoracic, and 2/12 a discordant response of non-thoracic lesions between the reference and the realigned image. FDG uptake values of corresponding tumor voxels in the original and realigned reference PET correlated well (R

The correlation between cell-free DNA and tumour burden was estimated by PET/CT in patients with advanced NSCLC

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Nygaard, A D; Holdgaard, Paw; Spindler, K-L G

2014-01-01

Background:Cell-free DNA (cfDNA) circulating in the blood holds a possible prognostic value in malignant diseases. Under malignant conditions, the level of cfDNA increases but the biological mechanism remains to be fully understood. We aimed to examine the correlation between cfDNA and total tumour...... burden defined by positron emission tomography (PET) parameters.Methods:Patients with advanced non-small cell lung cancer (NSCLC) were enrolled into a prospective biomarker trial. Before treatment, plasma was extracted and the level of cfDNA was determined by qPCR. An (18)F-fluorodeoxyglucose ((18)F...... analysis. MTV>the median was associated with a significantly shorter OS (P=0.02). There was no significant difference in OS according to TLG (P=0.08).Conclusion:Cell-free DNA may not be a simple measure of tumour burden, but seems to reflect more complex mechanisms of tumour biology, making it attractive...

Next-Generation Sequencing Workflow for NSCLC Critical Samples Using a Targeted Sequencing Approach by Ion Torrent PGM™ Platform.

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Vanni, Irene; Coco, Simona; Truini, Anna; Rusmini, Marta; Dal Bello, Maria Giovanna; Alama, Angela; Banelli, Barbara; Mora, Marco; Rijavec, Erika; Barletta, Giulia; Genova, Carlo; Biello, Federica; Maggioni, Claudia; Grossi, Francesco

2015-12-03

Next-generation sequencing (NGS) is a cost-effective technology capable of screening several genes simultaneously; however, its application in a clinical context requires an established workflow to acquire reliable sequencing results. Here, we report an optimized NGS workflow analyzing 22 lung cancer-related genes to sequence critical samples such as DNA from formalin-fixed paraffin-embedded (FFPE) blocks and circulating free DNA (cfDNA). Snap frozen and matched FFPE gDNA from 12 non-small cell lung cancer (NSCLC) patients, whose gDNA fragmentation status was previously evaluated using a multiplex PCR-based quality control, were successfully sequenced with Ion Torrent PGM™. The robust bioinformatic pipeline allowed us to correctly call both Single Nucleotide Variants (SNVs) and indels with a detection limit of 5%, achieving 100% specificity and 96% sensitivity. This workflow was also validated in 13 FFPE NSCLC biopsies. Furthermore, a specific protocol for low input gDNA capable of producing good sequencing data with high coverage, high uniformity, and a low error rate was also optimized. In conclusion, we demonstrate the feasibility of obtaining gDNA from FFPE samples suitable for NGS by performing appropriate quality controls. The optimized workflow, capable of screening low input gDNA, highlights NGS as a potential tool in the detection, disease monitoring, and treatment of NSCLC.

Serum tumor markers CEA, CYFRA21-1, and CA-125 are associated with worse prognosis in advanced non-small-cell lung cancer (NSCLC).

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Cedrés, Susana; Nuñez, Isaac; Longo, Marina; Martinez, Pablo; Checa, Eva; Torrejón, Davis; Felip, Enriqueta

2011-05-01

Serum tumor markers are considered a negative prognostic factor in early-stages NSCLC but its role in advanced disease is controversial. The aim of this study is to analyze the prognostic value of tumor markers in advanced NSCLC. Two hundred and seventy seven patients diagnosed in our institution were retrospectively reviewed. Baseline prognostic factors analyzed were gender, histology and brain metastases. Baseline patients characteristics: median age 63 years (30-81 years); males 84.4%, stage IV: 61.7%; adenocarcinoma 38.6%, squamous carcinoma 22.4%. High levels of CEA, CYFRA21-1, and CA125 levels were detected in 179 (55.9%), 119 (65%), and 129 (46.6%) patients respectively. Significant higher levels of CEA and CA125 at baseline were present in adenocarcinoma (P CEA, CYFRA21-1, and CA125 was 5.3 months (m), 3.5 m and 4.6 m versus 7.4 m, 6.2 m and 7.5 m in patients with normal levels (P tumor markers was 10.0 m vs 14.0 m (P = 0.085) for CEA; 5.6 vs 12.1 m for CYFRA21-1 (P = .002), and 8.7 vs 14.0 (P = .03) for CA125. In the multivariate analysis high levels of tumor markers, histology and clinical stage were significant correlated with worse prognostic. Patients with all the tumor markers elevated presented the worst prognosis (3.6 m for PFS and 7.1 m for OS, P tumor markers at baseline are correlated with worse survival in stage III-IV NSCLC patients. Copyright © 2011 Elsevier Inc. All rights reserved.

Resistance gene expression determines the in vitro chemosensitivity of non-small cell lung cancer (NSCLC

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Amer Khalid

2009-08-01

Full Text Available Abstract Background NSCLC exhibits considerable heterogeneity in its sensitivity to chemotherapy and similar heterogeneity is noted in vitro in a variety of model systems. This study has tested the hypothesis that the molecular basis of the observed in vitro chemosensitivity of NSCLC lies within the known resistance mechanisms inherent to these patients' tumors. Methods The chemosensitivity of a series of 49 NSCLC tumors was assessed using the ATP-based tumor chemosensitivity assay (ATP-TCA and compared with quantitative expression of resistance genes measured by RT-PCR in a Taqman Array™ following extraction of RNA from formalin-fixed paraffin-embedded (FFPE tissue. Results There was considerable heterogeneity between tumors within the ATP-TCA, and while this showed no direct correlation with individual gene expression, there was strong correlation of multi-gene signatures for many of the single agents and combinations tested. For instance, docetaxel activity showed some dependence on the expression of drug pumps, while cisplatin activity showed some dependence on DNA repair enzyme expression. Activity of both drugs was influenced more strongly still by the expression of anti- and pro-apoptotic genes by the tumor for both docetaxel and cisplatin. The doublet combinations of cisplatin with gemcitabine and cisplatin with docetaxel showed gene expression signatures incorporating resistance mechanisms for both agents. Conclusion Genes predicted to be involved in known mechanisms drug sensitivity and resistance correlate well with in vitro chemosensitivity and may allow the definition of predictive signatures to guide individualized chemotherapy in lung cancer.

Patient Care Planning: An Interdisciplinary Approach

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Prophet, Colleen M.

1989-01-01

The INFORMM Patient Care Planning System provides interdepartmental communication and individualized patient care plans based upon current standards of care. This interdisciplinary system facilitates the identification of patient problems and nursing diagnoses as well as patient care orders. The selected nurses' and physicians' orders are integrated and organized by care plan categories in printouts. As a system by-product, Patient Care Planning automatically generates and calculates patient ...

Correlation between Pre-treatment Anemia and Prognosis in Non-small Cell Lung Cancer Patients

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Qiuhua DENG

2010-07-01

Full Text Available Background and objective The patients with non-small cell lung cancer (NSCLC might contract anemia, however, whether anemia is one of the independent prognostic factors to the patients with NSCLC is still controversial. So the aim of this study is to investigate the correlation between anemia and overall survival (OS in patients with NSCLC. Methods 1 018 patients with operable NSCLC were retrospectively analyzed in our hospital from January 2000 to December 2008. Results The occurrence of anemia before operation was 252/1 018 (24.1%. The OS in NSCLC patients without anemia was (2 425.98±50.03 days, and the OS in patients with anemia was (2 107.15±93.86 days. There was significant difference in the OS between them (P=0.001. The patients with anemia in stage I had shorter survival time than those without anemia (P < 0.001. But there was no difference in other stage patients. TNM stage, gender, tumor size and lymph nodes metastasis were correlated with OS using Cox regression analysis. Conclusion Anemia is correlated with survival in operable NSCLC patients. Moreover, it is an independent prognostic factor in NSCLC patients with stage I.

The tissue microlocalisation and cellular expression of CD163, VEGF, HLA-DR, iNOS, and MRP 8/14 is correlated to clinical outcome in NSCLC.

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Ohri, Chandra M; Shikotra, Aarti; Green, Ruth H; Waller, David A; Bradding, Peter

2011-01-01

We have previously investigated the microlocalisation of M1 and M2 macrophages in NSCLC. This study investigated the non-macrophage (NM) expression of proteins associated with M1 and M2 macrophages in NSCLC. Using immunohistochemistry, CD68(+) macrophages and proteins associated with either a cytotoxic M1 phenotype (HLA-DR, iNOS, and MRP 8/14), or a non-cytotoxic M2 phenotype (CD163 and VEGF) were identified. NM expression of the markers was analysed in the islets and stroma of surgically resected tumours from 20 patients with extended survival (ES) (median 92.7 months) and 20 patients with poor survival (PS) (median 7.7 months). The NM expression of NM-HLA-DR (pMRP 8/14 (p = 0.02) was increased in ES compared to PS patients in the tumour islets. The tumour islet expression of NM-VEGF, was decreased in ES compared to PS patients (pMRP 8/14 (p = 0.01) expression in the stroma of ES patients compared with PS patients. The 5-year survival for patients with above and below median NM expression of the markers in the islets was 74.9% versus 4.7% (NM-HLA-DR pMRP 8/14 p = 0.04), as opposed to 34.1% versus 44.4% (NM-CD163 p = 0.41) and 19.4% versus 59.0% (NM-VEGF p = 0.001). Cell proteins associated with M1 and M2 macrophages are also expressed by other cell types in the tumour islets and stroma of patients with NSCLC. Their tissue and cellular microlocalisation is associated with important differences in clinical outcome.

Therapeutic value of EGFR inhibition in CRC and NSCLC: 15 years of clinical evidence.

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Troiani, Teresa; Napolitano, Stefania; Della Corte, Carminia Maria; Martini, Giulia; Martinelli, Erika; Morgillo, Floriana; Ciardiello, Fortunato

2016-01-01

Epidermal growth factor receptor (EGFR) plays a key role in tumour evolution, proliferation and immune evasion, and is one of the most important targets for biological therapy, especially for non-small-cell lung cancer (NSCLC) and colorectal cancer (CRC). In the past 15 years, several EGFR antagonists have been approved for the treatment of NSCLC and metastatic CRC (mCRC). To optimise the use of anti-EGFR agents in clinical practice, various clinical and molecular biomarkers have been investigated, thus moving their indication from unselected to selected populations. Nowadays, anti-EGFR drugs represent a gold-standard therapy for metastatic NSCLC harbouring EGFR activating mutation and for RAS wild-type mCRC. Their clinical efficacy is limited by the presence of intrinsic resistance or the onset of acquired resistance. In this review, we provide an overview of the antitumour activity of EGFR inhibitors in NSCLC and CRC and of mechanisms of resistance, focusing on the development of a personalised approach through 15 years of preclinical and clinical research.

Combination of EGFR-TKIs and chemotherapy as first-line therapy for advanced NSCLC: a meta-analysis.

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OuYang, Pu-Yun; Su, Zhen; Mao, Yan-Ping; Deng, Wuguo; Xie, Fang-Yun

2013-01-01

The impact of combining epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and chemotherapy as first-line therapy for patients with advanced non-small-cell lung cancer (NSCLC) remains controversial. Therefore, randomized trials that compared this combined regimen with chemotherapy or EGFR-TKIs monotherapy were included for this meta-analysis. We used published hazard ratios (HRs), if available, or derived treatment estimates from other survival data. Pooled estimates of treatment efficacy of the combined regimen in the entire unselected population and selected patients by EGFR-mutation status and smoking history were calculated. Eight trials eventually entered into this meta-analysis, including 4585 patients. Overall, the combined regimen significantly delayed disease progression (HR = 0.81, 95% CI 0.69-0.95, P = 0.01); subgroup analysis showed significantly higher progression free survival advantages in Asian patients (Pchemotherapy (P = 0.02). In selected patients by EGFR-mutation, both mutation positive (HR = 0.48, 95% CI 0.28-0.83, P = 0.009) and negative (HR = 0.84, 95% CI 0.72-0.98, P = 0.02) patients gained progression free survival benefit from the combined regimen, albeit the magnitude of benefit was marginally larger in mutation positive patients (P = 0.05). In selected patients by smoking history, never/light smokers achieved a great progression free survival benefit from the combined regimen (HR = 0.51, 95% CI 0.35-0.74, P = 0.0004). Unfortunately, the combined regimen had no significant impact on overall survival, irrespective of ethnicity, dose schedules or EGFR-mutation status. Severe anorexia (RR = 2.01, 95% CI 1.11-3.63; P = 0.02) and diarrhea (RR = 2.70, 95% CI 1.94-3.76; Pchemotherapy deserved to be considered in the future, although it is not approved for advanced NSCLC at the moment.

Volumetric response analysis during chemoradiation as predictive tool for optimizing treatment strategy in locally advanced unresectable NSCLC

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Bral, Samuel; Duchateau, Michael; De Ridder, Mark; Everaert, Hendrik; Tournel, Koen; Schallier, Denis; Verellen, Dirk; Storme, Guy

2009-01-01

Purpose: To study the feasibility of measuring volumetric changes in the primary tumor on megavoltage-computed tomography (MVCT) during chemoradiation and to examine the correlation with local response. Patients and methods: Fifteen consecutive patients with stage III, inoperable, locally advanced non-small cell lung cancer (NSCLC) were treated in a prospective dose escalation study protocol of concurrent chemoradiation. They were monitored for acute toxicity and evaluated with daily MVCT imaging. The volumetric changes were fitted to a negative exponential resulting in a regression coefficient (RC). Local response evaluation was done with positron emission tomography using the radio-labeled glucose analogue F18 fluorodeoxyglucose (FDG-PET). Results: The mean volume decrease (±standard deviation) was 73% (±18%). With a mean treatment time of 42 days this treatment schedule resulted in a mean decrease of 1.74%/day. Of the 13 evaluable patients seven developed a metabolic complete remission (MCR). The mean RC of the patients with MCR is 0.050 versus a mean RC of 0.023 in non-responders (p = 0.0074). Using a proposed cut-off value for the RC of 0.03 80% of the non-responders will be detected correctly while misclassifying 16.4% of patients who will eventually achieve an MCR. The total cumulative percentage of esophageal grade 3 or more toxicity was 46.7%. Conclusion: The RC derived from volumetric analysis of daily MVCT is prognostic and predictive for local response in patients treated with chemoradiation for a locally advanced NSCLC. Because this treatment schedule is toxic in nearly half of the patient population, MVCT is a tool in the implementation of patient-individualized treatment strategies.

Multidisciplinary management of non small cell lung cancer (NSCLC in stage III: clinical case description. Recommendations and state of the art

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Simona Carnio

2013-03-01

Full Text Available Lung cancer is the leading cause of cancer death in industrialized countries with progressive increase of its mortality rate. Non Small Cell Lung Cancer (NSCLC is approximately 80-85% of all lung cancers, being adenocarcinoma and squamous cell carcinoma the most common histologies. The majority of the patients with stage III clinical stage, presents a mediastinal lymph node involvement described with computed tomography (TC and/or positron emission tomography (PET. The current approach to patients with NSCLC is multidisciplinary, especially for those staged as potentially operable, both for staging and for a correct definition of best treatment strategy. Updated international and national Guidelines and recommendations can provide valuable support to the clinician.The case described concerns the accidental detection of a tumour in the lung in a 58-year-old man with arterial hypertension controlled with ACE inhibitors. The treatments agreed after a multidisciplinary approach are cisplatin and docetaxel, the surgical resection, and the radiotherapy. After three months the patient has neither metastasis nor relapse.

PGE2 mediates EGFR internalization and nuclear translocation via caveolin endocytosis promoting its transcriptional activity and proliferation in human NSCLC cells.

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Bazzani, Lorenzo; Donnini, Sandra; Giachetti, Antonio; Christofori, Gerhard; Ziche, Marina

2018-03-13

Prostaglandin E 2 (PGE 2 ) contributes to tumor progression by promoting cancer cell growth, invasion and by creating a favorable pro-tumor microenvironment. PGE 2 has been reported to transactivate and internalize into the nucleus receptor tyrosine kinases such as Epidermal growth factor receptor (EGFR), thereby supporting tumor progression. Here we demonstrate that in non-small cell lung carcinoma (NSCLC) cells, PGE 2 induces EGFR nuclear translocation via different dynamin-dependent endocytic pathways, promotes the formation of an EGFR-STAT3 complex, affects nuclear EGFR target gene expression and mediates tumor cell proliferation. Indeed, we find that PGE 2 induces EGFR internalization and consequent nuclear import through Clathrin- and Caveolin-mediated endocytosis and through the interaction of EGFR with Importin β1. Within the nucleus, EGFR forms a complex with STAT3, an event blocked by ablation of Clathrin Heavy Chain or Caveolin-1. The combination of EGF and PGE 2 prolongs nuclear EGFR transcriptional activity manifested by the upregulation of CCND1 , PTGS2 , MYC and NOS2 mRNA levels and potentiates nuclear EGFR-induced NSCLC cell proliferation. Additionally, NSCLC patients with high expression of a nuclear EGFR gene signature display shorter survival times than those with low expression, thus showing a putative correlation between nuclear EGFR and poor prognosis in NSCLC. Together, our findings indicate a complex mechanism underlying PGE 2 -induced EGF/EGFR signaling and transcriptional control, which plays a key role in cancer progression.

Overexpression of matrix metalloproteinase-7 and -9 in NSCLC tumor and stromal cells: correlation with a favorable clinical outcome.

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Stenvold, Helge; Donnem, Tom; Andersen, Sigve; Al-Saad, Samer; Al-Shibli, Khalid; Busund, Lill-Tove; Bremnes, Roy M

2012-02-01

Matrix metalloproteinases (MMPs) are considered important players in angiogenesis and cancer progression. Several drugs developed for targeting MMPs have until now been without clinical efficacy. As both malignant cells and cells of the surrounding stroma contribute to tumor growth, we have explored the impact of MMP-2, -7 and -9 expression in both the tumor and stromal compartment of non-small-cell lung cancers (NSCLC). From 335 unselected stage I to IIIA NSCLC carcinomas, duplicate tumor and tumor-associated stromal cores were collected in tissue microarrays (TMAs). Immunohistochemistry was used to detect the expression of MMP-2, -7 and -9 in tumor and stromal cells. In univariate analyses, high tumor cell MMP-7 expression (P=0.029) and high stromal MMP-9 expression (P=0.001) were positive prognostic factors. In the multivariate analysis, high tumor cell MMP-7 expression (HR 1.58, CI 1.08-2.32, P=0.020) and high stromal MMP-9 expression (HR 1.92, CI 1.25-2.96, P=0.003) were independent positive prognostic factors for disease-specific survival. High levels of MMP-7 in tumor cells and high levels of MMP-9 in tumor associated stroma were independent positive prognostic factors in NSCLC patients. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Percutaneous microwave ablation for early-stage non-small cell lung cancer (NSCLC) in the elderly: a promising outlook

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Acksteiner, Christian; Steinke, Karin

2015-01-01

Microwave ablation (MWA) is a relatively new minimally invasive treatment option for lung cancer with substantially lower morbidity and mortality than surgery. This retrospective study was performed to evaluate the safety, effectiveness and follow-up imaging of MWA in the elderly aged 75 years and above. Eleven percutaneous computed tomography (CT)-guided MWA of early-stage non-small cell lung cancer (NSCLC) were performed in 10 patients aged 75 years and older. All but one patient were treated with a high-powered MWA system delivering maximally 140 W. Follow-up with CT and fluorodeoxyglucose-positron emission tomography (FDG-PET) was carried out over a maximum period of 30 months and a median period of 12 months. There were no peri-procedural deaths or major complications. Seven patients were disease free at the time of manuscript submission. Three patients showed growth of the treated lesions, one patient aged 90 years deceased due to unknown cause after approximately 18 months. One patient presented with local progression and disseminated metastatic disease at 12 months; he is still alive. One patient showed increasing soft tissue at the ablation site 15 months post-treatment. Three consecutive core biopsies over 2 months failed to confirm tumour recurrence. MWA therapy is a promising option of treating early-stage NSCLC in the elderly with good treatment outcome and negligible morbidity. Determining successful treatment outcome may be challenging at times as local tissue increase and PET-CT positivity do not seem to necessarily correlate with recurrence of malignancy.

Pyrosequencing, a method approved to detect the two major EGFR mutations for anti EGFR therapy in NSCLC

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Richard Marie-Jeanne

2011-05-01

Full Text Available Abstract Background Epidermal Growth Factor Receptor (EGFR mutations, especially in-frame deletions in exon 19 (ΔLRE and a point mutation in exon 21 (L858R predict gefitinib sensitivity in patients with non-small cell lung cancer. Several methods are currently described for their detection but the gold standard for tissue samples remains direct DNA sequencing, which requires samples containing at least 50% of tumor cells. Methods We designed a pyrosequencing assay based on nested PCR for the characterization of theses mutations on formalin-fixed and paraffin-embedded tumor tissue. Results This method is highly specific and permits precise characterization of all the exon 19 deletions. Its sensitivity is higher than that of "BigDye terminator" sequencing and enabled detection of 3 additional mutations in the 58 NSCLC tested. The concordance between the two methods was very good (97.4%. In the prospective analysis of 213 samples, 7 (3.3% samples were not analyzed and EGFR mutations were detected in 18 (8.7% patients. However, we observed a deficit of mutation detection when the samples were very poor in tumor cells. Conclusions pyrosequencing is then a highly accurate method for detecting ΔLRE and L858R EGFR mutations in patients with NSCLC when the samples contain at least 20% of tumor cells.

The superiority of hybrid-volumetric arc therapy (VMAT) technique over double arcs VMAT and 3D-conformal technique in the treatment of locally advanced non-small cell lung cancer – A planning study

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Chan, Oscar S.H.; Lee, Michael C.H.; Hung, Albert W.M.; Chang, Amy T.Y.; Yeung, Rebecca M.W.; Lee, Anne W.M.

2011-01-01

Purpose: To compare the dosimetric performance of three different treatment techniques – conformal radiotherapy (CRT), double arcs volumetric modulated arc therapy (RapidArc, RA) and Hybrid-RapidArc (H-RA) for locally-advanced non-small cell lung cancer (NSCLC). Material and methods: CRT, RA and H-RA plans were optimized for 24 stage III NSCLC patients. The target prescription dose was 60 Gy. CRT consisted of 5–7 coplanar fields, while RA comprised of two 204 o arcs. H-RA referred to two 204 o arcs plus 2 static fields, which accounted for approximately half of the total dose. The plans were optimized to fulfill the departmental plan acceptance criteria. Results: RA and H-RA yielded a 20% better conformity compared with CRT. Lung volume receiving >20 Gy (V20) and mean lung dose (MLD) were the lowest in H-RA (V20 1.7% and 2.1% lower, MLD 0.59 Gy and 0.41 Gy lower than CRT and RA respectively) without jeopardizing the low-dose lung volume (V5). H-RA plans gave the lowest mean maximum spinal cord dose (34.4 Gy, 3.9 Gy < CRT and 2.2 Gy < RA plans) and NTCP of lung. Higher average MU per fraction (addition 52.4 MU) was observed with a reduced treatment time compared with CRT plans. Conclusion: The H-RA technique was superior in dosimetric outcomes for treating locally-advanced NSCLC compared to CRT and RA.

EGFR testing and clinical management of advanced NSCLC: a Galician Lung Cancer Group study (GGCP 048-10

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Vázquez S

2016-02-01

Full Text Available Sergio Vázquez,1 Joaquín Casal,2 Francisco Javier Afonso Afonso,3 José Luis Fírvida,4 Lucía Santomé,5 Francisco Barón,6 Martín Lázaro,7 Carolina Pena,7 Margarita Amenedo,8 Ihab Abdulkader,9 Carmen González-Arenas,10 Laura Fachal,11 Ana Vega11 On behalf of the Galician Lung Cancer Group (GGCP1Medical Oncology Department, Lucus Augusti University Hospital, Lugo, 2Medical Oncology Department, University Hospital Complex of Vigo, Pontevedra, 3Medical Oncology Department, University Hospital Complex of Ferrol, Ferrol, 4Medical Oncology Department, University Hospital Complex of Ourense, Ourense, 5Medical Oncology Department Povisa Hospital, Vigo, 6Medical Oncology Department, University Hospital Complex of Santiago de Compostela, Santiago de Compostela, 7Medical Oncology Department, Hospital Complex of Pontevedra, Pontevedra, 8Medical Oncology Department, Oncology Center of Galicia, A Coruña, 9Anatomical Pathology Department, University Hospital Complex of Santiago de Compostela, Santiago de Compostela, 10AstraZeneca, Madrid, 11Galician Public Foundation of Genomic Medicine-SERGAS, Santiago de Compostela Clinic Hospital, Santiago de Compostela, Spain Purpose: This study aimed to assess the incidence of mutations in the epidermal growth factor receptor (EGFR gene in non-small-cell lung cancer (NSCLC patients in the Galician region of Spain and the clinical management and outcome of patients carrying EGFR mutations. Patients and methods: All newly diagnosed advanced or metastatic NSCLC patients were screened for EGFR mutations in matched tumor samples (tissue or cytology specimens and serum samples. Results: Of 198 patients screened for EGFR mutations in tumor samples, 184 had evaluable data and, of these, 25 (13.6% had EGFR mutations (84% sensitizing mutations. EGFR mutation was found in serum in 14 (8.1% patients (of 174 evaluable. Compared to matched tumor tissue, serum EGFR mutation testing specificity and sensitivity were 99% and 52

18F-FAZA PET/CT in the Preoperative Evaluation of NSCLC: Comparison with 18F-FDG and Immunohistochemistry.

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Mapelli, Paola; Bettinardi, Valentino; Fallanca, Federico; Incerti, Elena; Compierchio, Antonia; Rossetti, Francesca; Coliva, Angela; Savi, Annarita; Doglioni, Claudio; Negri, Giampiero; Gianolli, Luigi; Picchio, Maria

2018-01-01

To assess the capability of 18F-FAZA PET/CT in identifying intratumoral hypoxic areas in early and locally advanced non-small cell lung cancer (NSCLC) patients and to compare 18FFAZA PET/CT with 18F-FDG PET/CT and histopathological biomarkers and to investigate whether the assessment of tumour to blood (T/B) and tumour to muscle (T/M) ratios provide comparable information regarding the hypoxic fractions of the tumour. Seven patients with NSCLC were prospectively enrolled (3 men, 4 women; median age: 71 years; range 63-80). All patients underwent to 18F-FDG PET/CT and 18F-FAZA PET/CT before surgery. Maximum standardized uptake value (SUVmax) was used to evaluate 18FFDG PET/CT images, while 18F-FAZA PET/CT images have been interpreted by using tumour-toblood (T/B) and tumour-to-muscle (T/M) ratio. Surgery was performed in all patients; immunohistochemical analysis for hypoxia biomarkers was performed on histologic tumor samples. All lung lesions showed intense 18F-FDG uptake (mean SUVmax: 7.35; range: 2.35-25.20). A faint 18F-FAZA uptake was observed in 6/7 patients (T/B < 1.2) while significant uptake was present in the remaining 1/7 (T/B and T/M=2.24). On both 2 and 4 h imaging after injection, no differences were observed between T/M and T/B (p=0.5), suggesting that both blood and muscle are equivalent in estimating the background activity for image analysis. Immunohisotchemical analysis showed low or absent staining for hypoxia biomarkers in 3 patients (CA-IX and GLUT-1: 0%; HIF-1α: mean 3.3%; range 0-10). Two patients showed staining for HIF-1α of 5%, with CA-IX being 60% and 30%, respectively and GLUT-1 being 30% and 80%, respectively; in 1/7 HIF-1α was 10%, CA-IX was 50% and GLUT-1 was 90%. In one patient a higher percentage of HIF-1α and CA-IX (20% and 70%, respectively) positive cells was present, with GLUT-1 being 30%. To the best of our knowledge, this is the first paper assessing hypoxia and glucose metabolism in comparison with immunohistochemistry

Sarcopenia is a novel poor prognostic factor in male patients with pathological Stage I non-small cell lung cancer.

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Tsukioka, Takuma; Nishiyama, Noritoshi; Izumi, Nobuhiro; Mizuguchi, Shinjiro; Komatsu, Hiroaki; Okada, Satoshi; Toda, Michihito; Hara, Kantaro; Ito, Ryuichi; Shibata, Toshihiko

2017-04-01

Sarcopenia is the progressive loss of muscle mass and strength, and has a risk of adverse outcomes such as disability, poor quality of life and death. As prognosis depends not only on disease aggressiveness, but also on a patient's physical condition, sarcopenia can predict survival in patients with various cancer types. However, its effects on postoperative prognosis in patients with localized non-small cell lung cancers (NSCLC) have never been reported. We retrospectively investigated 215 male patients with pathological Stage I NSCLC. L3 muscle index is defined as the cross-section area of muscle at the third lumbar vertebra level, normalized for height, and is a clinical measurement of sarcopenia. We then investigated the effect of preoperative sarcopenia on their postoperative prognosis. Our 215 subjects included 30 patients with sarcopenia. Sarcopenia was significantly associated with body mass index, nutritional condition, serum CYFRA 21-1 level and pathological stage, but not with preoperative respiratory function or performance status. Frequency of postoperative complications, length of postoperative hospital stay, thoracic drainage period or causes of death were not correlated with the presence of sarcopenia. The sarcopenia group had a significantly shorter median overall survival (32 months) than the no-sarcopenia group. Sarcopenia might not affect short-term outcomes in patients with early-stage lung cancer. Sarcopenia was a predictor of poor prognosis in male patients with Stage I NSCLC. As sarcopenic patients with NSCLC patients are at risk for significantly worse outcomes, their treatments require careful planning, even for those with Stage I disease. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Comparison of the utility of whole-body MRI with and without contrast-enhanced Quick 3D and double RF fat suppression techniques, conventional whole-body MRI, PET/CT and conventional examination for assessment of recurrence in NSCLC patients

International Nuclear Information System (INIS)

Ohno, Yoshiharu; Nishio, Mizuho; Koyama, Hisanobu; Yoshikawa, Takeshi; Matsumoto, Sumiaki; Takenaka, Daisuke; Seki, Shinichiro; Tsubakimoto, Maho; Sugimura, Kazuro

2013-01-01

Purpose: The purpose of this study was to compare diagnostic capabilities for assessment of recurrence in non-small cell lung cancer (NSCLC) patients by contrast-enhanced whole-body MRI (CE-WB-MRI) with and without CE-Quick 3D and double RF fat suppression technique (DFS), FDG-PET/CT and conventional radiological examinations. Materials and methods: A total of 134 pathologically proven and completely resected NSCLC patients (78 males, 56 females; mean age: 72 years) underwent FDG-PET/CT, CE-WB-MRI with and without Quick 3D and DFS at 3 T as well as conventional radiological examinations. The probability of recurrence was assessed with a 5-point scoring system on a per-patient basis, and final diagnosis was made by consensus between two readers. The capability for overall recurrence assessment by all the methods was compared by means of ROC analysis and their sensitivity, specificity and accuracy by means of McNemar's test. Results: Although areas under the curve did not show any significant differences, specificity (100%) and accuracy (95.5%) of CE-WB-MRI with CE-Quick 3D and DFS were significantly higher than those of FDG-PET/CT (specificity: 93.6%, p = 0.02; accuracy: 89.6%, p = 0.01) and conventional radiological examinations (specificity: 92.7%, p = 0.01; accuracy: 91.0%, p = 0.03). In addition, specificity of CE-WB-MRI without CE-Quick 3D and DFS (100%) was significantly higher than that of FDG-PET/CT (p = 0.02) and conventional radiological examinations (p = 0.01). Conclusion: Specificity and accuracy of CE-WB-MRI with CE-Quick 3D and DFS for assessment of recurrence in NSCLC patients are at least as high as, or higher than those of others

Comparison of the utility of whole-body MRI with and without contrast-enhanced Quick 3D and double RF fat suppression techniques, conventional whole-body MRI, PET/CT and conventional examination for assessment of recurrence in NSCLC patients

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Ohno, Yoshiharu, E-mail: yosirad@kobe-u.ac.jp [Advanced Biomedical Imaging Research Center, Kobe University Graduate School of Medicine (Japan); Division of Functional and Diagnostic Imaging Research, Department of Radiology, Kobe University Graduate School of Medicine, Kobe (Japan); Nishio, Mizuho [Advanced Biomedical Imaging Research Center, Kobe University Graduate School of Medicine (Japan); Division of Functional and Diagnostic Imaging Research, Department of Radiology, Kobe University Graduate School of Medicine, Kobe (Japan); Koyama, Hisanobu [Division of Radiology, Department of Radiology, Kobe University Graduate School of Medicine, Kobe (Japan); Yoshikawa, Takeshi; Matsumoto, Sumiaki [Advanced Biomedical Imaging Research Center, Kobe University Graduate School of Medicine (Japan); Division of Functional and Diagnostic Imaging Research, Department of Radiology, Kobe University Graduate School of Medicine, Kobe (Japan); Takenaka, Daisuke [Division of Radiology, Department of Radiology, Kobe University Graduate School of Medicine, Kobe (Japan); Department of Radiology, Hyogo Cancer Center, Akashi (Japan); Seki, Shinichiro [Division of Radiology, Department of Radiology, Kobe University Graduate School of Medicine, Kobe (Japan); Tsubakimoto, Maho [Division of Radiology, Department of Radiology, Kobe University Graduate School of Medicine, Kobe (Japan); Department of Radiology, Graduate School of Medical Science, University of the Ryukyus, Nishihara, Okinawa (Japan); Sugimura, Kazuro [Division of Radiology, Department of Radiology, Kobe University Graduate School of Medicine, Kobe (Japan)

2013-11-01

Purpose: The purpose of this study was to compare diagnostic capabilities for assessment of recurrence in non-small cell lung cancer (NSCLC) patients by contrast-enhanced whole-body MRI (CE-WB-MRI) with and without CE-Quick 3D and double RF fat suppression technique (DFS), FDG-PET/CT and conventional radiological examinations. Materials and methods: A total of 134 pathologically proven and completely resected NSCLC patients (78 males, 56 females; mean age: 72 years) underwent FDG-PET/CT, CE-WB-MRI with and without Quick 3D and DFS at 3 T as well as conventional radiological examinations. The probability of recurrence was assessed with a 5-point scoring system on a per-patient basis, and final diagnosis was made by consensus between two readers. The capability for overall recurrence assessment by all the methods was compared by means of ROC analysis and their sensitivity, specificity and accuracy by means of McNemar's test. Results: Although areas under the curve did not show any significant differences, specificity (100%) and accuracy (95.5%) of CE-WB-MRI with CE-Quick 3D and DFS were significantly higher than those of FDG-PET/CT (specificity: 93.6%, p = 0.02; accuracy: 89.6%, p = 0.01) and conventional radiological examinations (specificity: 92.7%, p = 0.01; accuracy: 91.0%, p = 0.03). In addition, specificity of CE-WB-MRI without CE-Quick 3D and DFS (100%) was significantly higher than that of FDG-PET/CT (p = 0.02) and conventional radiological examinations (p = 0.01). Conclusion: Specificity and accuracy of CE-WB-MRI with CE-Quick 3D and DFS for assessment of recurrence in NSCLC patients are at least as high as, or higher than those of others.

The challenge of NSCLC diagnosis and predictive analysis on small samples. Practical approach of a working group

DEFF Research Database (Denmark)

Thunnissen, Erik; Kerr, Keith M; Herth, Felix J F

2012-01-01

Until recently, the division of pulmonary carcinomas into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) was adequate for therapy selection. Due to the emergence of new treatment options subtyping of NSCLC and predictive testing have become mandatory. A practical approach to...

Influence of the number and interval of treatment cycles on cytokine-induced killer cells and their adjuvant therapeutic effects in advanced non-small-cell lung cancer (NSCLC).

Science.gov (United States)

Gu, Yuanlong; Lv, Huimin; Zhao, Juan; Li, Qi; Mu, Guannan; Li, Jiade; Wuyang, Jiazi; Lou, Ge; Wang, Ruitao; Zhang, Yanqiao; Huang, Xiaoyi

2017-09-01

Cytokine-induced killer (CIK) cells have important therapeutic effects in adoptive cell transfer (ACT) for the treatment of various malignancies. In this study, we focused on in vitro expansion of CIK cells and their clinical efficacy in combination with chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). A total of 64 patients with NSCLC (enrolled from 2011 to 2012), including 32 patients who received chemotherapy alone or with sequential radiotherapy (conventional treatment, control group) and 32 patients who received conventional treatment and sequential CIK infusion (study group), were retrospectively analyzed. The time to progression (TTP), overall survival (OS) and adverse effects were analyzed and the phenotype of lymphocytes in CIK population was also determined by flow cytometry. After in vitro expansion, the average percentage of CIK cells was 26.35%. During the 54-month follow up, the median OS and TTP were significantly longer in the study group than in the control group (P=0.0189 and P=0.0129, respectively). The median OS of the ACT≥4cycles subgroup was significantly longer than that of the ACTcells in patients who received ≥4cycles of ACT was higher than that in patients treated with cells were difficult to expand in vitro in some patients after the first ACT cycle but became much easier as the treatment cycles increased monthly. Longer treatment interval negatively impacted the expansion of CIK cells. Systematic immune levels can be increasingly boosted by reinfusion of ACT. Conventional treatment plus CIK cells is an effective therapeutic strategy to prevent progression and prolong survival of patients with advanced NSCLC. Copyright © 2017. Published by Elsevier B.V.

A phase I, pharmacokinetic, and pharmacodynamic study of panobinostat, an HDAC inhibitor, combined with erlotinib in patients with advanced aerodigestive tract tumors.

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Gray, Jhanelle E; Haura, Eric; Chiappori, Alberto; Tanvetyanon, Tawee; Williams, Charles C; Pinder-Schenck, Mary; Kish, Julie A; Kreahling, Jenny; Lush, Richard; Neuger, Anthony; Tetteh, Leticia; Akar, Angela; Zhao, Xiuhua; Schell, Michael J; Bepler, Gerold; Altiok, Soner

2014-03-15

Panobinostat, a histone deacetylase (HDAC) inhibitor, enhances antiproliferative activity in non-small cell lung cancer (NSCLC) cell lines when combined with erlotinib. We evaluated this combination in patients with advanced NSCLC and head and neck cancer. Eligible patients were enrolled in a 3+3 dose-escalation design to determine the maximum tolerated dose (MTD) of twice weekly panobinostat plus daily erlotinib at four planned dose levels (DL). Pharmacokinetics, blood, fat pad biopsies (FPB) for histone acetylation, and paired pre and posttherapy tumor biopsies for checkpoint kinase 1 (CHK1) expression were assessed. Of 42 enrolled patients, 33 were evaluable for efficacy. Dose-limiting toxicities were prolonged-QTc and nausea at DL3. Adverse events included fatigue and nausea (grades 1-3), and rash and anorexia (grades 1-2). Disease control rates were 54% for NSCLC (n = 26) and 43% for head and neck cancer (n = 7). Of 7 patients with NSCLC with EGF receptor (EGFR) mutations, 3 had partial response, 3 had stable disease, and 1 progressed. For EGFR-mutant versus EGFR wild-type patients, progression-free survival (PFS) was 4.7 versus 1.9 months (P = 0.43) and overall survival was 41 (estimated) versus 5.2 months (P = 0.39). Erlotinib pharmacokinetics was not significantly affected. Correlative studies confirmed panobinostat's pharmacodynamic effect in blood, FPB, and tumor samples. Low CHK1 expression levels correlated with PFS (P = 0.006) and response (P = 0.02). We determined MTD at 30 mg (panobinostat) and 100 mg (erlotinib). Further studies are needed to further explore the benefits of HDAC inhibitors in patients with EGFR-mutant NSCLC, investigate FPB as a potential surrogate source for biomarker investigations, and validate CHK1's predictive role. ©2014 AACR.

Moderate hypofractionated image-guided thoracic radiotherapy for locally advanced node-positive non-small cell lung cancer patients with very limited lung function: a case report

International Nuclear Information System (INIS)

Manapov, Farkhad; Roengvoraphoj, Olarn; Li, Ming Lun; Eze, Chukwuka

2017-01-01

Patients with locally advanced lung cancer and very limited pulmonary function (forced expiratory volume in 1 second [FEV1] ≤ 1 L) have dismal prognosis and undergo palliative treatment or best supportive care. We describe two cases of locally advanced node-positive non-small cell lung cancer (NSCLC) patients with very limited lung function treated with induction chemotherapy and moderate hypofractionated image-guided radiotherapy (Hypo-IGRT). Hypo-IGRT was delivered to a total dose of 45 Gy to the primary tumor and involved lymph nodes. Planning was based on positron emission tomography-computed tomography (PET/ CT) and four-dimensional computed tomography (4D-CT). Internal target volume (ITV) was defined as the overlap of gross tumor volume delineated on 10 phases of 4D-CT. ITV to planning target volume margin was 5 mm in all directions. Both patients showed good clinical and radiological response. No relevant toxicity was documented. Hypo-IGRT is feasible treatment option in locally advanced node-positive NSCLC patients with very limited lung function (FEV1 ≤ 1 L)

Moderate hypofractionated image-guided thoracic radiotherapy for locally advanced node-positive non-small cell lung cancer patients with very limited lung function: a case report

Energy Technology Data Exchange (ETDEWEB)

Manapov, Farkhad; Roengvoraphoj, Olarn; Li, Ming Lun; Eze, Chukwuka [Dept. of Radiation Oncology, Ludwig-Maximilian University of Munich, Munich (Germany)

2017-06-15

Patients with locally advanced lung cancer and very limited pulmonary function (forced expiratory volume in 1 second [FEV1] ≤ 1 L) have dismal prognosis and undergo palliative treatment or best supportive care. We describe two cases of locally advanced node-positive non-small cell lung cancer (NSCLC) patients with very limited lung function treated with induction chemotherapy and moderate hypofractionated image-guided radiotherapy (Hypo-IGRT). Hypo-IGRT was delivered to a total dose of 45 Gy to the primary tumor and involved lymph nodes. Planning was based on positron emission tomography-computed tomography (PET/ CT) and four-dimensional computed tomography (4D-CT). Internal target volume (ITV) was defined as the overlap of gross tumor volume delineated on 10 phases of 4D-CT. ITV to planning target volume margin was 5 mm in all directions. Both patients showed good clinical and radiological response. No relevant toxicity was documented. Hypo-IGRT is feasible treatment option in locally advanced node-positive NSCLC patients with very limited lung function (FEV1 ≤ 1 L)

Improvement of Radiation-Mediated Immunosuppression of Human NSCLC Tumour Xenografts in a Nude Rat Model

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Sergey V. Tokalov

2010-01-01

Full Text Available Human tumour xenografts in a nude rat model have consistently been used as an essential part of preclinical studies for anticancer drugs activity in human. Commonly, these animals receive whole body irradiation to assure immunosuppression. But whole body dose delivery might be inhomogeneous and the resulting incomplete bone marrow depletion may modify tumour behaviour. To improve irradiation-mediated immunosuppression of human non-small cell lung cancer (NSCLC xenografts in a nude rat model irradiation (2 + 2 Gy from opposite sides of animals has been performed using a conventional X-ray tube. The described modification of whole body irradiation improves growth properties of human NSCLC xenografts in a nude rat model. The design of the whole body irradiation mediated immunosuppression described here for NSCLC xenografts may be useful for research applications involving other types of human tumours.

The feasibility of evaluating radiation dose to the heart by integrating kilovoltage-cone beam computed tomography in stereotactic body radiotherapy of early non-small-cell lung cancer patients

International Nuclear Information System (INIS)

Liu, Chengxin; Gong, Guanzhong; Guo, Chen; Liu, Tonghai; Lu, Jie; Zhao, Hong; Dong, Wei; Yin, Yong

2013-01-01

To investigate the feasibility of contouring the planning risk organ volume (PRV) for the heart, and to determine the probability of evaluating radiation dose to the heart using kilovoltage-cone beam computed tomography (kV-CBCT) in early-stage non-small-cell lung cancer (NSCLC) patients, who received stereotactic body radiotherapy (SBRT). Seventeen NSCLC patients who received SBRT (5Gy/f × 10f dose) were enrolled and subjected to CBCT and CT imaging analyses to plan treatment. Sequential planning CBCT images of individual patient’s hearts were analyzed for reproducibility of heart contouring and volume. Comparative analyses were made between the planning CT- and CBCT-detected heart margins and dose-volume indices for treatment. The heart volume from planning CT images was significantly smaller than that from CBCT scans (p < 0.05), and the volumes based on the different series of CBCT images were similar (p > 0.05).The overlap of the heart region on the same anatomical section between the first series of CBCT scans and other scans reached 0.985 ± 0.020 without statistically significant differences (p > 0.05). The mean margins of the heart from planning CT and CBCT scans were 10.5 ± 2.8 mm in the left direction, 5.9 ± 2.8 mm in the right direction, 2.2 ± 1.6 mm in the direction of the head, 3.3 ± 2.2 mm in the direction of the foot, 6.7 ± 1.1 mm in the anterior direction, and 4.5 mm ± 2.5 mm in the posterior direction. All relative and absolute dose-volume indices obtained from CBCT images were significantly larger than those from planning CT scans (p < 0.05), with the exception of the volume in the 5Gy region. The PRV of heart contouring based on kV-CBCT is feasible with good reproducibility. More accurate and objective dose-volume indices may be obtained for NSCLC patients by using kV-CBCT, instead of CT, to plan SBRT

18F-Fluoromisonidazole (FMISO) as a molecular marker of hypoxia in non small cell lung carcinoma (NSCLC)

International Nuclear Information System (INIS)

Pathmaraj, K.; Foo, S.; Sachinidis, J.; Scott, A.M.

2002-01-01

Full text: FMISO is a hypoxic marker with the potential ability to predict tumour resistance to chemoradiation. We present preliminary findings from pilot studies to determine the significance of FMISO Positron Emission Tomography (PET) in NSCLC. We are currently studying 2 cohorts of patients with NSCLC and a case study will be presented from each cohort. Patients in the first cohort have surgically resectable tumours: we aim to evaluate the extent of intratumoural hypoxia preoperatively and then validate and correlate this at a molecular level. Patients in the second cohort have locally advanced disease being treated with radiotherapy and will have pretreatment and sequential FMISO-PET scans. Mr GH, a 51 year old man presented with a suspicious lesion in the right upper lobe of the lung. Biopsy was non diagnostic and a FDG-PET scan showed a hypermetabolic focus in the right upper lobe highly indicative of malignancy. The FMISO-PET scan showed a small hypoxic area in the right upper lobe of the lung. The FDG-PET and FMISO-PET images were coregistered and the hypoxic focus correlated well with the hypermetabolic FDG focus. Wedge resection demonstrated moderately differentiated adenocarcinoma. Mr JS was a 61-year-old male with stage III inoperable NSCLC. CT scan showed extensive disease around the left lung hilum with mediastinal lymphadenopathy. The FDG-PET scan showed metabolic findings consistent with a large necrotic malignancy in the left lung with left hilar and mediastinal nodal involvement. FMISO uptake was observed in the left lung hilum corresponding to the areas of FDG uptake. A subsequent FMISO-PET study midway through his radiotherapy showed decreased tracer concentration in the left hilar region with a suggestion of cystic changes inferiorly to the hilum. To our knowledge, there has been no correlation of FMISO-PET studies with molecular markers of hypoxia. This pilot study will be important in confirming FMISO-PET studies as a feasible non invasive

Analysis of Differentially Expressed Proteome in Urine 
from Non-small Cell Lung Cancer Patients

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Zhengang CHEN

2015-03-01

Full Text Available Background and objective Screen differentially expressed proteins in patients with non-small cell lung cancer (NSCLC, and aim to identify biomarkers for early screening, monitoring prognosis and evaluating therapy of NSCLC. Methods Urinary samples were collected from 40 newly diagnosed NSCLC patients, 8 patients with lung benign disorders and 22 healthy people. 0.9% sodium dodecylsulfate- polyacrylamide gel electrophoresis (1D SDS-PAGE and MS-Thermo-Orbitrap-Velos were applied to separate, extract and identify proteins in urinary samples from non-neoplastic groups and NSCLC patients, in order to find out differentially expressed proteins in patients with NSCLC. Then, sensitivity and specificity of candidate proteins were tested by certain experiments. Finally, biomarkers related to NSCLC could be determined. Results The differences of urinary proteins between non-neoplastic groups and NSCLC patients mainly focused on 90 kDa, 60 kDa and 20 kDa-30 kDa stripes. Four differently expressed proteins were found in urinary proteins in NSCLC group, including LRG1, CA1 (up-regulating proteins and VPS4B, YWHAZ (down-regulating proteins. The sensitivity of these four proteins for biomarker of NSCLC was relatively low when they were used to screen or diagnose independently. The sensitivity and specificity of LRG1 was 83.0% (25/30 and 90.0% (18/20, respectively; 60.0% (18/30 and 90.0% (18/20 for CA1; 73.3% (22/30 and 90.0% (18/20 for VPS4B; 60.0% (18/30 and 95.0% (19/20 for YWHAZ. However, the sensitivity and specificity would increase to 96.7% (29/30 and 85% (17/20 after the four biomarkers were combined. Conclusion LRG1 and CA1 are abundant in urine in patients with NSCLC, while VPS4B and YWHAZ are low-abundance proteins. They could be regarded as biomarkers for early screening, monitoring prognosis and evaluating therapy of patients with NSCLC because of differential expression. The sensitivity of the four biomarkers of NSCLC is relatively low when they

SU-F-J-207: Non-Small Cell Lung Cancer Patient Survival Prediction with Quantitative Tumor Textures Analysis in Baseline CT

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Wu, Y; Zou, J; Murillo, P; Nosher, J; Amorosa, J; Bramwit, M; Yue, N; Jabbour, S; Foran, D [Rutgers University, New Brunswick, NJ (United States)

2016-06-15

Purpose: Chemo-radiation therapy (CRT) is widely used in treating patients with locally advanced non-small cell lung cancer (NSCLC). Determination of the likelihood of patient response to treatment and optimization of treatment regime is of clinical significance. Up to date, no imaging biomarker has reliably correlated to NSCLC patient survival rate. This pilot study is to extract CT texture information from tumor regions for patient survival prediction. Methods: Thirteen patients with stage II-III NSCLC were treated using CRT with a median dose of 6210 cGy. Non-contrast-enhanced CT images were acquired for treatment planning and retrospectively collected for this study. Texture analysis was applied in segmented tumor regions using the Local Binary Pattern method (LBP). By comparing its HU with neighboring voxels, the LBPs of a voxel were measured in multiple scales with different group radiuses and numbers of neighbors. The LBP histograms formed a multi-dimensional texture vector for each patient, which was then used to establish and test a Support Vector Machine (SVM) model to predict patients’ one year survival. The leave-one-out cross validation strategy was used recursively to enlarge the training set and derive a reliable predictor. The predictions were compared with the true clinical outcomes. Results: A 10-dimensional LBP histogram was extracted from 3D segmented tumor region for each of the 13 patients. Using the SVM model with the leave-one-out strategy, only 1 out of 13 patients was misclassified. The experiments showed an accuracy of 93%, sensitivity of 100%, and specificity of 86%. Conclusion: Within the framework of a Support Vector Machine based model, the Local Binary Pattern method is able to extract a quantitative imaging biomarker in the prediction of NSCLC patient survival. More patients are to be included in the study.

SU-F-J-207: Non-Small Cell Lung Cancer Patient Survival Prediction with Quantitative Tumor Textures Analysis in Baseline CT

International Nuclear Information System (INIS)

Wu, Y; Zou, J; Murillo, P; Nosher, J; Amorosa, J; Bramwit, M; Yue, N; Jabbour, S; Foran, D

2016-01-01

Purpose: Chemo-radiation therapy (CRT) is widely used in treating patients with locally advanced non-small cell lung cancer (NSCLC). Determination of the likelihood of patient response to treatment and optimization of treatment regime is of clinical significance. Up to date, no imaging biomarker has reliably correlated to NSCLC patient survival rate. This pilot study is to extract CT texture information from tumor regions for patient survival prediction. Methods: Thirteen patients with stage II-III NSCLC were treated using CRT with a median dose of 6210 cGy. Non-contrast-enhanced CT images were acquired for treatment planning and retrospectively collected for this study. Texture analysis was applied in segmented tumor regions using the Local Binary Pattern method (LBP). By comparing its HU with neighboring voxels, the LBPs of a voxel were measured in multiple scales with different group radiuses and numbers of neighbors. The LBP histograms formed a multi-dimensional texture vector for each patient, which was then used to establish and test a Support Vector Machine (SVM) model to predict patients’ one year survival. The leave-one-out cross validation strategy was used recursively to enlarge the training set and derive a reliable predictor. The predictions were compared with the true clinical outcomes. Results: A 10-dimensional LBP histogram was extracted from 3D segmented tumor region for each of the 13 patients. Using the SVM model with the leave-one-out strategy, only 1 out of 13 patients was misclassified. The experiments showed an accuracy of 93%, sensitivity of 100%, and specificity of 86%. Conclusion: Within the framework of a Support Vector Machine based model, the Local Binary Pattern method is able to extract a quantitative imaging biomarker in the prediction of NSCLC patient survival. More patients are to be included in the study.

A prospective randomized study of postoperative adjuvant chemo-radiotherapy (CT+RT) vs. radiotherapy(RT) alone in resected stage II and IIIA non-small cell lung cancer (NSCLC)

International Nuclear Information System (INIS)

Chang, Geol Lee; Joo, Hang Kim; Kyung, Young Chung; Doo, Yun Lee; Kil, Dong Kim; Won, Young Lee; Sung, Kyu Kim; Sei, Kyu Kim; Gwi, Eon Kim

1995-01-01

Objective: A prospective randomized study has been conducted to compare the results of treatment between CT+RT and RT alone as an adjuvant setting in completely resected stage II and IIIA NSCLC. Materials and Methods: Patients who had completely resected stage II and IIIA NSCLC were randomized into a CT+RT arm(arm A) and a RT alone arm(arm B) as an adjuvant setting after stratification according to cell type(squamous vs. non-squamous) and stage(II vs. IIIA). CT(Etoposide 100mg/m2 I.V. infusion d1-3, Cisplatin 20mg/m2 I.V. infusion d1-5, total 6cycles) was started in postop. 3 weeks with a 4 weeks interval. RT(5040cGy/5-6wks, 180cGy/fr) was started in postoperative 5 weeks after the first cycle of CT for group A and in postoperative 4 weeks for group B. A total of 69 patients were registered from Sep. 1990 to Jun. 1993. Sixty five of these patients were evaluable because 4 patients were ineligible due to distant metastasis before adjuvant treatment. Two patients who refused adjuvant treatment were included in this study to avoid selection bias. Results: Sixteen patients (48%) have received CT of more than 3 cycles and 51 patients(78%) have received RT of more than 50Gy. Four patients died due to treatment-related complications [broncho-pleural fistula 3(arm A:B=2:1), pneumonia 1(arm A)]. Survival and the patterns of failure are as follows: Conclusion: There is no statistical significance in either the overall survival or the patterns of failure between the CT+RT arm and RT alone arm as an adjuvant setting in resected stage II and IIIA NSCLC

The relationship between glasgow prognostic score and serum tumor markers in patients with advanced non-small cell lung cancer

International Nuclear Information System (INIS)

Jiang, Ai-Gui; Chen, Hong-Lin; Lu, Hui-Yu

2015-01-01

Glasgow Prognostic Score (GPS) has been reported as a powerful prognostic tool for patients with advanced non–small cell lung cancer (NSCLC). The aim of this study was to assess the relationship between GPS and prognosis related tumor markers in patients with advanced NSCLC. We included 138 advanced NSCLC patients and twenty healthy controls in the study. GPS was calculated by combined serum C-reactive protein (CRP) and albumin. Three serum tumor markers, which included cytokeratin 19 fragment antigen 21-1 (CYFRA21–1), carcinoembryonic antigen (CEA) and tissue polypeptide specific antigen (TPS), were detected by enzyme-linked immunosorbent assay (ELISA). GPS and tumor markers were all assessed before chemotherapy. All patients received at least 2 courses of cisplatin-based chemotherapy. After that, 2 to 5 years follow-up was conducted. Median levels of CYFRA21–1 were 1.5 ng/ml (0.1–3.1 ng/ml) in healthy controls, and 4.6 ng/ml (0.7–35.2 ng/ml) in GPS 0 advanced NSCLC, 11.2 ng/ml (0.4–89.2) ng/ml in GPS 1 advanced NSCLC, and 15.7 ng/ml (2.9–134.6 ng/ml) in GPS 2 advanced NSCLC, respectively. Median levels of CYFRA21-1 were higher in NSCLC patients than in healthy controls, and CYFRA21-1 increased gradually according to GPS category in NSCLC patients (P < 0.05). Similar results were found for median levels of CEA and TPS in healthy controls and NSCLC patients (P < 0.05). In NSCLC patients, positive correlations were found between CYFRA21-1 and GPS, CEA and GPS, TPS and GPS. The Spearman’s rank correlation coefficient were 0.67 (P < 0.05), 0.61 (P < 0.05) and 0.55 (P < 0.05), respectively. Survival analyses showed GPS was an independent prognostic factor for advanced NSCLC. CYFRA21-1(>3.3 ng/ml) and TPS (>80 U/l) were related with the prognosis of advanced NSCLC by univariate analyses, but multivariate analyses showed CYFRA21-1, TPS and CEA were not the independent prognostic factors for advanced NSCLC. Our results showed GPS were positive correlated

Three-dimensional conformal radiotherapy by delineations on CT-based simulation in different respiratory phases for the treatment of senile patients with non-small cell lung cancer.

Science.gov (United States)

Wang, Weifeng; Yuan, Feng; Wang, Guoping; Lin, Zhiren; Pan, Yanling; Chen, Longhua

2015-01-01

This study aimed to evaluate the application of three-dimensional conformal radiotherapy (3D-CRT) for elderly patients with non-small cell lung cancer (NSCLC) based on computed tomography (CT) simulations in different respiratory phases. A total of 64 patients aged >70 years old with NSCLC were treated by 3D-CRT using CT images in different respiratory phases. The gross tumor volumes (GTVs) at the end of inspiration and end of expiration were combined to obtain the total GTV, which was close to the motional range of tumors during respiration, and no additional expansion of the clinical target volume (CTAV) to planning target volume (PTV) (CTAV:PTV) was included during the recording of respiratory movements. Patients were also planned according to the classic 3D-CRT approach. Efficacy, prognostic factors, and side effects were evaluated. Compared with the classic approach, the average PTV was 18.9% lower (median: 17.3%), and the average lung volume receiving a prescribed dose for a tumor was 22.4% lower (median: 20.9%). The 1-, 2-, and 3-year survival rates were 70.6%, 54.9%, and 29.4%, respectively, with an overall tumor response rate of 79.7%. The Karnofsky performance status and N stage were independent prognostic factors, whereas age was not. Without affecting therapeutic effects, CT simulations in different respiratory phases were well-tolerated in elderly patients with NSCLC, could effectively reduce PTV, and could improve the quality of life.

Role of Radiotherapy in Metastatic Non-small Cell Lung Cancer (NSCLC

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Sergio L. Faria

2014-10-01

Full Text Available Radiotherapy has had important role in the palliation of NSCLC. Randomized trials tend to suggest that, in general, short regimens give similar palliation and toxicity compared to longer regimens. The benefit of combining chemotherapy to radiosensitize the palliative radiation treatment is an open question, but so far it has not been proved to be very useful in NSCLC. The addition of molecular targeted drugs to radiotherapy outside of approved regimens or clinical trials warrants careful consideration for every single case and probably should not be used as a routine management.Stereotactic radiosurgery (SRS and stereotactic body radiation therapy (SBRT are modern techniques being used each time more frequently in the treatment of single or oligometastases. In general, they offer good tumour control with little toxicity (with a more expensive cost compared to the traditionally fractionated radiotherapy regimens.

The relationship between Glasgow Prognostic Score and serum tumor markers in patients with advanced non-small cell lung cancer.

Science.gov (United States)

Jiang, Ai-Gui; Chen, Hong-Lin; Lu, Hui-Yu

2015-05-10

Glasgow Prognostic Score (GPS) has been reported as a powerful prognostic tool for patients with advanced non-small cell lung cancer (NSCLC). The aim of this study was to assess the relationship between GPS and prognosis related tumor markers in patients with advanced NSCLC. We included 138 advanced NSCLC patients and twenty healthy controls in the study. GPS was calculated by combined serum C-reactive protein (CRP) and albumin. Three serum tumor markers, which included cytokeratin 19 fragment antigen 21-1 (CYFRA21-1), carcinoembryonic antigen (CEA) and tissue polypeptide specific antigen (TPS), were detected by enzyme-linked immunosorbent assay (ELISA). GPS and tumor markers were all assessed before chemotherapy. All patients received at least 2 courses of cisplatin-based chemotherapy. After that, 2 to 5 years follow-up was conducted. Median levels of CYFRA21-1 were 1.5 ng/ml (0.1-3.1 ng/ml) in healthy controls, and 4.6 ng/ml (0.7-35.2 ng/ml) in GPS 0 advanced NSCLC, 11.2 ng/ml (0.4-89.2) ng/ml in GPS 1 advanced NSCLC, and 15.7 ng/ml (2.9-134.6 ng/ml) in GPS 2 advanced NSCLC, respectively. Median levels of CYFRA21-1 were higher in NSCLC patients than in healthy controls, and CYFRA21-1 increased gradually according to GPS category in NSCLC patients (PGPS, CEA and GPS, TPS and GPS. The Spearman's rank correlation coefficient were 0.67 (P GPS was an independent prognostic factor for advanced NSCLC. CYFRA21-1(>3.3 ng/ml) and TPS (>80 U/l) were related with the prognosis of advanced NSCLC by univariate analyses, but multivariate analyses showed CYFRA21-1, TPS and CEA were not the independent prognostic factors for advanced NSCLC. Our results showed GPS were positive correlated with CYFRA21-1, CEA and TPS in patients with advanced NSCLC. However, GPS was more efficient in predicting prognosis of advanced NSCLC than these three single prognosis related tumor markers.

Prediction of PET/CT to alleviate radiation pneumonitis in patients with non-small cell lung cancer for 3-dimentional conformal radiotherapy

International Nuclear Information System (INIS)

Gong Heyi; Yu Jinming; Li Jianbin; Li Baosheng; Fu Zheng; Liu Tonghai

2005-01-01

Objective: To investigate the impact of PET/CT on clinical staging of non-small cell lung cancer (NSCLC), delineation of target volume, and prediction to alleviate radiation pneumonitis (RP) from 3-dimentional conformal radiotherapy (3D-CRT) planning. Methods: From October 2002 to June 2004, 34 patients diagnosed cytologically or pathologically with NSCLC, who were candidates for radical radiotherapy or surgery, received PET/CT scanning. Both images were transmitted into treatment planning system (TPS) workstations respectively and were fused and reconstructed. All patients were staged according to the 1997 World Health Organization (WHO) staging system. The impact of PET/CT on the clinical staging of all the patients was determined. The gross tumor volume (GTV) was delineated on the CT imaging and PET/CTfused imaging respectively. Based on the two images, 3D- CRT planning was made respectively at the TPS workstation with Topslane software, the planning target volumes (PTV) being defined with a 15 mm margin around GTV of primary lumps (PTV 1 ) and 7 mm for involved lymph nodes (PTV 2 ). Evaluating indexes including V PTV (volume of PTV, V PTV = V PTV1 + V PTV2 ), V 20 (percentage of the total lung volume receiving more than 20 Gy), MLD (mean lung dose) , TCP (tumor control probability) , NTCP (normal tissue complication probability) , and Ds (dose to spinal cord) were selected to be paralleled to compare the quality of the two plans and the impact of PET/CT on RP was further analyzed. Results: In 13 of 34 (38.2%) cases, PET/CT information changed the clinical staging, 8 of which were upstaged and 5 downstaged. For 10 of 34 (29.4%) cases, PET/CT results modified their management decisions. Among 16 patients performed by surgery, 14 had consistent PET/CT staging with pathologic staging. The sensitivity of PET/CT was 93.3% and accuracy 87.5%. Difference of indexes including V PTV , V 20 and MLD between the two radiation planning was statistically significant, but Ds

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.

Impact of target area selection in 125 Iodine seed brachytherapy on locoregional recurrence in patients with non-small cell lung cancer.

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Yan, Wei-Liang; Lv, Jin-Shuang; Guan, Zhi-Yu; Wang, Li-Yang; Yang, Jing-Kui; Liang, Ji-Xiang

2017-05-01

Computed tomography (CT)-guided percutaneous implantation of 125 Iodine radioactive seeds requires the precise arrangement of seeds by tumor shape. We tested whether selecting target areas, including subclinical areas around tumors, can influence locoregional recurrence in patients with non-small cell lung cancer (NSCLC). We divided 82 patients with NSCLC into two groups. Target areas in group 1 (n = 40) were defined along tumor margins based on lung-window CT. Target areas in group 2 (n = 42) were extended by 0.5 cm in all dimensions outside tumor margins. Preoperative plans for both groups were based on a treatment plan system, which guided 125 I seed implantation. Six months later, patients underwent chest CT to evaluate treatment efficacy (per Response Evaluation Criteria in Solid Tumors version 1). We compared locoregional recurrences between the groups after a year of follow-up. We then used the treatment plan system to extend target areas for group 1 patients by 0.5 cm (defined as group 3 data) and compared these hypothetical group 3 planned seeds with the actual seed numbers used in group 1 patients. All patients successfully underwent implantation; none died during the follow-up period. Recurrence was significantly lower in group 2 than in group 1 ( P  area for 125 I seeds can decrease recurrence risk by eradicating cancerous lymph-duct blockades within the extended areas. © 2017 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

The tissue microlocalisation and cellular expression of CD163, VEGF, HLA-DR, iNOS, and MRP 8/14 is correlated to clinical outcome in NSCLC.

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Chandra M Ohri

Full Text Available BACKGROUND: We have previously investigated the microlocalisation of M1 and M2 macrophages in NSCLC. This study investigated the non-macrophage (NM expression of proteins associated with M1 and M2 macrophages in NSCLC. METHODS: Using immunohistochemistry, CD68(+ macrophages and proteins associated with either a cytotoxic M1 phenotype (HLA-DR, iNOS, and MRP 8/14, or a non-cytotoxic M2 phenotype (CD163 and VEGF were identified. NM expression of the markers was analysed in the islets and stroma of surgically resected tumours from 20 patients with extended survival (ES (median 92.7 months and 20 patients with poor survival (PS (median 7.7 months. RESULTS: The NM expression of NM-HLA-DR (p<0.001, NM-iNOS (p = 0.02 and NM-MRP 8/14 (p = 0.02 was increased in ES compared to PS patients in the tumour islets. The tumour islet expression of NM-VEGF, was decreased in ES compared to PS patients (p<0.001. There was more NM-CD163 expression (p = 0.04 but less NM-iNOS (p = 0.002 and MRP 8/14 (p = 0.01 expression in the stroma of ES patients compared with PS patients. The 5-year survival for patients with above and below median NM expression of the markers in the islets was 74.9% versus 4.7% (NM-HLA-DR p<0.001, 65.0% versus 14.6% (NM-iNOS p = 0.003, and 54.3% versus 22.2% (NM-MRP 8/14 p = 0.04, as opposed to 34.1% versus 44.4% (NM-CD163 p = 0.41 and 19.4% versus 59.0% (NM-VEGF p = 0.001. CONCLUSIONS: Cell proteins associated with M1 and M2 macrophages are also expressed by other cell types in the tumour islets and stroma of patients with NSCLC. Their tissue and cellular microlocalisation is associated with important differences in clinical outcome.

Clinical decision-making and health-related quality of life during first-line and maintenance therapy in patients with advanced non-small cell lung cancer (NSCLC): findings from a real-world setting.

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Sztankay, Monika; Giesinger, Johannes Maria; Zabernigg, August; Krempler, Elisabeth; Pall, Georg; Hilbe, Wolfgang; Burghuber, Otto; Hochmair, Maximilian; Rumpold, Gerhard; Doering, Stephan; Holzner, Bernhard

2017-08-23

Maintenance therapy (MT) with pemetrexed has been shown to improve overall and progression-free survival of patients with non-squamous non-small cell lung cancer (NSCLC), without impairing patients' health-related quality of life (HRQOL) substantially. Comprehensive data on HRQOL under real-life conditions are necessary to enable informed decision-making. This study aims to (1) assess HRQOL during first-line chemotherapy and subsequent MT and (2) record patients' and physicians' reasons leading to clinical decisions on MT. Patients treated for NSCLC at three Austrian medical centres were included. HRQOL was assessed at every chemotherapy cycle using the EORTC QLQ-C30/+LC13 questionnaire. Semi-structured interviews were conducted before MT initiation and at the time of discontinuation to evaluate patients' and physicians' reasons for treatment decisions. Longitudinal QOL analysis was based on linear mixed models. Sixty-one (73%) out of 84 patients were considered for MT. Thirty-six patients (43%) received MT and 29 (35%) discontinued therapy. Decisions on MT initiation (in 20 cases by the physician vs 4 by the patient) and discontinuation (19 vs 10) were mainly voiced by the physician. Treatment toxicity of first-line chemotherapy was the main reason for rejection of MT in patients with stable disease and was more often indicated by patients than clinicians. HRQOL data were collected from 83 patients at 422 assessment time points and indicated significantly lower symptom severity during MT compared with first-line therapy for nausea and vomiting (p = 0.006), sleep disturbances (p loss (p = 0.043), constipation (p = 0.017) and chest pain (p = 0.022), and a deterioration in emotional functioning (p = 0.023) and cognitive functioning (p = 0.044) during MT. Our results indicate that HRQOL and symptom burden improve between first-line treatment to MT in some respects, although some late toxicity persists. Discrepancies between patients' and physicians

Factors which influence quality of life in patients with non-small cell lung cancer (NSCLC): A radiation therapy oncology group study (RTOG 89-01)

International Nuclear Information System (INIS)

Scott, C.B.; Sause, W.T.; Johnson, D.; Dar, A.R.; Wasserman, T.H.; Rubin, P.; Khandekar, J.; Byhardt, R.B.; Taylor, S.; McDonald, A.

1997-01-01

Purpose: Prospectively evaluate the quality of life (QOL) of patients with NSCLC participating in a randomized phase III study conducted by the RTOG and Eastern Cooperative Oncology Group. Determine the factors which influence QOL during and post therapy. Materials and Methods: From (4(90)) to (4(94)) to 75 patients (pts) were randomized on RTOG 89-01 between a regimen containing radiation therapy (RT) versus a regimen containing surgery (S). All pts received induction vinblastine and cisplatin, followed by either S or RT and consolidation chemotherapy (CT). Pts were given the self-assessment QOL forms prior to the start of therapy, post induction CT, post RT or S, and periodically during follow-up. Two questionnaires were used: Functional Assessment of Cancer Therapy for lung cancer patients (FACT-L) and Functional Living Index-Cancer (FLIC). The FACT-L consists of 44 questions covering 6 domains (physical, social, and emotional well-being, relationship with physician, fulfilment, and lung cancer specific concerns), FLIC contains 22 questions summing to one total score. Results: 51 pts participated in the QOL endpoint, 24 were excluded: 3 pts refused, institution did not administer QOL questionnaires in 9 pts, 3 completed QOL after start of therapy, 1 institution refused to participate, 5 questionnaires were incomplete/unusable, 1 pt could not read English, and 2 were ineligible for treatment. Participation in QOL was not predicted by any pretreatment characteristic. Women had worse pretreatment QOL (p<0.005, by FLIC) and more problems with disease-related symptoms (p<0.005, by FACT) than men. Pts with KPS 90-100 had better pretreatment QOL than pts with KPS 60-80 (p<0.025, FLIC). Neither race, marital status, education level, age, prior weight loss, nor disease symptoms statistically significantly influenced pretreatment QOL. Initial QOL did not predict overall survival. FACT-L was reported on 25 pts post induction CT. Follow-up FACT-L was available on 12 pts

Vinorelbine and gemcitabine vs vinorelbine and carboplatin as first-line treatment of advanced NSCLC. A phase III randomised controlled trial by the Norwegian Lung Cancer Study Group

DEFF Research Database (Denmark)

Fløtten, Ø; Grønberg, B H; Bremnes, R

2012-01-01

BACKGROUND: Platinum-based doublet chemotherapy is the standard first-line treatment for advanced non-small cell lung cancer (NSCLC), but earlier studies have suggested that non-platinum combinations are equally effective and better tolerated. We conducted a national, randomised study to compare...... a non-platinum with a platinum combination. METHODS: Eligible patients had stage IIIB/IV NSCLC and performance status (PS) 0-2. Patients received up to three cycles of vinorelbine 60 mg m(-2) p.o.+gemcitabine 1000 mg m(-2) i.v. day 1 and 8 (VG) or vinorelbine 60 mg m(-2) p.o. day 1 and 8+carboplatin...... was 65 years, 58% were men and 25% had PS 2. Median survival was VG: 6.3 months; VC: 7.0 months, P=0.802. Vinorelbine plus carboplatin patients had more grade III/IV nausea/vomiting (VG: 4%, VC: 12%, P=0.008) and grade IV neutropenia (VG: 7%, VC: 19%, P

Co-clinical quantitative tumor volume imaging in ALK-rearranged NSCLC treated with crizotinib

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Nishino, Mizuki, E-mail: Mizuki_Nishino@DFCI.HARVARD.EDU [Department of Radiology, Brigham and Women’s Hospital, 450 Brookline Ave., Boston MA, 02215 (United States); Department of Imaging, Dana-Farber Cancer Institute, 450 Brookline Ave., Boston MA, 02215 (United States); Sacher, Adrian G.; Gandhi, Leena; Chen, Zhao; Akbay, Esra [Department of Medical Oncology and Department of Medicine Dana-Farber Cancer Institute and Brigham and Women’s Hospital 450 Brookline Ave., Boston MA, 02215 (United States); Fedorov, Andriy; Westin, Carl F.; Hatabu, Hiroto [Department of Radiology, Brigham and Women’s Hospital, 450 Brookline Ave., Boston MA, 02215 (United States); Johnson, Bruce E.; Hammerman, Peter; Wong, Kwok-kin [Department of Medical Oncology and Department of Medicine Dana-Farber Cancer Institute and Brigham and Women’s Hospital 450 Brookline Ave., Boston MA, 02215 (United States)

2017-03-15

Highlights: • Role of co-clinical studies in precision cancer medicine is increasingly recognized. • This study compared tumor volume in co-clinical trials of ALK-rearranged NSCLC. • Similarities and differences of tumor volume changes in mice and humans were noted. • The study provides insights to optimize murine co-clinical trial designs. - Abstract: Purpose: To evaluate and compare the volumetric tumor burden changes during crizotinib therapy in mice and human cohorts with ALK-rearranged non-small-cell lung cancer (NSCLC). Methods: Volumetric tumor burden was quantified on serial imaging studies in 8 bitransgenic mice with ALK-rearranged adenocarcinoma treated with crizotinib, and in 33 human subjects with ALK-rearranged NSCLC treated with crizotinib. The volumetric tumor burden changes and the time to maximal response were compared between mice and humans. Results: The median tumor volume decrease (%) at the maximal response was −40.4% (range: −79.5%–+11.7%) in mice, and −72.9% (range: −100%–+72%) in humans (Wilcoxon p = 0.03). The median time from the initiation of therapy to maximal response was 6 weeks in mice, and 15.7 weeks in humans. Overall volumetric response rate was 50% in mice and 97% in humans. Spider plots of tumor volume changes during therapy demonstrated durable responses in the human cohort, with a median time on therapy of 13.1 months. Conclusion: The present study described an initial attempt to evaluate quantitative tumor burden changes in co-clinical imaging studies of genomically-matched mice and human cohorts with ALK-rearranged NSCLC treated with crizotinib. Differences are noted in the degree of maximal volume response between the two cohorts in this well-established paradigm of targeted therapy, indicating a need for further studies to optimize co-clinical trial design and interpretation.

Co-clinical quantitative tumor volume imaging in ALK-rearranged NSCLC treated with crizotinib

International Nuclear Information System (INIS)

Nishino, Mizuki; Sacher, Adrian G.; Gandhi, Leena; Chen, Zhao; Akbay, Esra; Fedorov, Andriy; Westin, Carl F.; Hatabu, Hiroto; Johnson, Bruce E.; Hammerman, Peter; Wong, Kwok-kin

2017-01-01

Highlights: • Role of co-clinical studies in precision cancer medicine is increasingly recognized. • This study compared tumor volume in co-clinical trials of ALK-rearranged NSCLC. • Similarities and differences of tumor volume changes in mice and humans were noted. • The study provides insights to optimize murine co-clinical trial designs. - Abstract: Purpose: To evaluate and compare the volumetric tumor burden changes during crizotinib therapy in mice and human cohorts with ALK-rearranged non-small-cell lung cancer (NSCLC). Methods: Volumetric tumor burden was quantified on serial imaging studies in 8 bitransgenic mice with ALK-rearranged adenocarcinoma treated with crizotinib, and in 33 human subjects with ALK-rearranged NSCLC treated with crizotinib. The volumetric tumor burden changes and the time to maximal response were compared between mice and humans. Results: The median tumor volume decrease (%) at the maximal response was −40.4% (range: −79.5%–+11.7%) in mice, and −72.9% (range: −100%–+72%) in humans (Wilcoxon p = 0.03). The median time from the initiation of therapy to maximal response was 6 weeks in mice, and 15.7 weeks in humans. Overall volumetric response rate was 50% in mice and 97% in humans. Spider plots of tumor volume changes during therapy demonstrated durable responses in the human cohort, with a median time on therapy of 13.1 months. Conclusion: The present study described an initial attempt to evaluate quantitative tumor burden changes in co-clinical imaging studies of genomically-matched mice and human cohorts with ALK-rearranged NSCLC treated with crizotinib. Differences are noted in the degree of maximal volume response between the two cohorts in this well-established paradigm of targeted therapy, indicating a need for further studies to optimize co-clinical trial design and interpretation.

The role of Gefitinib in patients with non-small-cell lung cancer in India

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Asmita Anilkumar Mehta

2013-01-01

Full Text Available Background: Gefitinib, an epidermal growth factor receptor-tyrosine kinase inhibitor, represents a new treatment option for patients with advanced non-small-cell lung cancer (NSCLC. We analyzed the data of patients who received Gefitinib for NSCLC in a tertiary care center in South India. Materials and Methods: Sixty-three patients with advanced NSCLC who had received Gefitinib either after failure of conventional chemotherapy or were previously not treated as they were unfit or unwilling for conventional treatment were included in the analysis. Results: The median follow-up for the cohort was 311 days (range 11-1544 days. Median time to progression was 161 (range 9-883 days. Complete and partial remission was seen in 1 (2% and 6 (9% patients, respectively, with overall response rate of 11%. Twenty-four (38% patients had stable disease. Gefitinib was well tolerated with no significant side effects. Conclusion: Gefitinib shows anti-tumor activity in pretreated or previously untreated patients with advanced NSCLC. It has a favorable toxicity profile and is well tolerated. Gefitinib should be considered as a viable therapy in patients with NSCLC.

Patient admission planning using Approximate Dynamic Programming

NARCIS (Netherlands)

Hulshof, P.J.H.; Mes, Martijn R.K.; Boucherie, Richardus J.; Hans, Elias W.

2016-01-01

Tactical planning in hospitals involves elective patient admission planning and the allocation of hospital resource capacities. We propose a method to develop a tactical resource allocation and patient admission plan that takes stochastic elements into consideration, thereby providing robust plans.

Randomized Adjuvant Chemotherapy of EGFR-Mutated Non-Small Cell Lung Cancer Patients with or without Icotinib Consolidation Therapy.

Science.gov (United States)

Feng, Siyang; Wang, Yuanyuan; Cai, Kaican; Wu, Hua; Xiong, Gang; Wang, Haofei; Zhang, Ziliang

2015-01-01

Epidermal growth factor receptor (EGFR) mutations occur in up to 50% of Asian patients with non-small cell lung cancer (NSCLC). Treatment of advanced NSCLC patients with EGFR-tyrosine kinase inhibitor (EGFR-TKI) confers a significant survival benefit. This study assessed the efficacy and safety of chemotherapy with or without icotinib in patients undergoing resection of stage IB to ⅢA EGFR-mutated NSCLC. Patients with surgically resected stage IB (with high risk factors) to ⅢA EGFR-mutated NSCLC were randomly assigned (1:1) to one of two treatment plans. One group received four cycles of platinum-based doublet chemotherapy every three weeks, and the other group received platinum-based chemotherapy supplemented with consolidation therapy of orally administered icotinib (125 mg thrice daily) two weeks after chemotherapy. The icotinib treatment continued for four to eight months, or until the occurrence of disease relapse, metastasis or unacceptable icotinib or chemotherapy toxicity. The primary endpoint was disease-free survival (DFS). 41 patients were enrolled between Feb 9, 2011 and Dec 17, 2012. 21 patients were assigned to the combined chemotherapy plus icotinib treatment group, while 20 patients received chemotherapy only. DFS at 12 months was 100% for icotinib-treated patients and 88.9% for chemotherapy-only patients (p = 0. 122). At 18 months DFS for icotinib-treated vs. chemotherapy-only patients was 95.2% vs. 83.3% (p = 0. 225), respectively, and at 24 months DFS was 90.5% vs. 66.7% (p = 0. 066). The adverse chemotherapy effects predominantly presented as gastrointestinal reactions and marrow suppression, and there was no significant difference between the two treatment groups. Patients in the chemotherapy plus icotinib treatment group showed favorable tolerance to oral icotinib. The results suggest that chemotherapy plus orally icotinib displayed better DFS compared with chemotherapy only, yet the difference in DFS was not significant. We would think

Randomized Adjuvant Chemotherapy of EGFR-Mutated Non-Small Cell Lung Cancer Patients with or without Icotinib Consolidation Therapy.

Directory of Open Access Journals (Sweden)

Siyang Feng

Full Text Available Epidermal growth factor receptor (EGFR mutations occur in up to 50% of Asian patients with non-small cell lung cancer (NSCLC. Treatment of advanced NSCLC patients with EGFR-tyrosine kinase inhibitor (EGFR-TKI confers a significant survival benefit. This study assessed the efficacy and safety of chemotherapy with or without icotinib in patients undergoing resection of stage IB to ⅢA EGFR-mutated NSCLC.Patients with surgically resected stage IB (with high risk factors to ⅢA EGFR-mutated NSCLC were randomly assigned (1:1 to one of two treatment plans. One group received four cycles of platinum-based doublet chemotherapy every three weeks, and the other group received platinum-based chemotherapy supplemented with consolidation therapy of orally administered icotinib (125 mg thrice daily two weeks after chemotherapy. The icotinib treatment continued for four to eight months, or until the occurrence of disease relapse, metastasis or unacceptable icotinib or chemotherapy toxicity. The primary endpoint was disease-free survival (DFS.41 patients were enrolled between Feb 9, 2011 and Dec 17, 2012. 21 patients were assigned to the combined chemotherapy plus icotinib treatment group, while 20 patients received chemotherapy only. DFS at 12 months was 100% for icotinib-treated patients and 88.9% for chemotherapy-only patients (p = 0. 122. At 18 months DFS for icotinib-treated vs. chemotherapy-only patients was 95.2% vs. 83.3% (p = 0. 225, respectively, and at 24 months DFS was 90.5% vs. 66.7% (p = 0. 066. The adverse chemotherapy effects predominantly presented as gastrointestinal reactions and marrow suppression, and there was no significant difference between the two treatment groups. Patients in the chemotherapy plus icotinib treatment group showed favorable tolerance to oral icotinib.The results suggest that chemotherapy plus orally icotinib displayed better DFS compared with chemotherapy only, yet the difference in DFS was not significant. We would

Overexpression of the duffy antigen receptor for chemokines (DARC) by NSCLC tumor cells results in increased tumor necrosis

International Nuclear Information System (INIS)

Addison, Christina L; Belperio, John A; Burdick, Marie D; Strieter, Robert M

2004-01-01

The Duffy antigen receptor for chemokines (DARC) is known to be a promiscuous chemokine receptor that binds a variety of CXC and CC chemokines in the absence of any detectable signal transduction events. Within the CXC group of chemokines, DARC binds the angiogenic CXC chemokines including IL-8 (CXCL8), GROα (CXCL1) and ENA-78 (CXCL5), all of which have previously been shown to be important in non-small cell lung carcinoma (NSCLC) tumor growth. We hypothesized that overexpression of DARC by a NSCLC tumor cell line would result in the binding of the angiogenic ELR+ CXC chemokines by the tumor cells themselves, and thus interfere with the stimulation of endothelial cells and induction of angiogenesis by the tumor cell-derived angiogenic chemokines. NSCLC tumor cells that constitutively expressed DARC were generated and their growth characteristics were compared to control transfected cells in vitro and in vivo in SCID animals. We found that tumors derived from DARC-expressing cells were significantly larger in size than tumors derived from control-transfected cells. However, upon histological examination we found that DARC-expressing tumors had significantly more necrosis and decreased tumor cellularity, as compared to control tumors. Expression of DARC by NSCLC cells was also associated with a decrease in tumor-associated vasculature and a reduction in metastatic potential. The expression of DARC in the context of NSCLC tumors may act as a chemokine decoy receptor and interferes with normal tumor growth and chemokine-induced tumor neovascularization

Comparison of outcomes in patients with stage III versus limited stage IV non-small cell lung cancer

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Cheruvu, Praveena; Metcalfe, Su K; Metcalfe, Justin; Chen, Yuhchyau; Okunieff, Paul; Milano, Michael T

2011-01-01

Standard therapy for metastatic non small cell lung cancer (NSCLC) includes palliative systemic chemotherapy and/or radiotherapy. Recent studies of patients with limited metastases treated with curative-intent stereotactic body radiation therapy (SBRT) have shown encouraging survival. We hypothesized that patients treated with SBRT for limited metastases have comparable outcomes with those treated with curative-intent radiation for Stage III NSCLC. We retrospectively reviewed the records of NSCLC patients treated with curative-intent radiotherapy at the University of Rochester from 2000-2008. We identified 3 groups of patients with NSCLC: stage III, stage IV, and recurrent stage IV (initial stage I-II). All stage IV NSCLC patients treated with SBRT had ≤ 8 lesions. Of 146 patients, 88% had KPS ≥ 80%, 30% had > 5% weight loss, and 95% were smokers. The 5-year OS from date of NSCLC diagnosis for stage III, initial stage IV and recurrent stage IV was 7%, 14%, and 27% respectively. The 5-year OS from date of metastatic diagnosis was significantly (p < 0.00001) superior among those with limited metastases (≤ 8 lesions) versus stage III patients who developed extensive metastases not amenable to SBRT (14% vs. 0%). Stage IV NSCLC is a heterogeneous patient population, with a selected cohort apparently faring better than Stage III patients. Though patients with limited metastases are favorably selected by virtue of more indolent disease and/or less bulky disease burden, perhaps staging these patients differently is appropriate for prognostic and treatment characterization. Aggressive local therapy may be indicated in these patients, though prospective clinical studies are needed

Admission planning and patient mix optimisation

NARCIS (Netherlands)

Adan, I.J.B.F.; Vissers, J.M.H.; Eijdems, M.; Vissers, J.M.H.; Beech, R.

2005-01-01

Admisson planning is an important area of planning hospital operations for elective patients that do not need emergency care. Its purpose is not only to admit patients according to medical priority but also to take into consideration the resource use of admitted patients in order to balance the

Pleural lavage cytology as an independent prognostic factor in non-small-cell lung cancer patients with stage I disease and adenocarcinoma.

Science.gov (United States)

Hokka, Daisuke; Uchino, Kazuya; Tane, Kenta; Ogawa, Hiroyuki; Tane, Sinya; Tanaka, Yugo; Tauchi, Shunsuke; Nishio, Wataru; Yoshimura, Masahiro; Maniwa, Yoshimasa

2015-01-01

We previously reported that cancer cells may be detected through pleural lavage cytology (PLC). In this study, we sought to re-examine the prognostic significance of the PLC status based on an extended dataset with an additional follow-up period. Pleural lavage following thoracotomy was cytologically examined in 1,317 consecutive patients who were diagnosed with NSCLC between 1987 and 2004 at the Thoracic Surgery Units of Kobe University Graduate School of Medicine and Hyogo Cancer Center. Among the investigated patients, 46 exhibited positive cytological findings. The prognosis of these patients was significantly worse compared to that of patients without positive PLC. Of the 844 pathological stage I patients, 18 had a positive PLC status and their prognosis was significantly worse compared to that of patients with stage I disease without positive PLC. In conclusion, positive PLC findings were associated with a poor prognosis and this finding was significant for patients with stage I disease. These results suggest the need for PLC status evaluation during staging and treatment planning in patients with NSCLC.

Health-related quality of life in end-stage COPD and lung cancer patients.

Science.gov (United States)

Habraken, Jolanda M; ter Riet, Gerben; Gore, Justin M; Greenstone, Michael A; Weersink, Els J M; Bindels, Patrick J E; Willems, Dick L

2009-06-01

Historically, palliative care has been developed for cancer patients and is not yet generally available for patients suffering from chronic life-limiting illnesses, such as chronic obstructive pulmonary disease (COPD). To examine whether COPD patients experience similar or worse disease burden in comparison with non-small cell lung cancer (NSCLC) patients, we compared the health-related quality of life (HRQOL) scores of severe COPD patients with those of advanced NSCLC patients. We also formally updated previous evidence in this area provided by a landmark study published by Gore et al. in 2000. In updating this previous evidence, we addressed the methodological limitations of this study and a number of confounding variables. Eighty-two GOLD IV COPD patients and 19 Stage IIIb or IV NSCLC patients completed generic and disease-specific HRQOL questionnaires. We used an individual patient data meta-analysis to integrate the new and existing evidence (total n=201). Finally, to enhance between-group comparability, we performed a sensitivity analysis using a subgroup of patients with a similar degree of "terminality," namely those who had died within one year after study entry. Considerable differences in HRQOL were found for physical functioning, social functioning, mental health, general health perceptions, dyspnea, activities of daily living, and depression. All differences favored the NSCLC patients. The sensitivity analysis, using only terminal NSCLC and COPD patients, confirmed these findings. In conclusion, end-stage COPD patients experience poor HRQOL comparable to or worse than that of advanced NSCLC patients. We discuss these findings in the light of the notion that these COPD patients may have a similar need for palliative care.

Budget Impact Analysis of Afatinib for First-Line Treatment of Patients with Metastatic Non-Small Cell Lung Cancer with Epidermal Growth Factor Receptor Exon 19 Deletions or Exon 21 Substitution Mutations in a U.S. Health Plan.

Science.gov (United States)

Graham, Jonathan; Earnshaw, Stephanie; Burslem, Kate; Lim, Jonathan

2018-06-01

Afatinib is 1 of 3 tyrosine kinase inhibitors approved in the United States for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions (del19) or exon 21 (L858R) substitution mutations. In clinical trials, afatinib has demonstrated improvement in progression-free survival versus standard chemotherapy and gefitinib. To analyze the impact of increases in afatinib treatment share on the cost and health outcomes in a commercial health plan in the United States. A decision model was developed to evaluate the budget impact of increases in afatinib share for the first-line treatment of patients with metastatic NSCLC with EGFR del19 or L858R substitution mutations over a 5-year time horizon. The model compared the total annual costs for a health plan with 1 million covered lives in a scenario in which afatinib share increased 5 percentage points annually to one in which all treatment shares remained constant over time. The number of patients eligible for treatment was estimated using published incidence data. Therapies included in the model were afatinib, erlotinib, gefitinib, and the chemotherapy doublet, pemetrexed in combination with cisplatin. The mean time spent by patients in progression-free and progressive disease states was based on survival data from clinical trials and a network meta-analysis. Therapy-related costs included monthly drug acquisition and administration costs and costs of managing adverse reactions. Disease management costs were also assessed in the model. Scenario analyses were performed to assess alternative scenarios of afatinib treatment share. Additionally, a one-way sensitivity analysis was performed to test the robustness of the model, given parameter uncertainty. Using the base-case parameter assumptions and a 5-percentage-point annual increase in afatinib treatment share, we estimated the total budget increases in years 1 through 5

Correlation of FDG-PET measurements with morphometric tumor response after induction chemotherapy and adjuvant radiotherapy in stage III non-small cell lung cancer (NSCLC)

International Nuclear Information System (INIS)

Baum, R.P.; Niesen, A.; Griesinger, F.

2002-01-01

Full text: Docetaxel (D) and carboplatin (C) combination chemotherapy (DC) has shown high response rates in advanced NSCLC. Histologic tumor response after chemotherapy or combined modality induction is strongly associated with systemic tumor control and potentially cure. Metabolic tumor response assessed by FDG-PET after induction chemotherapy with etoposide, ifosfamide and cisplatin (VIP) has been shown to be predictive of outcome in NSCLC. Finally, erythropoietin (EPO) may prevent the decrease in hemoglobin levels that was seen in a previous study of DC (median drop 2.7 g/dl) and thus may enhance treatment efficacy. The aim of the present study was to correlate FDG-PET studies with histomorphometric findings after DC induction chemotherapy plus Epo. 33 patients (pts) with NSCLC stage IIIA (7 pts) or IIIB (24 pts) were enrolled and received treatment with D 100 mg/m 2 dl and C AUC 7.5 d2 q21 days for 4 cycles. Epo was given at 10,000 IU s.c. three times a week. All pts received adjuvant radiotherapy. Of 33 enrolled patients, 22 were evaluable for response by CT imaging. 14/22 pts (64 %) achieved PR. Of the 22 responders, 20 were evaluable for repeated FDG-PET studies. 13/20 pts had a decrease of standardized uptake values (SUV) and of the metabolic tumor index (MTI) by >50 %, 9/20 had SUV <2.5 (CR). Seven of these 9 pts underwent tumor resection, and specimens were subjected to morphometric analysis. In 7/7 cases, no vital tumor cells were detected in the specimens. In contrast to our previous study, hemoglobin levels increased by a median of 0.3 g/dl. Morphometric tumor response after induction chemotherapy correlates strongly with metabolic remission by FDG-PET. FDG-PET appears to be a useful non-invasive diagnostic tool to predict pathologic response and potentially long-term outcome in stage III NSCLC. (author)

Epigenetic activation of SIN1 promotes NSCLC cell proliferation and metastasis by affecting the epithelial–mesenchymal transition

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Hu, Zhongwu; Wang, Yaqin; Wang, Yuemei; Zang, Bao; Hui, Hongxia; You, Zhenbing; Wang, Xiaowei

2017-01-01

Stress-activated protein kinase (SAPK) interacting protein 1 (SIN1) is an essential component of mTORC2. Previous studies have shown that SIN1 is a key regulator of Akt pathway which plays an important role in various pathological conditions including cancer. While its effects and mechanisms on the progression of NSCLC remain unknown. In this study, we report that SIN1 is able to promote the growth and migration of NSCLC cells both in vitro and in vivo. Overexpression of SIN1 promoted A549 and H1299 cells proliferation by both MTT and colony formation assays. Consistently, knockdown of SIN1 inhibited the proliferation of these cells. In transwell assay, overexpression of SIN1 increased the migration of A549 and H1299 cells, while SIN1 knockdown reduced their migration. In a tumor xenograft model, overexpression of SIN1 promoted tumor growth of A549 cells in vivo, while SIN1 knockdown suppresses the tumor growth. We also found a mechanistic link between SIN1 and H3K4me3, H3K4me3 is involved in SIN1 upregulation. Moreover, SIN1 can significantly promote the in vitro migration and invasion of NSCLC cells via induction epithelial mesenchymal transition (EMT) process, which subsequently leads to transcriptional downregulation of epithelial marker E-cadherin and upregulation of mesenchymal markers N-cadherin and Vimentin expression. Together, our results reveal that SIN1 plays an important role in NSCLC and SIN1 is a potential biomarker and a promising target in the treatment of NSCLC.

Gefitinib inhibits invasive phenotype and epithelial-mesenchymal transition in drug-resistant NSCLC cells with MET amplification.

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Silvia La Monica

Full Text Available Despite the initial response, all patients with epidermal growth factor receptor (EGFR-mutant non-small cell lung cancer (NSCLC eventually develop acquired resistance to EGFR tyrosine kinase inhibitors (TKIs. The EGFR-T790M secondary mutation is responsible for half of acquired resistance cases, while MET amplification has been associated with acquired resistance in about 5-15% of NSCLCs. Clinical findings indicate the retained addiction of resistant tumors on EGFR signaling. Therefore, we evaluated the molecular mechanisms supporting the therapeutic potential of gefitinib maintenance in the HCC827 GR5 NSCLC cell line harbouring MET amplification as acquired resistance mechanism. We demonstrated that resistant cells can proliferate and survive regardless of the presence of gefitinib, whereas the absence of the drug significantly enhanced cell migration and invasion. Moreover, the continuous exposure to gefitinib prevented the epithelial-mesenchymal transition (EMT with increased E-cadherin expression and down-regulation of vimentin and N-cadherin. Importantly, the inhibition of cellular migration was correlated with the suppression of EGFR-dependent Src, STAT5 and p38 signaling as assessed by a specific kinase array, western blot analysis and silencing functional studies. On the contrary, the lack of effect of gefitinib on EGFR phosphorylation in the H1975 cells (EGFR-T790M correlated with the absence of effects on cell migration and invasion. In conclusion, our findings suggest that certain EGFR-mutated patients may still benefit from a second-line therapy including gefitinib based on the specific mechanism underlying tumor cell resistance.

SU-E-J-266: Cone Beam Computed Tomography (CBCT) Inter-Scan and Inter-Observer Tumor Volume Variability Assessment in Patients Treated with Stereotactic Body Radiation Therapy (SBRT) for Early Stage Non-Small Cell Lung Cancer (NSCLC)

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Hou, Y; Aileen, C; Kozono, D; Killoran, J; Wagar, M; Lee, S; Hacker, F; Aerts, H; Lewis, J; Mak, R [Brigham and Women’s Hospital, Boston, MA (United States)

2015-06-15

Purpose: Quantification of volume changes on CBCT during SBRT for NSCLC may provide a useful radiological marker for radiation response and adaptive treatment planning, but the reproducibility of CBCT volume delineation is a concern. This study is to quantify inter-scan/inter-observer variability in tumor volume delineation on CBCT. Methods: Twenty earlystage (stage I and II) NSCLC patients were included in this analysis. All patients were treated with SBRT with a median dose of 54 Gy in 3 to 5 fractions. Two physicians independently manually contoured the primary gross tumor volume on CBCTs taken immediately before SBRT treatment (Pre) and after the same SBRT treatment (Post). Absolute volume differences (AVD) were calculated between the Pre and Post CBCTs for a given treatment to quantify inter-scan variability, and then between the two observers for a given CBCT to quantify inter-observer variability. AVD was also normalized with respect to average volume to obtain relative volume differences (RVD). Bland-Altman approach was used to evaluate variability. All statistics were calculated with SAS version 9.4. Results: The 95% limit of agreement (mean ± 2SD) on AVD and RVD measurements between Pre and Post scans were −0.32cc to 0.32cc and −0.5% to 0.5% versus −1.9 cc to 1.8 cc and −15.9% to 15.3% for the two observers respectively. The 95% limit of agreement of AVD and RVD between the two observers were −3.3 cc to 2.3 cc and −42.4% to 28.2% respectively. The greatest variability in inter-scan RVD was observed with very small tumors (< 5 cc). Conclusion: Inter-scan variability in RVD is greatest with small tumors. Inter-observer variability was larger than inter-scan variability. The 95% limit of agreement for inter-observer and inter-scan variability (∼15–30%) helps define a threshold for clinically meaningful change in tumor volume to assess SBRT response, with larger thresholds needed for very small tumors. Part of the work was funded by a Kaye

SU-E-J-266: Cone Beam Computed Tomography (CBCT) Inter-Scan and Inter-Observer Tumor Volume Variability Assessment in Patients Treated with Stereotactic Body Radiation Therapy (SBRT) for Early Stage Non-Small Cell Lung Cancer (NSCLC)

International Nuclear Information System (INIS)

Hou, Y; Aileen, C; Kozono, D; Killoran, J; Wagar, M; Lee, S; Hacker, F; Aerts, H; Lewis, J; Mak, R

2015-01-01

Purpose: Quantification of volume changes on CBCT during SBRT for NSCLC may provide a useful radiological marker for radiation response and adaptive treatment planning, but the reproducibility of CBCT volume delineation is a concern. This study is to quantify inter-scan/inter-observer variability in tumor volume delineation on CBCT. Methods: Twenty earlystage (stage I and II) NSCLC patients were included in this analysis. All patients were treated with SBRT with a median dose of 54 Gy in 3 to 5 fractions. Two physicians independently manually contoured the primary gross tumor volume on CBCTs taken immediately before SBRT treatment (Pre) and after the same SBRT treatment (Post). Absolute volume differences (AVD) were calculated between the Pre and Post CBCTs for a given treatment to quantify inter-scan variability, and then between the two observers for a given CBCT to quantify inter-observer variability. AVD was also normalized with respect to average volume to obtain relative volume differences (RVD). Bland-Altman approach was used to evaluate variability. All statistics were calculated with SAS version 9.4. Results: The 95% limit of agreement (mean ± 2SD) on AVD and RVD measurements between Pre and Post scans were −0.32cc to 0.32cc and −0.5% to 0.5% versus −1.9 cc to 1.8 cc and −15.9% to 15.3% for the two observers respectively. The 95% limit of agreement of AVD and RVD between the two observers were −3.3 cc to 2.3 cc and −42.4% to 28.2% respectively. The greatest variability in inter-scan RVD was observed with very small tumors (< 5 cc). Conclusion: Inter-scan variability in RVD is greatest with small tumors. Inter-observer variability was larger than inter-scan variability. The 95% limit of agreement for inter-observer and inter-scan variability (∼15–30%) helps define a threshold for clinically meaningful change in tumor volume to assess SBRT response, with larger thresholds needed for very small tumors. Part of the work was funded by a Kaye

[Subgroup Analysis of the Non-interventional REASON Study: PFS and OS According to Age, Smoking History, Gender, and Histology in NSCLC Patients Treated with Gefitinib or Chemotherapy].

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Schuette, W; Eberhardt, W E E; Waller, C; Schirmacher, P; Dietel, M; Zirrgiebel, U; Radke, S; Thomas, M

2016-09-01

Assessment of several clinical factors on progression-free (PFS) and overall survival (OS) in NSCLC patients (pts.) (stage IV) with mutated epidermal growth factor receptor (EGFRm+) treated with gefitinib (gef) or with chemotherapy (CT) under real-world conditions. 285 EGFRm+ pts. of the non-interventional REASON study treated with gef (n = 206) or CT (n = 79) as first-line therapy or with gef (n = 213) or CT (n = 61) in any line throughout the course of therapy were analyzed according to age, gender, smoking history and histology. Compared with CT, patients treated with gef showed prolongation of PFS and OS in all subgroups. PFS was significantly increased in women and non-smokers. OS was significantly increased in women, non-smokers, (ex)-smokers, patients with adenocarcinoma and elderly patients when treated with gef compared to CT. Female gender turned out to be an independent positive predictive factor for OS in patients treated with gef (HRmale: 1.74, p = 0.0009). A clinical benefit of gef was shown for all analyzed clinical subgroups of EGFRm+ pts. This was confirmed for the female gender in a multivariate analysis. © Georg Thieme Verlag KG Stuttgart · New York.

Comparisons of dose-volume histograms for proton-beam versus 3-D conformal X-ray therapy in patients with stage I non-small cell lung cancer

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Wang, Changlu; Nakayama, Hidetsugu; Sugahara, Shinji; Sakae, Takeji; Tokuuye, Koichi

2009-01-01

Dose-volume histograms (DVHs) were reviewed to determine if there is an advantage of the two modalities when treating patients with non-small cell lung cancer (NSCLC). 24 stage I NSCLC patients who underwent proton-beam therapy (PBT) from June 2003 to May 2007 were included in this study. Based on the same clinical target volumes (CTVs), treatment planning was made to cover CTV within 90% isodose lines. Each patient was evaluated by two sets of DVHs, one for PBT and the other for three-dimensional conformal X-ray therapy (3D-CRT). For all patients, the 95% isodose line covered 86.4% of the CTV for PBT, and 43.2% for 3D-CRT. PBT was associated with significantly lower mean doses to the ipsilateral lung, total lung, heart, esophagus, and spinal cord than 3D-CRT. PBT offered reduced radiation doses to the lung when evaluated in terms of percentage lung volumes receiving ≥ 5 Gy (V 5 ), ≥ 10 Gy (V 10 ), and ≥ 20 Gy (V 20 ) when compared to 3D-CRT. PBT is advantageous over 3D-CRT in reducing doses to the lung, heart, esophagus, and spinal cord in treating stage I NSCLC. (orig.)

Dendrimer-Based Selective Proteostasis-Inhibition Strategy to Control NSCLC Growth and Progression.

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Kyla Walworth

Full Text Available Elevated valosin containing protein (VCP/p97 levels promote the progression of non-small cell lung carcinoma (NSCLC. Although many VCP inhibitors are available, most of these therapeutic compounds have low specificity for targeted tumor cell delivery. Hence, the primary aim of this study was to evaluate the in vitro efficacy of dendrimer-encapsulated potent VCP-inhibitor drug in controlling non-small cell lung carcinoma (NSCLC progression. The VCP inhibitor(s (either in their pure form or encapsulated in generation-4 PAMAM-dendrimer with hydroxyl surface were tested for their in vitro efficacy in modulating H1299 (NSCLC cells proliferation, migration, invasion, apoptosis and cell cycle progression. Our results show that VCP inhibition by DBeQ was significantly more potent than NMS-873 as evident by decreased cell proliferation (p<0.0001, MTT-assay and migration (p<0.05; scratch-assay, and increased apoptosis (p<0.05; caspase-3/7-assay as compared to untreated control cells. Next, we found that dendrimer-encapsulated DBeQ (DDNDBeQ treatment increased ubiquitinated-protein accumulation in soluble protein-fraction (immunoblotting of H1299 cells as compared to DDN-control, implying the effectiveness of DBeQ in proteostasis-inhibition. We verified by immunostaining that DDNDBeQ treatment increases accumulation of ubiquitinated-proteins that co-localizes with an ER-marker, KDEL. We observed that proteostasis-inhibition with DDNDBeQ, significantly decreased cell migration rate (scratch-assay and transwell-invasion as compared to the control-DDN treatment (p<0.05. Moreover, DDNDBeQ treatment showed a significant decrease in cell proliferation (p<0.01, MTT-assay and increased caspase-3/7 mediated apoptotic cell death (p<0.05 as compared to DDN-control. This was further verified by cell cycle analysis (propidium-iodide-staining that demonstrated significant cell cycle arrest in the G2/M-phase (p<0.001 by DDNDBeQ treatment as compared to control

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.

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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.

Combined use of (18)F-FDG and (18)F-FMISO in unresectable non-small cell lung cancer patients planned for radiotherapy: a dynamic PET/CT study.

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Sachpekidis, Christos; Thieke, Christian; Askoxylakis, Vasileios; Nicolay, Nils H; Huber, Peter E; Thomas, Michael; Dimitrakopoulou, Georgia; Debus, Juergen; Haberkorn, Uwe; Dimitrakopoulou-Strauss, Antonia

2015-01-01

Aim of this study was to evaluate and compare, by means of dynamic and static PET/CT, the distribution patterns and pharmacokinetics of fluorine-18 fluorodeoxyglucose ((18)F-FDG) and of fluorine-18-fluoromisonidazole ((18)F-FMISO) in non-small cell lung cancer (NSCLC) patients scheduled for intensity modulated radiation therapy (IMRT). Thirteen patients suffering from inoperable stage III NSCLC underwent PET/CTs with (18)F-FDG and (18)F-FMISO for tumor metabolism and hypoxia assessment accordingly. Evaluation of PET/CT studies was based on visual analysis, semi-quantitative (SUV) calculations and absolute quantitative estimations, after application of a two-tissue compartment model and a non-compartmental approach. (18)F-FDG PET/CT revealed all thirteen primary lung tumors as sites of increased (18)F-FDG uptake. Six patients demonstrated also in total 43 (18)F-FDG avid metastases; these patients were excluded from radiotherapy. (18)F-MISO PET/CT demonstrated 12/13 primary lung tumors with faint tracer uptake. Only one tumor was clearly (18)F-FMISO avid, (SUVaverage = 3.4, SUVmax = 5.0). Mean values for (18)F-FDG, as derived from dPET/CT data, were SUVaverage = 8.9, SUVmax = 15.1, K1 = 0.23, k2 = 0.53, k3 = 0.17, k4 = 0.02, influx = 0.05 and fractal dimension (FD) = 1.25 for the primary tumors. The respective values for (18)F-FMISO were SUVaverage = 1.4, SUVmax = 2.2, K1 = 0.26, k2 = 0.56, k3 = 0.06, k4 = 0.06, influx = 0.02 and FD = 1.14. No statistically significant correlation was observed between the two tracers. (18)F-FDG PET/CT changed therapy management in six patients, by excluding them from planned IMRT. (18)F-FMISO PET/CT revealed absence of significant tracer uptake in the majority of the (18)F-FDG avid NSCLCs. Lack of correlation between the two tracers' kinetics indicates that they reflect different molecular mechanisms and implies the discordance between increased glycolysis and hypoxia in the malignancy.

Ki-67 as a prognostic marker in early-stage non-small cell lung cancer in Asian patients: a meta-analysis of published studies involving 32 studies

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Wen, Song; Zhou, Wei; Li, Chun-ming; Hu, Juan; Hu, Xiao-ming; Chen, Ping; Shao, Guo-liang; Guo, Wu-hua

2015-01-01

Despite the large number of published papers analyzing the prognostic role of Ki-67 in NSCLC, it is still not considered an established factor for routine use in clinical practice. The present meta-analysis summarizes and analyses the associations between Ki-67 expression and clinical outcome in NSCLC patients. PubMed, Cochrane, and Embase databases were searched systematically using identical search strategies. The impacts of Ki-67 expression on survival in patients with NSCLC and NSCLC subtypes were evaluated. Furthermore, the association between Ki-67 expression and the clinicopathological features of NSCLC were evaluated. In total, 32 studies from 30 articles met the inclusion criteria, involving 5600 patients. Meta-analysis results suggested that high Ki-67 expression was negatively associated with overall survival (OS; HR = 1.59, 95 % CI 1.35-1.88, P < 0.001) and disease-free survival (DFS; HR = 2.21, 95 % CI 1.43-3.42, P < 0.001) in NSCLC patients. Analysis of the different subgroups of NSCLC suggested that the negative association between high Ki-67 expression and OS and DFS in Asian NSCLC patients was stronger than that in non-Asian NSCLC patients, particularly in early-stage (Stage I-II) adenocarcinoma (ADC) patients. Additionally, while high expression was more common in males, smokers, and those with poorer differentiation, there was no correlation between high Ki-67 expression and age or lymph node status. Importantly, significant correlations between high Ki-67 expression and clinicopathological features (males, higher tumor stage, poor differentiation) were seen only in Asian NSCLC patients. The present meta-analysis indicated that elevated Ki-67 expression was associated with a poorer outcome in NSCLC patients, particularly in early-stage Asian ADC patients. Studies with larger numbers of patients are needed to validate our findings. The online version of this article (doi:10.1186/s12885-015-1524-2) contains supplementary material, which is

Systematic Analysis of Icotinib Treatment for Patients with Non-Small Cell Lung Cancer.

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Shi, Bing; Zhang, Xiu-Bing; Xu, Jian; Huang, Xin-En

2015-01-01

This analysis was conducted to evaluate the efficacy and safety of icotinib based regimens in treating patients with non-small cell lung cancer (NSCLC). Clinical studies evaluating the efficacy and safety of icotinib-based regimens with regard to response and safety for patients with NSCLC were identified using a predefined search strategy. Pooled response rates of treatment were calculated. With icotinib-based regimens, 7 clinical studies which including 5,985 Chinese patients with NSCLC were considered eligible for inclusion. The pooled analysis suggested that, in all patients, the positive reponse rate was 30.1% (1,803/5,985) with icotinib-based regimens. Mild skin itching, rashes and diarrhea were the main side effects. No grade III or IV renal or liver toxicity was observed. No treatment-related death occurred in patients treated with icotinib-based regimens. This evidence based analysis suggests that icotinib based regimens are associated with mild response rate and acceptable toxicity for treating Chinese patients with NSCLC.

A Case Study in Advanced Lung Cancer Patients with Vimentin Over Expression.

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Karim, Nagla A; Eldessouki, Ihab; Yellu, Mahendar; Namad, Tariq; Wang, Jiang; Gaber, Ola

2017-10-01

Vimentin belongs to an intermediate filament (IF) family of proteins, mainly present in mesenchymal cells and has a crucial role in maintaining cellular integrity. Vimentin can induce epithelial to mesenchymal transition, and thus increase migration and invasion capacity of the cells. It has been shown to be a useful and reliable diagnostic and prognostic marker in several cancers including colon cancers, breast and hepatocellular cancers. Recent studies suggest that it may have a role in distant metastasis of non-small cell lung cancer (NSCLC) accounting for poor survival [1]. The aim of the study is to assess the impact of vimentin testing as a diagnostic and prognostic marker in NSCLC. This is a case study of 12 NSCLC patients who had vimentin testing as a part of their work up over the past five years at the University of Cincinnati. A total of 12 patients with advanced lung cancer were included in this case study as they were found to have strong vimentin expression. This was correlated with overall survival of this group of patients. Median survival of the patients was 4.66 months. This is 7.34 months less compared to the median survival of patients with stage IV NSCLC which is reported to be 12 months. More studies are warranted into the use of vimentin as an emerging useful marker for early diagnosis, aggressive transformation relapse, and prognostication of NSCLC. It may have therapeutic value in NSCLC as observed in other cancers.

Proactive management strategies for potential gastrointestinal adverse reactions with ceritinib in patients with advanced ALK-positive non-small-cell lung cancer

International Nuclear Information System (INIS)

Schaefer, Eric S; Baik, Christina

2016-01-01

Anaplastic lymphoma kinase (ALK) gene fusions occur in 3%–7% of non-small-cell lung cancer (NSCLC) cases. Ceritinib, a once-daily, oral ALK inhibitor, has activity against crizotinib-resistant and crizotinib-naïve NSCLC, including brain metastases. Ceritinib (Zykadia™) was granted accelerated approval by the US Food and Drug Administration in 2014 for treating crizotinib-resistant ALK-positive NSCLC. Adverse events (AEs), particularly gastrointestinal (GI) AEs, are commonly experienced at the recommended dose of 750 mg/d and ∼38% of patients require dose interruption or reduction for GI AEs. This case study details our experience with the use of proactive GI AE management regimens in patients treated with ceritinib (750 mg/d) across two study sites. Proactive Regimens A and B were implemented in patients with metastatic ALK-positive NSCLC treated with ceritinib to manage drug-related GI AEs. Regimen A comprised ondansetron and diphenoxylate/atropine or loperamide, taken 30 minutes prior to ceritinib dose. Regimen B included dicyclomine (taken with the first ceritinib dose), ondansetron (taken 30 minutes prior to ceritinib dose for the first seven doses), and loperamide (taken as needed with the onset of diarrhea). The proactive medications were tapered off depending on patient tolerability to ceritinib. Nine patient cases are presented. Starting Regimens A or B before the first dose of ceritinib, or as soon as GI symptoms were encountered, prevented the need for dose reduction due to GI toxicity in eight of the nine patients. Using these regimens, 78% of patients were able to remain on 750 mg/d fasting. Two patients received 23 months and 16 months of therapy and remain on ceritinib 750 mg/d and 600 mg/d, respectively. Although not currently recommended or implemented in clinical studies, based on the patients evaluated here, upfront or proactive treatment plans that address AEs early on can allow the majority of patients to remain on the approved 750 mg

Second-line Treatment of Stage III/IV Non-Small-Cell Lung Cancer (NSCLC with pemetrexed in routine clinical practice: Evaluation of performance status and health-related quality of life

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Schuette Wolfgang

2012-01-01

Full Text Available Abstract Background Second-line treatment of advanced non-small-cell lung cancer (NSCLC improves overall survival. There is a lack of data regarding the impact on patients' overall health condition. This prospective, non-interventional study evaluated performance status (PS and health-related quality of life (HR-QoL during second-line pemetrexed treatment in routine clinical practice. Methods Stage III/IV NSCLC patients who initiated second-line pemetrexed (standard vitamin and dexamethasone supplementation were observed for a maximum of 9 treatment cycles. The primary objective was to evaluate the proportion of patients achieving improvement of Karnofsky Index (KI of ≥ 10% (absolute or maintaining KI ≥ 80% after the second treatment cycle ("KI benefit response". HR-QoL was self-rated using the EuroQoL-5D questionnaire (EQ-5D. Factors potentially associated with KI benefit response were evaluated using logistic regression models. Results Of 521 eligible patients (73.5% Stage IV, median age 66.3 yrs, 36.1% ≥ 70 yrs, 62.0% with KI ≥ 80%, 471 (90.4% completed at least 2 treatment cycles. 58.0% (95%CI 53.6%;62.2% achieved KI benefit response after the second cycle. Patients with baseline KI ≥ 80%, no Grade 3/4 toxicities during the first 2 cycles, or combination regimen as prior first-line therapy were more likely to achieve a KI benefit response. EQ-5D scores improved over time. Grade 3/4 toxicities were reported in 23.8% of patients (mainly fatigue/asthenia 15.9%, neutropenia 8.7%. Conclusions In this large prospective, non-interventional study of second-line pemetrexed treatment in patients with advanced NSCLC, including 36% elderly patients ( ≥ 70 years, physician-rated PS and self-rated HR-QoL were maintained or improved in the majority of patients. Trial registration Registered on ClinicalTrials.gov (NCT00540241 on October 4, 2007

A comparison of QuantStudio™ 3D Digital PCR and ARMS-PCR for measuring plasma EGFR T790M mutations of NSCLC patients

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Feng Q

2018-01-01

Full Text Available Qin Feng,1,* Fei Gai,2,* Yaxiong Sang,2 Jie Zhang,3 Ping Wang,1 Yue Wang,1 Bing Liu,2 Dongmei Lin,1 Yang Yu,2 Jian Fang3 1Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Department of Pathology, Peking University Cancer Hospital & Institute, 2Oncology Business Division, Beijing Novogene Bioinformatics Technology Co., Ltd, 3Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Department of Thoracic Oncology II, Peking University Cancer Hospital & Institute, Beijing, China *These authors contributed equally to this work Background: The AURA3 clinical trial has shown that advanced non-small cell lung cancer (NSCLC patients with EGFR T790M mutations in circulating tumor DNA (ctDNA could benefit from osimertinib.Purpose: The aim of this study was to assess the usefulness of QuantStudio™ 3D Digital PCR System platform for the detection of plasma EGFR T790M mutations in NSCLC patients, and compare the performances of 3D Digital PCR and ARMS-PCR.Patients and methods: A total of 119 Chinese patients were enrolled in this study. Mutant allele frequency of plasma EGFR T790M was detected by 3D Digital PCR, then 25 selected samples were verified by ARMS-PCR and four of them were verified by next generation sequencing (NGS.Results: In total, 52.94% (69/119 had EGFR T790M mutations detected by 3D Digital PCR. In 69 positive samples, the median mutant allele frequency (AF was 1.09% and three cases presented low concentration (AF <0.1%. Limited by the amount of plasma DNA, 17 samples (AF <2.5% and eight samples (T790M- were selected for verification by ARMS-PCR. Four of those samples were verified by NGS as a third verification method. Among the selected 17 positive cases, ten samples presented mutant allele frequency <0.5%, and seven samples presented intermediate mutant allele frequency (0.5%＜AF＜2.5%. However, only three samples (3/17 were identified as positive by ARMS-PCR, namely, P6

Study of percutaneous 125I seeds implantation guided by CT in elderly patients of stage I peripheral non-small cell lung cancer

International Nuclear Information System (INIS)

Ke Mingyao; Yong Yazhi; Luo Bingqing; Wu Xuemei; Chen Lingling; Xie Hongqi

2011-01-01

Objective: To evaluate the efficacy, feasibility and safety of CT guided percutaneous 125 I seeds implantation in elderly patients of stage I peripheral non-small cell lung cancer (NSCLC). Methods: Clinical data of 16 elderly peripheral stage I NSCLC patients (10 squamous carcinoma and 6 adenocarcinoma; 13 stage I A and 3 stage I B ) who received radioactive 125 I seeds implantation because of refusal or being unsuited to operation or external radiotherapy were retrospectively analyzed. Prescribed dose was 140 - 160 Gy. Under CT guidance, 125 I seeds were implanted percutaneously into tumors for interstitial radiotherapy according to treatment plan system. Results: Mean number of 125 I seeds each patient received was 21.1. 12 complete response (CR) and 4 partial response (PR) were achieved. Total response rate (CR + PR) was 100%. 100% patients completed 10 to 56 months of follow-up, 15, 13, 8 and 6 patients completed 1-, 2-, 3-and 4-years' follow-up, respectively. The median local progression free time was 14 months. The 1-, 2-, 3-and 4-year overall survival rate were 60%, 54%, 50% and 33%, respectively (median : 14 months). 7 cases died of non-tumor disease and 5 died of metastasis. No severe complications were observed. Conclusions: CT guided 125 I seeds implantation is a safe, reliable and effective radical treatment method for elderly stage I peripheral NSCLC patients, who refuse to or are unsuitable to operation or external radiotherapy. (authors)

Clinical pharmacokinetics, safety, and preliminary efficacy evaluation of icotinib in patients with advanced non-small cell lung cancer.

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Liu, Dongyang; Zhang, Li; Wu, Yiwen; Jiang, Ji; Tan, Fenlai; Wang, Yingxiang; Liu, Yong; Hu, Pei

2015-09-01

To receive pharmacokinetics, safety, and anti-tumor activity of icotinib, a novel epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), in patients with advanced non-small-cell lung cancer (NSCLC). Patients (n=40) with advanced NSCLC were enrolled to receive escalating doses of icotinib, which was administrated on Day 1 followed by 28-day continuous dosing starting from Day 4. Four dosing regimens, 100mg b.i.d., 150 mg b.i.d., 125 mg t.i.d., and 200mg b.i.d. were studied. Pharmacokinetics (PK), safety, and efficacy of icotinib were evaluated. Icotinib was well tolerated in Chinese patients with refractory NSCLC. No toxicity with >3 grades were reported in more than 2 patients under any dose levels. One complete response (3%) and 9 partial responses (23%) were received. Total disease control rate could reach at 73% and median progress-free survival (range) was 154 (17-462) days. PK exposure of icotinib increased with increase of dose in NSCLC patients. Food was suggested to increase PK exposure by ∼30%. Mean t1/2β was within 5.31-8.07 h. No major metabolite (>10% plasma exposure of icotinib) was found in NSCLC patients. Icotinib with up to 400 mg/day exhibited good tolerance and preliminary antitumor activity in Chinese NSCLC patients. Pharmacokinetics of icotinib and 5 major metabolites were fully investigated in NSCLC patients. Optimized biologic dose (OBD) was finally recommended to be 125 mg t.i.d. for the later clinical study. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Use of Maximum Intensity Projections (MIPs) for target outlining in 4DCT radiotherapy planning.

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Muirhead, Rebecca; McNee, Stuart G; Featherstone, Carrie; Moore, Karen; Muscat, Sarah

2008-12-01

Four-dimensional computed tomography (4DCT) is currently being introduced to radiotherapy centers worldwide, for use in radical radiotherapy planning for non-small cell lung cancer (NSCLC). A significant drawback is the time required to delineate 10 individual CT scans for each patient. Every department will hence ask the question if the single Maximum Intensity Projection (MIP) scan can be used as an alternative. Although the problems regarding the use of the MIP in node-positive disease have been discussed in the literature, a comprehensive study assessing its use has not been published. We compared an internal target volume (ITV) created using the MIP to an ITV created from the composite volume of 10 clinical target volumes (CTVs) delineated on the 10 phases of the 4DCT. 4DCT data was collected from 14 patients with NSCLC. In each patient, the ITV was delineated on the MIP image (ITV_MIP) and a composite ITV created from the 10 CTVs delineated on each of the 10 scans in the dataset. The structures were compared by assessment of volumes of overlap and exclusion. There was a median of 19.0% (range, 5.5-35.4%) of the volume of ITV_10phase not enclosed by the ITV_MIP, demonstrating that the use of the MIP could result in under-treatment of disease. In contrast only a very small amount of the ITV_MIP was not enclosed by the ITV_10phase (median of 2.3%, range, 0.4-9.8%), indicating the ITV_10phase covers almost all of the tumor tissue as identified by MIP. Although there were only two Stage I patients, both demonstrated very similar ITV_10phase and ITV_MIP volumes. These findings suggest that Stage I NSCLC tumors could be outlined on the MIP alone. In Stage II and III tumors the ITV_10phase would be more reliable. To prevent under-treatment of disease, the MIP image can only be used for delineation in Stage I tumors.

Comparative Survival in Patients With Postresection Recurrent Versus Newly Diagnosed Non-Small-Cell Lung Cancer Treated With Radiotherapy

International Nuclear Information System (INIS)

Cai Xuwei; Xu Luying; Wang Li; Hayman, James A.; Chang, Andrew C.; Pickens, Allan; Cease, Kemp B.; Orringer, Mark B.; Kong, F.-M.

2010-01-01

Purpose: To compare the survival of postresection recurrent vs. newly diagnosed non-small-cell lung cancer (NSCLC) patients treated with radiotherapy or chemoradiotherapy. Methods and Materials: The study population consisted of 661 consecutive patients with NSCLC registered in the radiation oncology databases at two medical centers in the United States between 1992 and 2004. Of the 661 patients, 54 had postresection recurrent NSCLC and 607 had newly diagnosed NSCLC. Kaplan-Meier and Cox regression models were used for the survival analyses. Results: The distribution of relevant clinical factors between these two groups was similar. The median survival time and 5-year overall survival rates were 19.8 months (95% confidence interval [CI], 13.9-25.7) and 14.8% (95% confidence interval, 5.4-24.2%) vs. 12.2 months (95% CI, 10.8-13.6) and 11.0% (95% CI, 8.5-13.5%) for recurrent vs. newly diagnosed patients, respectively (p = .037). For Stage I-III patients, no significant difference was observed in the 5-year overall survival (p = .297) or progression-free survival (p = .935) between recurrent and newly diagnosed patients. For the 46 patients with Stage I-III recurrent disease, multivariate analysis showed that chemotherapy was a significant prognostic factor for 5-year progression-free survival (hazard ratio, 0.45; 95% CI, 0.224-0.914; p = .027). Conclusion: Our institutional data have shown that patients with postresection recurrent NSCLC achieved survival comparable to that of newly diagnosed NSCLC patients when they were both treated with radiotherapy or chemoradiotherapy. These findings suggest that patients with postresection recurrent NSCLC should be treated as aggressively as those with newly diagnosed disease.

Tumor cavitation in patients with stage III non-small-cell lung cancer undergoing concurrent chemoradiotherapy: incidence and outcomes.

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Phernambucq, Erik C J; Hartemink, Koen J; Smit, Egbert F; Paul, Marinus A; Postmus, Pieter E; Comans, Emile F I; Senan, Suresh

2012-08-01

Commonly reported complications after concurrent chemoradiotherapy (CCRT) in patients with stage III non-small-cell lung cancer (NSCLC) include febrile neutropenia, radiation esophagitis, and pneumonitis. We studied the incidence of tumor cavitation and/or "tumor abscess" after CCRT in a single-institutional cohort. Between 2003 and 2010, 87 patients with stage III NSCLC underwent cisplatin-based CCRT and all subsequent follow-up at the VU University Medical Center. Diagnostic and radiotherapy planning computed tomography scans were reviewed for tumor cavitation, which was defined as a nonbronchial air-containing cavity located within the primary tumor. Pulmonary toxicities scored as Common Toxicity Criteria v3.0 of grade III or more, occurring within 90 days after end of radiotherapy, were analyzed. In the entire cohort, tumor cavitation was observed on computed tomography scans of 16 patients (18%). The histology in cavitated tumors was squamous cell (n = 14), large cell (n = 1), or adenocarcinoma (n = 1). Twenty patients (23%) experienced pulmonary toxicity of grade III or more, other than radiation pneumonitis. Eight patients with a tumor cavitation (seven squamous cell carcinoma) developed severe pulmonary complications; tumor abscess (n = 5), fatal hemorrhage (n = 2), and fatal embolism (n = 1). Two patients with a tumor abscess required open-window thoracostomy post-CCRT. The median overall survival for patients with or without tumor cavitation were 9.9 and 16.3 months, respectively (p = 0.09). With CCRT, acute pulmonary toxicity of grade III or more developed in 50% of patients with stage III NSCLC, who also had radiological features of tumor cavitation. The optimal treatment of patients with this presentation is unclear given the high risk of a tumor abscess.

Living with a diagnosis of non-small cell lung cancer: patients' lived experiences.

LENUS (Irish Health Repository)

McCarthy, Ita

2012-01-31

The aim of this study was to explore patients\\' experience of living with non-small cell lung cancer (NSCLC). Patients diagnosed with NSCLC know that their treatment is not with curative intent and can expect distressing symptoms. In this phenomenological study, six adults with a diagnosis of NSCLC were interviewed. Data was analysed guided by van Manen\\'s six-step process. Four main themes were interpreted: \\'Maintaining my life\\'; \\'The enemy within\\'; \\'Staying on the train\\

Vorinostat and metformin sensitize EGFR-TKI resistant NSCLC cells via BIM-dependent apoptosis induction.

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Chen, Hengyi; Wang, Yubo; Lin, Caiyu; Lu, Conghua; Han, Rui; Jiao, Lin; Li, Li; He, Yong

2017-11-07

There is a close relationship between low expression of BIM and resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). Vorinostat is a pan-histone deacetylase inhibitor (HDACi) that augments BIM expression in various types of tumor cells, however, this effect is attenuated by the high expression of anti-apoptotic proteins in EGFR-TKI resistant non-small cell lung cancer (NSCLC) cells. Vorinostat in combination with metformin - a compound that can inhibit anti-apoptotic proteins expression, might cooperate to activate apoptotic signaling and overcome EGFR-TKI resistance. This study aimed to investigate the cooperative effect and evaluate possible molecular mechanisms. The results showed that vorinostat combined with gefitinib augmented BIM expression and increased the sensitivity of EGFR-TKI resistant NSCLC cells to gefitinib, adding metformin simultaneously could obviously inhibit the expression of anti-apoptotic proteins, and further increased expression levels of BIM and BAX, and as a result, further improved the sensitivity of gefitinib both on the NSCLC cells with intrinsic and acquired resistance to EGFR-TKI. In addition, autophagy induced by gefitinib and vorinostat could be significantly suppressed by metformin, which might also contribute to enhance apoptosis and improve sensitivity of gefitinib. These results suggested that the combination of vorinostat and metformin might represent a novel strategy to overcome EGFR-TKI resistance associated with BIM-dependent apoptosis in larger heterogeneous populations.

Radiobiological impact of dose calculation algorithms on biologically optimized IMRT lung stereotactic body radiation therapy plans

International Nuclear Information System (INIS)

Liang, X.; Penagaricano, J.; Zheng, D.; Morrill, S.; Zhang, X.; Corry, P.; Griffin, R. J.; Han, E. Y.; Hardee, M.; Ratanatharathom, V.

2016-01-01

The aim of this study is to evaluate the radiobiological impact of Acuros XB (AXB) vs. Anisotropic Analytic Algorithm (AAA) dose calculation algorithms in combined dose-volume and biological optimized IMRT plans of SBRT treatments for non-small-cell lung cancer (NSCLC) patients. Twenty eight patients with NSCLC previously treated SBRT were re-planned using Varian Eclipse (V11) with combined dose-volume and biological optimization IMRT sliding window technique. The total dose prescribed to the PTV was 60 Gy with 12 Gy per fraction. The plans were initially optimized using AAA algorithm, and then were recomputed using AXB using the same MUs and MLC files to compare with the dose distribution of the original plans and assess the radiobiological as well as dosimetric impact of the two different dose algorithms. The Poisson Linear-Quadatric (PLQ) and Lyman-Kutcher-Burman (LKB) models were used for estimating the tumor control probability (TCP) and normal tissue complication probability (NTCP), respectively. The influence of the model parameter uncertainties on the TCP differences and the NTCP differences between AAA and AXB plans were studied by applying different sets of published model parameters. Patients were grouped into peripheral and centrally-located tumors to evaluate the impact of tumor location. PTV dose was lower in the re-calculated AXB plans, as compared to AAA plans. The median differences of PTV(D 95% ) were 1.7 Gy (range: 0.3, 6.5 Gy) and 1.0 Gy (range: 0.6, 4.4 Gy) for peripheral tumors and centrally-located tumors, respectively. The median differences of PTV(mean) were 0.4 Gy (range: 0.0, 1.9 Gy) and 0.9 Gy (range: 0.0, 4.3 Gy) for peripheral tumors and centrally-located tumors, respectively. TCP was also found lower in AXB-recalculated plans compared with the AAA plans. The median (range) of the TCP differences for 30 month local control were 1.6 % (0.3 %, 5.8 %) for peripheral tumors and 1.3 % (0.5 %, 3.4 %) for centrally located tumors. The lower

TrkB is highly expressed in NSCLC and mediates BDNF-induced the activation of Pyk2 signaling and the invasion of A549 cells

International Nuclear Information System (INIS)

Zhang, Siyang; Guo, Dawei; Luo, Wenting; Zhang, Qingfu; Zhang, Ying; Li, Chunyan; Lu, Yao; Cui, Zeshi; Qiu, Xueshan

2010-01-01

Aberrant regulation in the invasion of cancer cells is closely associated with their metastatic potentials. TrkB functions as a receptor tyrosine kinase and is considered to facilitate tumor metastasis. Pyk2 is a non-receptor tyrosine kinase and integrates signals in cell invasion. However, little is known about the expression of TrkB in NSCLC and whether Pyk2 is involved in TrkB-mediated invasion of A549 cells. The expression of TrkB was investigated in NSCLC by immunohistochemical staining. Both HBE and A549 cells were treated with BDNF. The expression of TrkB, Pyk2 and ERK phosphorylations were assessed by western blot. Besides, A549 cells were transfected with TrkB-siRNA or Pyk2-siRNA, or treated with ERK inhibitor where indicated. Transwell assay was performed to evaluate cell invasion. 40 cases (66.7%) of NSCLC were found higher expression of TrkB and patients with more TrkB expression had significant metastatic lymph nodes (p = 0.028). BDNF facilitated the invasion of A549 cells and the activations of Pyk2 in Tyr402 and ERK. However, the effects of BDNF were not observed in HBE cells with lower expression of TrkB. In addition, the increased Pyk2 and ERK activities induced by BDNF were significantly inhibited by blocking TrkB expression, so was the invasion of A549 cells. Knockdown studies revealed the essential role of Pyk2 for BDNF-induced cell invasion, since the invasion of A549 cells was abolished by Pyk2-siRNA. The application of ERK inhibitor also showed the suppressed ERK phosphorylation and cell invasion. These data indicated that higher expression of TrkB in NSCLC was closely correlated with lymph node metastasis, and BDNF probably via TrkB/Pyk2/ERK promoted the invasion of A549 cells

Diffusion weighted MRI and 18F-FDG PET/CT in non-small cell lung cancer (NSCLC): Does the apparent diffusion coefficient (ADC) correlate with tracer uptake (SUV)?

International Nuclear Information System (INIS)

Regier, M.; Derlin, T.; Schwarz, D.; Laqmani, A.; Henes, F.O.; Groth, M.; Buhk, J.-H.; Kooijman, H.; Adam, G.

2012-01-01

Introduction: To investigate the potential correlation of the apparent diffusion coefficient assessed by diffusion-weighted MRI (DWI) and glucose metabolism determined by the standardized uptake value (SUV) at 18F-FDG PET/CT in non-small cell lung cancer (NSCLC). Materials and methods: 18F-FDG PET/CT and DWI (TR/TE, 2000/66 ms; b-values, 0 and 500 s/mm 2 ) were performed in 41 consecutive patients with histologically verified NSCLC. Analysing the PET-CT data calculation of the mean (SUV mean ) and maximum (SUV max ) SUV was performed. By placing a region-of-interest (ROI) encovering the entire tumor mean (ADC mean ) and minimum ADC (ADC min ) were determined by two independent radiologists. Results of 18F-FDG PET-CT and DWI were compared on a per-patient basis. For statistical analysis Pearson's correlation coefficient, Bland–Altman and regression analysis were assessed. Results: Data analysis revealed a significant inverse correlation of the ADC min and SUV max (r = −0.46; p = 0.032). Testing the correlation of the ADC min and SUV max for each histological subtype separately revealed that the inverse correlation was good for both adenocarcinomas (r = −0.47; p = 0.03) and squamouscell carcinomas (r = −0.71; p = 0.002), respectively. No significant correlation was found for the comparison of ADC min and SUV mean (r = −0.29; p = 0.27), ADC mean vs. SUV mean (r = −0.28; p = 0.31) or ADC mean vs. SUV max (r = −0.33; p = 0.23). The κ-value of 0.88 indicated a good agreement between both observers. Conclusion: This preliminary study is the first to verify the relation between the SUV and the ADC in NSCLC. The significant inverse correlation of these two quantitative imaging approaches points out the association of metabolic activity and tumor cellularity. Therefore, DWI with ADC measurement might represent a new prognostic marker in NSCLC

Highly frequent promoter methylation and PIK3CA amplification in non-small cell lung cancer (NSCLC)

International Nuclear Information System (INIS)

Ji, Meiju; Guan, Haixia; Gao, Cuixia; Shi, Bingyin; Hou, Peng

2011-01-01

Lung cancer is the leading cause of cancer-related death worldwide. Genetic and epigenetic alterations have been identified frequently in lung cancer, such as promoter methylation, gene mutations and genomic amplification. However, the interaction between genetic and epigenetic events and their significance in lung tumorigenesis remains poorly understood. We determined the promoter methylation of 6 genes and PIK3CA amplification using quantitative methylation-specific PCR (Q-MSP) and real-time quantitative PCR, respectively, and explore the association of promoter methylation with PIK3CA amplification in a large cohort of clinically well-characterized non-small cell lung cancer (NSCLC). Highly frequent promoter methylation was observed in NSCLC. With 100% diagnostic specificity, excellent sensitivity, ranging from 45.8 to 84.1%, was found for each of the 6 genes. The promoter methylation was associated with histologic type. Methylation of CALCA, CDH1, DAPK1, and EVX2 was more common in squamous cell carcinomas (SCC) compared to adenocarcinomas (ADC). Conversely, there was a trend toward a higher frequency of RASSF1A methylation in ADC than SCC. In addition, PIK3CA amplification was frequently found in NSCLC, and was associated with certain clinicopathologic features, such as smoking history, histologic type and pleural indentation. Importantly, aberrant promoter methylation of certain genes was significantly associated with PIK3CA amplification. Our data showed highly frequent promoter methylation and PIK3CA amplification in Chinese NSCLC population, and first demonstrated the associations of gene methylation with PIK3CA amplification, suggesting that these epigenetic events may be a consequence of overactivation of PI3K/Akt pathway

Safety and efficacy of first-line bevacizumab combination therapy in Chinese population with advanced non-squamous NSCLC: data of subgroup analyses from MO19390 (SAiL) study.

Science.gov (United States)

Zhou, C C; Bai, C X; Guan, Z Z; Jiang, G L; Shi, Y K; Wang, M Z; Wu, Y L; Zhang, Y P; Zhu, Y Z

2014-05-01

Bevacizumab is a monoclonal antibody with high antitumor activity against malignant diseases. Previous studies have demonstrated the efficacy of first-line bevacizumab combination therapy in advanced, non-squamous non-small cell lung cancer (NS-NSCLC). SAiL (MO19390), an open-label, multicenter, single-arm study, evaluated the safety and efficacy of first-line bevacizumab-based treatment in clinical practice. This report presents the results of a subgroup analysis of Chinese patients enrolled in SAiL. Chemo-naive Chinese patients with locally advanced, metastatic or recurrent NSCLC were randomized to receive Bev 15 mg/kg every 3 weeks plus carboplatin + paclitaxel for maximum of six cycles, followed by single-agent bevacizumab until disease progression. The primary endpoint was safety. Secondary endpoints included time to progression and overall survival. The Chinese intent-to-treat (ITT) population consists of 198 Chinese patients, among whom 107 (54 %) were non-smokers and 90 (45.5 %) were female. The median cycle of bevacizumab administration was 10 and median duration of bevacizumab treatment was 29.5 weeks. Only eight cases of severe adverse events were observed in the study, which were deemed to be related to bevacizumab. The incidence of AEs over grade 3 in Chinese ITT patients was generally low (SAiL study. No new safety signals were reported.

Correlation of pre-and post-induction chemotherapy 18-FDG PET findings with histopathology in patients with locally advanced non-small cell lung cancer

International Nuclear Information System (INIS)

Chan, Andrea M.; Berlangieri, Sam; Ngai, Michael W.

2009-01-01

Full text: Objective: To correlate 18F-FDG PET metabolic response to therapy with histopathology and survival, in patients with locally advanced (stage IIl) non-small cell lung carcinoma (NSCLC) receiving induction chemotherapy. Methods: A retrospective review of all patients with stage III NSCLC planned for induction chemotherapy and surgical resection, in whom pre- and post-chemotherapy FDG-PET at Austin Health between 2004 and 2007 was performed. The staging and positive nodal stations as determined by PET was compared to histopathological findings after resection. The tumour response on serial FDG PET was also compared to overall outcome. Results: 9 patients were included. There was a 100 % correlation between pre- or post- chemotherapy nodal staging and final histopathological nodal stage. Ninety percent of all positive nodal stations (9/10) seen on histopathology were correctly localised by pre- or post-chemotherapy FDG PET. Only one patient with a metastatic lymph node at nodal station 9 R could not be localised by prior PET studies. Of the patients in whom a down-staging in tumour status was observed on the postchemotherapy FDG-PET, 83% (5/6) of patients were still alive (follow-up range of 8 to 40 months) as compared with 33% (1/3 ) (follow-up range of 9-13 months) for non-responders. Conclusion: There is good correlation between pre- and/or post- chemotherapy FDG PET and final histopathology for the nodal staging of stage III NSCLC. There is an overall trend for those patients in whom PET resulted in a down-staging of tumour to have a longer survival.

Efficacy and safety evaluation of icotinib in patients with advanced non-small cell lung cancer.

Science.gov (United States)

Gu, Aiqin; Shi, Chunlei; Xiong, Liwen; Chu, Tianqing; Pei, Jun; Han, Baohui

2013-02-01

To evaluate the efficacy and safety of icotinib hydrochloride in patients with advanced non-small cell lung cancer (NSCLC). A total of 89 patients with stage IIIB or IV NSCLC received icotinib at a dose of 125 mg administered 3 times a day. Icotinib treatment was continued until disease progression or development of unacceptable toxicity. A total of 89 patients were assessable. In patients treated with icotinib, the overall response rate (RR) was 36.0% (32/89), and the disease control rate (DCR) was 69.7% (62/89). RR and DCR were significantly improved in patients with adenocarcinoma versus non-adenocarcinoma (Picotinib hydrochloride in the treatment of advanced NSCLC is efficacious and safe, and its toxic effects are tolerable.

Aptamer-miRNA-212 Conjugate Sensitizes NSCLC Cells to TRAIL

Directory of Open Access Journals (Sweden)

Margherita Iaboni

2016-01-01

Full Text Available TNF-related apoptosis-inducing ligand (TRAIL is a promising antitumor agent for its remarkable ability to selectively induce apoptosis in cancer cells, without affecting the viability of healthy bystander cells. The TRAIL tumor suppressor pathway is deregulated in many human malignancies including lung cancer. In human non-small cell lung cancer (NSCLC cells, sensitization to TRAIL therapy can be restored by increasing the expression levels of the tumor suppressor microRNA-212 (miR-212 leading to inhibition of the anti-apoptotic protein PED/PEA-15 implicated in treatment resistance. In this study, we exploited a previously described RNA aptamer inhibitor of the tyrosine kinase receptor Axl (GL21.T expressed on lung cancer cells, as a means to deliver miR-212 into human NSCLC cells expressing Axl. We demonstrate efficient delivery of miR-212 following conjugation of the miR to GL21.T (GL21.T-miR212 chimera. We show that the chimera downregulates PED and restores TRAIL-mediate cytotoxicity in cancer cells. Importantly, treatment of Axl+ lung cancer cells with the chimera resulted in (i an increase in caspase activation and (ii a reduction of cell viability in combination with TRAIL therapy. In conclusion, we demonstrate that the GL21.T-miR212 chimera can be employed as an adjuvant to TRAIL therapy for the treatment of lung cancer.

Preserving Functional Lung Using Perfusion Imaging and Intensity-Modulated Radiation Therapy for Advanced-Stage Non-Small Cell Lung Cancer

International Nuclear Information System (INIS)

Shioyama, Yoshiyuki; Jang, Si Young; Liu, H. Helen; Guerrero, Thomas; Wang, Xuanmin; Gayed, Isis W.; Erwin, William D.; Liao, Zhongxing; Chang, Joe Y.; Jeter, Melenda; Yaremko, Brian P.; Borghero, Yerko O.; Cox, James D.; Komaki, Ritsuko; Mohan, Radhe

2007-01-01

Purpose: To assess quantitatively the impact of incorporating functional lung imaging into intensity-modulated radiation therapy planning for locally advanced non-small cell lung cancer (NSCLC). Methods and Materials: Sixteen patients with advanced-stage NSCLC who underwent radiotherapy were included in this study. Before radiotherapy, each patient underwent lung perfusion imaging with single-photon-emission computed tomography and X-ray computed tomography (SPECT-CT). The SPECT-CT was registered with simulation CT and was used to segment the 50- and 90-percentile hyperperfusion lung (F50 lung and F90 lung). Two IMRT plans were designed and compared in each patient: an anatomic plan using simulation CT alone and a functional plan using SPECT-CT in addition to the simulation CT. Dosimetric parameters of the two types of plans were compared in terms of tumor coverage and avoidance of normal tissues. Results: In incorporating perfusion information in IMRT planning, the median reductions in the mean doses to the F50 and F90 lung in the functional plan were 2.2 and 4.2 Gy, respectively, compared with those in the anatomic plans. The median reductions in the percentage of volume irradiated with >5 Gy, >10 Gy, and >20 Gy in the functional plans were 7.1%, 6.0%, and 5.1%, respectively, for F50 lung, and 11.7%, 12.0%, and 6.8%, respectively, for F90 lung. A greater degree of sparing of the functional lung was achieved for patients with large perfusion defects compared with those with relatively uniform perfusion distribution. Conclusion: Function-guided IMRT planning appears to be effective in preserving functional lung in locally advanced-stage NSCLC patients

Partial stereotactic ablative boost radiotherapy in bulky non-small cell lung cancer: a retrospective study

Directory of Open Access Journals (Sweden)

Bai Y

2018-05-01

Full Text Available Yun Bai,1 Xian-shu Gao,1 Shang-bin Qin,1 Jia-yan Chen,1 Meng-meng Su,1 Qing Liu,2 Xiu-bo Qin,2 Ming-wei Ma,1 Bo Zhao,1 Xiao-bin Gu,1 Mu Xie,1 Ming Cui,1 Xin Qi,1 Xiao-ying Li1 1Department of Radiation Oncology, Peking University First Hospital, Beijing, China; 2Department of Medical Imaging, Peking University First Hospital, Beijing, China Purpose: Bulky non-small cell lung cancer (NSCLC is difficult to achieve effective local control by conventionally fractionated radiotherapy (CRT. The present work aims to evaluate the safety and efficacy of partial stereotactic ablative boost radiotherapy (P-SABR in bulky NSCLC. Patients and methods: From December 2012 through August 2017, 30 patients with bulky NSCLC treated with P-SABR technique were analyzed. The P-SABR plan consisted of one partial SABR plan (5–9 Gy/f, 3–6 fractions to gross tumor boost (GTVb, followed by one CRT plan to the planning target volume (PTV. GTVb was the max volume receiving SABR to guarantee the dose of organs-at-risks (OARs falloff to about 3 Gy/f. The total dose of PTV margin was planned to above 60 Gy. The simply CRT plans were created using the same planning parameters as the original plan, with the goal to achieve comparable OARs doses and PTV margin dose to the P-SABR plan. Dosimetric variables were acquired in both P-SABR and compared CRT plans. Toxicity, local control, and survival were also evaluated. Results: Median follow-up in survivors was 10.3 months (range=2.3–39.4 months. Eleven patients (36.7% had partial response (PR and ten patients (33.3% had stable disease (SD. Two-year overall survival was 55.6%. Two-year local control rate was 85.7%. No severe acute side effects .CTCAE Grade III were observed. Compared to the simply CRT plan, P-SABR plans achieved similar doses to the OARs and Dmin, but increased dose at the isocenter, Dmean, Dmax, and biological equivalent dose (BED significantly (P<0.05. BED in the tumor center could reach 107.3 Gy (93.2–132

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...

Differential effect of age on survival in advanced NSCLC in women versus men: analysis of recent Eastern Cooperative Oncology Group (ECOG) studies, with and without bevacizumab.

Science.gov (United States)

Wakelee, H A; Dahlberg, S E; Brahmer, J R; Schiller, J H; Perry, M C; Langer, C J; Sandler, A B; Belani, C P; Johnson, D H

2012-06-01

The impact of age on prognosis in advanced stage non-small cell lung cancer (NSCLC) may differ by sex. Eligible patients (N=1590) from E1594, a 4-arm platinum-based chemotherapy trial, and E4599 (carboplatin/paclitaxel ± bevacizumab) chemotherapy arm were divided into male and female cohorts and separated into age groups of women ≥60 years old treated with chemotherapy alone on E1594 and E4599 was 11.6 months versus 9.0 months for women women (younger had greater benefit), with no age effect in men. In this unplanned, exploratory subgroup analysis of advanced stage NSCLC ECOG trials, women ≥60 years old treated with chemotherapy live longer than men and younger women. In contrast, bevacizumab survival benefit was more pronounced in men of any age and in younger women on E4599. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

[Exon-dependent Subgroup-analysis of the Non-interventional REASON-Study: PFS and OS in EGFR-mutated NSCLC Patients Treated with Gefitinib or Chemotherapy].

Science.gov (United States)

Schuette, W; Dietel, M; Thomas, M; Eberhardt, W; Griesinger, F; Zirrgiebel, U; Radke, S; Schirmacher, P

2016-08-01

To analyze the influence of the localization of mutations in the epidermal growth factor receptor (EGFR) gene on progression-free (PFS) and overall survival (OS) in patients (pts) with locally advanced or metastatic non-small cell lung cancer (NSCLC) treated with gefitinib (gef) or chemotherapy (CT) under real world conditions within the REASON study. Subgroups of pts with mutations in exon 19 (n = 141), 18/20 (n = 43), and 21 (n = 104) were analyzed for PFS and OS according to gef or CT treatment and compared using the log-rank test. Pts with mutations in exon 19 and 18/20 treated with gef as first line therapy showed increased PFS and OS compared to CT. This increase was statistically significant in pts with exon 19 mutation (11.3 vs. 6.5 months), but was not found in pts with exon 21 mutation (9.1 vs. 9.3 months). Also, OS was significantly increased in patients with mutation in exon 19 treated with gef ever over all treatment lines compared to CT (21.8 vs. 10.6 months), whereas this was not found in pts with mutation in exon 21 (14.1 vs. 13.9 months). Localization and nature of EGFR mutations influences gefitinib treatment outcomes under routine conditions and should therefore be analyzed in detail. © Georg Thieme Verlag KG Stuttgart · New York.

Clinical Evaluation of Tumor Markers for Diagnosis in Patients with Non-small Cell Lung Cancer in China.

Science.gov (United States)

Ma, Li; Xie, Xiao-Wei; Wang, Hai-Yan; Ma, Ling-Yun; Wen, Zhong-Guang

2015-01-01

To evaluate the value of combined detection of serum carcinoembryonic antigen (CEA), cytokeratin 19 fragment (CYFRA21-1), and carbohydrateantigen 125 (CA125) for the clinical diagnosis of non- small cell lung cancer (NSCLC). Serum CEA, CYFRA21-1 and CA125 were assessed in 140 patients with NSCLC, 90 patients with benign lung disease and 90 normal control subjects, and differences of expression were compared in each group, and joint effects of these tumor markers in the diagnosis of NSCLC were analyzed. Serum CEA, CYFRA21-1 and CA125 in patients with NSCLC were significantly higher than those with benign lung disease and normal controls (PCEA, CYFRA21-1 and CA125 were 49.45%, 59.67%, and 44.87% respectively. As expected, combinations of these tumor markers improved their sensitivity for NSCLC. The combined detection of CEA+CYFRA21-1 was the most cost-effective combination which had higher sensitivity and specificity in NSCLC. Elevation of serum CEA and CYFRA21-1 was significantly associated with pathological types (PCEA, CYFRA21-1 and CA125 was significantly associated with TNM staging (PCEA, CYFRA21-1 and CA125 is of diagnostic value in the diagnosis of lung cancer, and a joint detection of these three tumor markers, could greatly improve the sensitivity of diagnosis on NSCLC. Combined detection of CEA+CYFRA21-1 proved to be the most economic and practical strategy in diagnosis of NSCLC, which can be used to screen the high-risk group.

Pemetrexed safety and pharmacokinetics in patients with third-space fluid

DEFF Research Database (Denmark)

Dickgreber, Nicolas J; Sorensen, Jens Benn; Paz-Ares, Luis G

2010-01-01

Pemetrexed is established as first-line treatment with cisplatin for malignant pleural mesothelioma and advanced nonsquamous non-small-cell lung cancer (NSCLC) and as single-agent second-line treatment for nonsquamous NSCLC. Because the structure and pharmacokinetics of pemetrexed are similar to ...... to those of methotrexate, and methotrexate is associated with severe toxicity in patients with third-space fluid (TSF), the safety of pemetrexed in patients with TSF was evaluated....

Effectiveness of different rescanning techniques for scanned proton radiotherapy in lung cancer patients

Science.gov (United States)

Engwall, E.; Glimelius, L.; Hynning, E.

2018-05-01

Non-small cell lung cancer (NSCLC) is a tumour type thought to be well-suited for proton radiotherapy. However, the lung region poses many problems related to organ motion and can for actively scanned beams induce severe interplay effects. In this study we investigate four mitigating rescanning techniques: (1) volumetric rescanning, (2) layered rescanning, (3) breath-sampled (BS) layered rescanning, and (4) continuous breath-sampled (CBS) layered rescanning. The breath-sampled methods will spread the layer rescans over a full breathing cycle, resulting in an improved averaging effect at the expense of longer treatment times. In CBS, we aim at further improving the averaging by delivering as many rescans as possible within one breathing cycle. The interplay effect was evaluated for 4D robustly optimized treatment plans (with and without rescanning) for seven NSCLC patients in the treatment planning system RayStation. The optimization and final dose calculation used a Monte Carlo dose engine to account for the density heterogeneities in the lung region. A realistic treatment delivery time structure given from the IBA ScanAlgo simulation tool served as basis for the interplay evaluation. Both slow (2.0 s) and fast (0.1 s) energy switching times were simulated. For all seven studied patients, rescanning improves the dose conformity to the target. The general trend is that the breath-sampled techniques are superior to layered and volumetric rescanning with respect to both target coverage and variability in dose to OARs. The spacing between rescans in our breath-sampled techniques is set at planning, based on the average breathing cycle length obtained in conjunction with CT acquisition. For moderately varied breathing cycle lengths between planning and delivery (up to 15%), the breath-sampled techniques still mitigate the interplay effect well. This shows the potential for smooth implementation at the clinic without additional motion monitoring equipment.

Functional image-based radiotherapy planning for non-small cell lung cancer: A simulation study

International Nuclear Information System (INIS)

Bates, Emma L.; Bragg, Christopher M.; Wild, Jim M.; Hatton, Matthew Q.F.; Ireland, Rob H.

2009-01-01

Background and purpose: To investigate the incorporation of data from single-photon emission computed tomography (SPECT) or hyperpolarized helium-3 magnetic resonance imaging ( 3 He-MRI) into intensity-modulated radiotherapy (IMRT) planning for non-small cell lung cancer (NSCLC). Material and methods: Seven scenarios were simulated that represent cases of NSCLC with significant functional lung defects. Two independent IMRT plans were produced for each scenario; one to minimise total lung volume receiving ≥20 Gy (V 20 ), and the other to minimise only the functional lung volume receiving ≥20 Gy (FV 20 ). Dose-volume characteristics and a plan quality index related to planning target volume coverage by the 95% isodose (V PTV95 /FV 20 ) were compared between anatomical and functional plans using the Wilcoxon signed ranks test. Results: Compared to anatomical IMRT plans, functional planning reduced FV 20 (median 2.7%, range 0.6-3.5%, p = 0.02), and total lung V 20 (median 1.5%, 0.5-2.7%, p = 0.02), with a small reduction in mean functional lung dose (median 0.4 Gy, 0-0.7 Gy, p = 0.03). There were no significant differences in target volume coverage or organ-at-risk doses. Plan quality index was improved for functional plans (median increase 1.4, range 0-11.8, p = 0.02). Conclusions: Statistically significant reductions in FV 20 , V 20 and mean functional lung dose are possible when IMRT planning is supplemented by functional information derived from SPECT or 3 He-MRI.

Stereotactic body radiotherapy for centrally located early-stage non-small cell lung cancer or lung metastases from the RSSearch® patient registry

International Nuclear Information System (INIS)

Davis, Joanne N.; Medbery, Clinton; Sharma, Sanjeev; Pablo, John; Kimsey, Frank; Perry, David; Muacevic, Alexander; Mahadevan, Anand

2015-01-01

The purpose of this study was to evaluate treatment patterns and outcomes of stereotactic body radiotherapy (SBRT) for centrally located primary non-small cell lung cancer (NSCLC) or lung metastases from the RSSearch ® Patient Registry, an international, multi-center patient registry dedicated to radiosurgery and SBRT. Eligible patients included those with centrally located lung tumors clinically staged T1-T2 N0, M0, biopsy-confirmed NSCLC or lung metastases treated with SBRT between November 2004 and January 2014. Descriptive analysis was used to report patient demographics and treatment patterns. Overall survival (OS) and local control (LC) were determined using Kaplan-Meier method. Toxicity was reported using the Common Terminology Criteria for Adverse Events version 3.0. In total, 111 patients with 114 centrally located lung tumors (48 T1-T2,N0,M0 NSCLC and 66 lung metastases) were treated with SBRT at 19 academic and community-based radiotherapy centers in the US and Germany. Median follow-up was 17 months (range, 1–72). Median age was 74 years for primary NSCLC patients and 65 years for lung metastases patients (p < 0.001). SBRT dose varied from 16 – 60 Gy (median 48 Gy) delivered in 1–5 fractions (median 4 fractions). Median dose to centrally located primary NSCLC was 48 Gy compared to 37.5 Gy for lung metastases (p = 0.0001) and median BED 10 was 105.6 Gy for primary NSCLC and 93.6 Gy for lung metastases (p = 0.0005). Two-year OS for T1N0M0 and T2N0M0 NSCLC was 79 and 32.1 %, respectively (p = 0.009) and 2-year OS for lung metastases was 49.6 %. Two-year LC was 76.4 and 69.8 % for primary NSCLC and lung metastases, respectively. Toxicity was low with no Grade 3 or higher acute or late toxicities. Overall, patients with centrally located primary NSCLC were older and received higher doses of SBRT than those with lung metastases. Despite these differences, LC and OS was favorable for patients with central lung tumors treated with SBRT. Reported toxicity

Should mediastinoscopy actually be incorporated into the FDG PET strategy for patients with non-small cell lung carcinoma?

International Nuclear Information System (INIS)

Hayashi, Katsumi; Abe, Katsumi; Yano, Fuzuki; Watanabe, Sadahiro; Iwasaki, Yoshie; Kosuda, Shigeru

2005-01-01

Incorporating mediastinoscopy (MS) into the PET-based strategy for non-small cell lung carcinoma (NSCLC) patients might be cost-effective because MS can allow unnecessary thoracotomies to be avoided. The objective of our study was to assess the cost-effectiveness of incorporating MS into a PET strategy for NSCLC patients. To determine life expectancy (LE), quality adjusted life years (QALY), and the incremental cost-effectiveness ratio (ICER), a decision-tree sensitivity analysis was designed for histopathologically confirmed NSCLC patients with M0 disease, based on the three competing strategies of chest CT only vs. PET+CT vs. PET+CT+MS. A simulation of 1,000 NSCLC patients was created using baselines of other relevant variables in regard to sensitivity, specificity, mortality, LE, utilities and cost from published data. One-way sensitivity analyses were performed to determine the influences of mediastinal metastasis prevalence on LE, QALY and ICER. The LE and QALY per patient in the CT only strategy, PET+CT strategy and PET+CT+MS strategy were 4.79 and 4.35, 5.33 and 4.93 and 5.68 and 5.33 years, respectively, with a 20% prevalence of mediastinal metastasis. The ICERs were 906.6 yen x 10 3 (US$7,555)/QALY/patient at a 20% mediastinal metastasis prevalence, and 2,194 yen x 10 3 (US$18,282)/QALY/patient at a 50% prevalence, but exceeded 5,280 yen x 10 3 (US$44,000)/QALY/patient at 80%. Our study quantitatively showed the CT+PET+MS strategy in place of the PET+CT strategy in managing NSCLC patients to be cost-effective. MS should be incorporated into the PET+CT strategy for NSCLC patients except in those highly suspected of having mediastinal disease on chest CT or PET. (author)

Elective nodal irradiation (ENI) vs. involved field radiotherapy (IFRT) for locally advanced non-small cell lung cancer (NSCLC): A comparative analysis of toxicities and clinical outcomes

International Nuclear Information System (INIS)

Fernandes, Annemarie T.; Shen, Jason; Finlay, Jarod; Mitra, Nandita; Evans, Tracey; Stevenson, James; Langer, Corey; Lin, Lilie; Hahn, Stephen; Glatstein, Eli; Rengan, Ramesh

2010-01-01

Background: Elective nodal irradiation (ENI) and involved field radiotherapy (IFRT) are definitive radiotherapeutic approaches used to treat patients with locally advanced non-small cell lung cancer (NSCLC). ENI delivers prophylactic radiation to clinically uninvolved lymph nodes, while IFRT only targets identifiable gross nodal disease. Because clinically uninvolved nodal stations may harbor microscopic disease, IFRT raises concerns for increased nodal failures. This retrospective cohort analysis evaluates failure rates and treatment-related toxicities in patients treated at a single institution with ENI and IFRT. Methods: We assessed all patients with stage III locally advanced or stage IV oligometastatic NSCLC treated with definitive radiotherapy from 2003 to 2008. Each physician consistently treated with either ENI or IFRT, based on their treatment philosophy. Results: Of the 108 consecutive patients assessed (60 ENI vs. 48 IFRT), 10 patients had stage IV disease and 95 patients received chemotherapy. The median follow-up time for survivors was 18.9 months. On multivariable logistic regression analysis, patients treated with IFRT demonstrated a significantly lower risk of high grade esophagitis (Odds ratio: 0.31, p = 0.036). The differences in 2-year local control (39.2% vs. 59.6%), elective nodal control (84.3% vs. 84.3%), distant control (47.7% vs. 52.7%) and overall survival (40.1% vs. 43.7%) rates were not statistically significant between ENI vs. IFRT. Conclusions: Nodal failure rates in clinically uninvolved nodal stations were not increased with IFRT when compared to ENI. IFRT also resulted in significantly decreased esophageal toxicity, suggesting that IFRT may allow for integration of concurrent systemic chemotherapy in a greater proportion of patients.

Elective nodal irradiation (ENI) vs. involved field radiotherapy (IFRT) for locally advanced non-small cell lung cancer (NSCLC): A comparative analysis of toxicities and clinical outcomes.

Science.gov (United States)

Fernandes, Annemarie T; Shen, Jason; Finlay, Jarod; Mitra, Nandita; Evans, Tracey; Stevenson, James; Langer, Corey; Lin, Lilie; Hahn, Stephen; Glatstein, Eli; Rengan, Ramesh

2010-05-01

Elective nodal irradiation (ENI) and involved field radiotherapy (IFRT) are definitive radiotherapeutic approaches used to treat patients with locally advanced non-small cell lung cancer (NSCLC). ENI delivers prophylactic radiation to clinically uninvolved lymph nodes, while IFRT only targets identifiable gross nodal disease. Because clinically uninvolved nodal stations may harbor microscopic disease, IFRT raises concerns for increased nodal failures. This retrospective cohort analysis evaluates failure rates and treatment-related toxicities in patients treated at a single institution with ENI and IFRT. We assessed all patients with stage III locally advanced or stage IV oligometastatic NSCLC treated with definitive radiotherapy from 2003 to 2008. Each physician consistently treated with either ENI or IFRT, based on their treatment philosophy. Of the 108 consecutive patients assessed (60 ENI vs. 48 IFRT), 10 patients had stage IV disease and 95 patients received chemotherapy. The median follow-up time for survivors was 18.9 months. On multivariable logistic regression analysis, patients treated with IFRT demonstrated a significantly lower risk of high grade esophagitis (Odds ratio: 0.31, p = 0.036). The differences in 2-year local control (39.2% vs. 59.6%), elective nodal control (84.3% vs. 84.3%), distant control (47.7% vs. 52.7%) and overall survival (40.1% vs. 43.7%) rates were not statistically significant between ENI vs. IFRT. Nodal failure rates in clinically uninvolved nodal stations were not increased with IFRT when compared to ENI. IFRT also resulted in significantly decreased esophageal toxicity, suggesting that IFRT may allow for integration of concurrent systemic chemotherapy in a greater proportion of patients. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

University of Texas Southwestern Medical Center: High-Throughput siRNA Screening of a Non-Small Cell Lung Cancer (NSCLC) Cell Line Panel | Office of Cancer Genomics

Science.gov (United States)

The goal of this project is to use siRNA screens to identify NSCLC-selective siRNAs from two genome-wide libraries that will allow us to functionally define genetic dependencies of subtypes of NSCLC. Using bioinformatics tools, the CTD2 center at the University of Texas Southwestern Medical Center are discovering associations between this functional data (siRNAs) and NSCLC mutational status, methylation arrays, gene expression arrays, and copy number variation data that will help us identify new targets and enrollment biomarkers. 

LATE-BREAKING ABSTRACT: Early relapse of non-small cell lung cancer (NSCLC) found after CNS-symptoms

DEFF Research Database (Denmark)

Hansen, Niels-Chr. G.; Laursen, Christian B.; Jeppesen, Stefan S.

2016-01-01

whether the introduction in 2010 of follow-up by CT of thorax and upper abdomen every three months has reduced the incidence of relapse suspected from CNS-symptoms.Results: All 827 NSCLC patients from Funen completing curative treatment from 2005 to 2013 were included. The total number of relapses found...... or III were found.Conclusion: CT-based follow-up has not reduced the incidence of relapse suspected from CNS-symptoms in stage II-IV, and therefore we suggest routine MR of the brain before curative treatment for this group of patients.Number, fractions(%), and [95%CI]Jan. 2005 - June 2010July 2010 - Dec...... after symptoms within 24 months decreased in the 3½ years after the introduction of CT-based follow-up, p < 0,001 (table), but the total fraction presenting with CNS-symptoms did not change, p = 0.296. Relapses after stage I cancer decreased (p = 0.025), while no differences or changes for stages II...

The combination of anti-KIR monoclonal antibodies with anti-PD-1/PD-L1 monoclonal antibodies could be a critical breakthrough in overcoming tumor immune escape in NSCLC

Directory of Open Access Journals (Sweden)

He YY

2018-04-01

Full Text Available Yayi He,1,2,* Sangtian Liu,1,* Jane Mattei,3 Paul A Bunn Jr,2 Caicun Zhou,1 Daniel Chan2 1Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China; 2Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; 3Oncology Department, Moinhos de Vento Hospital, Porto Alegre, Brazil *These authors contributed equally to this work Background: The anti-programmed death-1 (PD-1/programmed death ligand-1 (PD-L1 monoclonal antibody has a good effect in the treatment of non-small cell lung cancer (NSCLC, but not all PD-1/PD-L1 positive patients can get benefit from it. Compensatory expression of other immune checkpoints may be correlated with the poor efficacy of anti-PD-1/PD-L1 monoclonal antibodies. The inhibitory human leukocyte antigen (HLA/killer cell Ig-like receptor (KIR can effectively block the killing effect of natural killer (NK cells on tumors. Our previous studies have confirmed that high expression of KIR was correlated with poor prognosis of NSCLC. Inhibitory KIR expression was positively correlated with the expression of PD-1. Methods: The expressions of KIR 2D (L1, L3, L4, S4 (BC032422/ADQ31987/NP_002246/NP_036446, Abcam and PD-1 (NAT 105, Cell marque proteins was assessed by immunohis­tochemistry. Results: The expression of inhibitory KIR in tumor cells or tumor infiltrating lymphocytes (TILs is associated with PD-1 expression. Among PD-1 positive patients, 76.3% were KIR 2D (L1, L3, L4, S4 positive on tumor cells, and 74.6% were KIR 2D (L1, L3, L4, S4 positive on TILs. We compared the expression of inhibitory KIR before and after treatment with nivolumab in 11 patients with NSCLC. We found that five (45.5% patients had positive expression of inhibitory KIR in tumor tissue after being treated with anti-PD-1 monoclonal antibodies, two of whom exhibited a significant

Pemetrexed-carboplatin with intercalated icotinib in the treatment of patient with advanced EGFR wild-type lung adenocarcinoma

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Xu, Tongpeng; Wu, Hao; Jin, Shidai; Min, Huang; Zhang, Zhihong; Shu, Yongqian; Wen, Wei; Guo, Renhua

2017-01-01

Abstract Rationale: Tyrosine kinase inhibitors (TKIs) are known to have greater efficacy in epidermal growth factor receptor (EGFR) mutation nonsmall cell lung cancer (NSCLC). However, about 10% of EGFR wild-type (wt) patients respond to TKIs. Patient concerns: Several strategies to increase the efficacy of TKIs in wt NSCLC are the subjects of ongoing investigations. One of them is combining EGFR TKI with intercalated chemotherapy. Diagnoses: We describe a patient with EGFR wt NSCLC, who was found with ovarian and lung metastasis, was treated with pemetrexed and intercalated icotinib. Interventions: In this case, we reported the successful long-term maintenance treatment of a patient with EGFR wt NSCLC with pemetrexed and Icotinib. The patient (40-year-old female) was found with ovarian masses and lung masses. Pathological, immunohistochemical, and amplification refractory mutation system (ARMS) assay examinations of ovarian specimen suggested the expression of metastatic lung adenocarcinoma with wt EGFR. After failure treatment with paclitaxel-carboplatin, the patient received 4 cycles of pemetrexed plus platinum with intercalated icotinib and then remained on pemetrexed and icotinib. Outcomes: A partial response was achieved after the treatment. The patient's condition had remained stable on pemetrexed and icotinib for more than 20 months, with no evidence of progression. Lessons: To our knowledge, this is the first report using the long-term maintenance treatment with pemetrexed and intercalated icotinib in EGFR wt patient. The therapeutic strategies warrant further exploration in selected populations of NSCLC. PMID:28816950

Effect of ABCG2/BCRP Expression on Efflux and Uptake of Gefitinib in NSCLC Cell Lines.

Directory of Open Access Journals (Sweden)

Maricla Galetti

Full Text Available BCRP/ABCG2 emerged as an important multidrug resistance protein, because it confers resistance to several classes of cancer chemotherapeutic agents and to a number of novel molecularly-targeted therapeutics such as tyrosine kinase inhibitors. Gefitinib is an orally active, selective EGFR tyrosine kinase inhibitor used in the treatment of patients with advanced non small cell lung cancer (NSCLC carrying activating EGFR mutations. Membrane transporters may affect the distribution and accumulation of gefitinib in tumour cells; in particular a reduced intracellular level of the drug may result from poor uptake, enhanced efflux or increased metabolism.The present study, performed in a panel of NSCLC cell lines expressing different ABCG2 plasma membrane levels, was designed to investigate the effect of the efflux transporter ABCG2 on intracellular gefitinib accumulation, by dissecting the contribution of uptake and efflux processes.Our findings indicate that gefitinib, in lung cancer cells, inhibits ABCG2 activity, as previously reported. In addition, we suggest that ABCG2 silencing or overexpression affects intracellular gefitinib content by modulating the uptake rather than the efflux. Similarly, overexpression of ABCG2 affected the expression of a number of drug transporters, altering the functional activities of nutrient and drug transport systems, in particular inhibiting MPP, glucose and glutamine uptake.Therefore, we conclude that gefitinib is an inhibitor but not a substrate for ABCG2 and that ABCG2 overexpression may modulate the expression and activity of other transporters involved in the uptake of different substrates into the cells.

Diagnostic utility of LunX mRNA in peripheral blood and pleural fluid in patients with primary non-small cell lung cancer

Directory of Open Access Journals (Sweden)

Tian Zhigang

2008-05-01

Full Text Available Abstract Background Progress in lung cancer is hampered by the lack of clinically useful diagnostic markers. The goal of this study was to provide a detailed evaluation of lung cancer tumor markers indicative of molecular abnormalities and to assess their diagnostic utility in non-small cell lung cancer (NSCLC patients. Methods Quantitative real-time RT-PCR was used to determine LunX, CK19, CEA, VEGF-C and hnRNP A2/B1 mRNA levels in peripheral blood and pleural fluid from NSCLC patients, compared with those from patients with other epithelial cancer (esophagus cancer and breast cancer, benign lung disease (pneumonia and tuberculo pleurisy and from healthy volunteers. Results In peripheral blood LunX mRNA was detectable in 75.0% (33/44 of patients with NSCLC, but not in patients with other epithelial cancer (0/28, benign lung disease (0/10 or in healthy volunteers (0/15. In contrast, all other genetic markers were detected in patients with either NSCLC, other epithelia cancer or benign lung disease, and in healthy volunteers. The expression level and positive rate of LunX mRNA in peripheral blood correlated with the pathologic stage of NSCLC (P LunX mRNA was detected in 92.9% (13/14 of malignant pleural fluid samples and was the only marker whose expression level was significantly different between malignant and benign pleural fluid (P LunX mRNA in the peripheral blood of NSCLC patients decreased shortly after clinical treatment (P = 0.005. Conclusion Of several commonly used genetic markers, LunX mRNA is the most specific gene marker for lung cancer and has potential diagnostic utility when measured in the peripheral blood and pleural fluid of NSCLC patients.

CD147-CD98hc complex contributes to poor prognosis of non-small cell lung cancer patients through promoting cell proliferation via the PI3K/Akt signaling pathway.

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Fei, Fei; Li, Xiaofei; Xu, Li; Li, Deyang; Zhang, Zhipei; Guo, Xu; Yang, Hushan; Chen, Zhinan; Xing, Jinliang

2014-12-01

It has been reported that CD147 and CD98 heavy chain (CD98hc) form a complex on the cell plasma membrane of several cancers; however, whether this complex exists in non-small cell lung cancer (NSCLC) cells and affects the prognosis of patients remains to be elucidated. The expression of CD147 and CD98hc was assessed in tissue samples from 241 NSCLC patients and NSCLC cell lines. The correlation between CD147 and CD98hc expression and their association with the prognosis of NSCLC patients were analyzed. We also evaluated the impact of CD147 and CD98hc on the growth of NSCLC cells as well as Akt phosphorylation. Both CD147 and CD98hc were significantly upregulated in NSCLC cells, and their expression levels were significantly correlated (p CD147 and CD98hc could form a complex on NSCLC cells. Compared with NSCLC patients with CD147-/CD98hc-, those with CD147+/CD98hc+ exhibited a significantly poor overall survival (OS) with a hazard ratio (HR) of 1.92 (p = 0.010), and a significantly increased risk of recurrence with a HR of 1.97 (p = 0.004). Also, we demonstrated that the proliferation of lung cancer cell lines was significantly affected by knockdown and force-expression of the CD147-CD98hc complex. Western blot analysis indicated that the phosphorylation of Akt in NSCLC cells was significantly affected by knockdown and overexpression of either or both CD147 and CD98hc. Our findings indicate that the CD147-CD98hc complex significantly contributes to poor prognosis of NSCLC patients through promoting cell proliferation via the PI3K/Akt pathway.

Lymphovascular space invasion and tumor differentiation are predictors for postoperative recurrence in patients with pathological stage I nonsmall cell lung cancer

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Ying-Yi Chen

2014-08-01

Conclusion: Tumor differentiation and LVSI were predictors of postoperative relapse for patients with pathological stage I NSCLC. Risk factors of postoperative recurrence in patients with pathological Stage I NSCLC may enable us to optimize the patient selection for postoperative adjuvant therapies to prevent possibly occult micrometastases.

Efficacy of Icotinib for Advanced Non-small Cell Lung Cancer Patients with EGFR Status Identified

Directory of Open Access Journals (Sweden)

Yiping ZHANG

2013-03-01

Full Text Available Background and objective As the first epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI in China, icotinib shows promising anticancer activity in vitro and vivo. The phase III clinical study (ICOGEN showed that icotinib has a good efficacy and tolerability in Chinese patients with advanced non-small cell lung cancer (NSCLC compared with gefitinib. This retrospective study aims to evaluate the efficacy and tolerability of icotinib monotherapy for advanced NSCLC patients with EGFR mutation and wild-type patients in our hospital. Methods Patients with advanced NSCLC who were treated with icotinib in Zhejiang Cancer Hospital were retrospectively analyzed from August, 2011 to August, 2012. Survival was estimated using Kaplan-Meier analysis and Log-rank tests. Results The clinical data of 49 patients (13 with wild-type and 36 with EGFR mutation with NSCLC were enrolled in the current study. The patients’ overall objective response rate (ORR was 58.3% and the disease control rate (DCR in 36 EGFR mutation patients was 88.9%. The ORR was 7.7% and DCR was 53.8% in the wild-type patients. Median progression-free survival (PFS with icotinib treatment in EGFR mutation patients was 9.5 months and 2.2 months in wild-type patients (P<0.001. Nineteen patients with EGFR mutation received icotinib as first-line and 17 in further-line treatment. The PFS was 9.5 months in the first-line and 8.5 months for second-line or further-line patients (P=0.41. Median overall survival (OS in EGFR mutation patients was not reached, but was 12.6 months in wild-type patients. Most of the drug-related adverse events were mild (grade I or II and reversible with no grade IV toxicity. Conclusion Icotinib monotherapy showed significant antitumor activity in advanced NSCLC EGFR mutation patients. The toxicity was well tolerated and acceptable.

[Efficacy of icotinib for advanced non-small cell lung cancer patients with EGFR status identified].

Science.gov (United States)

Song, Zhengbo; Yu, Xinmin; Cai, Jufen; Shao, Lan; Lin, Baochai; He, Chunxiao; Zhang, Beibei; Zhang, Yiping

2013-03-01

As the first epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) in China, icotinib shows promising anticancer activity in vitro and vivo. The phase III clinical study (ICOGEN) showed that icotinib has a good efficacy and tolerability in Chinese patients with advanced non-small cell lung cancer (NSCLC) compared with gefitinib. This retrospective study aims to evaluate the efficacy and tolerability of icotinib monotherapy for advanced NSCLC patients with EGFR mutation and wild-type patients in our hospital. Patients with advanced NSCLC who were treated with icotinib in Zhejiang Cancer Hospital were retrospectively analyzed from August, 2011 to August, 2012. Survival was estimated using Kaplan-Meier analysis and Log-rank tests. The clinical data of 49 patients (13 with wild-type and 36 with EGFR mutation) with NSCLC were enrolled in the current study. The patients' overall objective response rate (ORR) was 58.3% and the disease control rate (DCR) in 36 EGFR mutation patients was 88.9%. The ORR was 7.7% and DCR was 53.8% in the wild-type patients. Median progression-free survival (PFS) with icotinib treatment in EGFR mutation patients was 9.5 months and 2.2 months in wild-type patients (Picotinib as first-line and 17 in further-line treatment. The PFS was 9.5 months in the first-line and 8.5 months for second-line or further-line patients (P=0.41). Median overall survival (OS) in EGFR mutation patients was not reached, but was 12.6 months in wild-type patients. Most of the drug-related adverse events were mild (grade I or II) and reversible with no grade IV toxicity. Icotinib monotherapy showed significant antitumor activity in advanced NSCLC EGFR mutation patients. The toxicity was well tolerated and acceptable.

Italian Nivolumab Expanded Access Program in Nonsquamous Non-Small Cell Lung Cancer Patients: Results in Never-Smokers and EGFR-Mutant Patients.

Science.gov (United States)

Garassino, Marina Chiara; Gelibter, Alain Jonathan; Grossi, Francesco; Chiari, Rita; Soto Parra, Hector; Cascinu, Stefano; Cognetti, Francesco; Turci, Daniele; Blasi, Livio; Bengala, Carmelo; Mini, Enrico; Baldini, Editta; Quadrini, Silvia; Ceresoli, Giovanni Luca; Antonelli, Paola; Vasile, Enrico; Pinto, Carmine; Fasola, Gianpiero; Galetta, Domenico; Macerelli, Marianna; Giannarelli, Diana; Lo Russo, Giuseppe; de Marinis, Filippo

2018-05-03

Nivolumab is the first checkpoint inhibitor approved for the treatment of nonsquamous NSCLC. We report results from the nivolumab Italian expanded access program focusing on never-smokers and patients with EGFR-mutant nonsqamous NSCLC. Nivolumab (3 mg/kg intravenously every 2 weeks) was administered upon physicians' request to patients who had relapsed after one or more prior systemic treatments for stage IIIB/IV nonsquamous NSCLC. Efficacy and safety were evaluated in patients who received at least one dose of nivolumab. Of 1588 patients with nonsquamous NSCLC, 305 (19.2%) were never-smokers. EGFR status was available for 1395 patients. Of the 102 patients (6.4%) with EGFR mutation-positive tumors, 51 (50%) were never-smokers. The objective response rate was significantly higher in patients with wild-type EGFR than patients with EGFR-mutant tumors (19.6% versus 8.8% [p = 0.007]), in former and current smokers than in never-smokers (21.5% versus 9.2% [p = 0.0001]), and in never-smokers with wild-type EGFR than in never-smokers with mutant EGFR (11.0% versus 1.9% [p = 0.04]). There was no significant difference in objective response rate between smokers with wild-type EGFR and smokers with mutant EGFR (22.0% versus 20.6%). There was no statistically significant difference in median progression-free survival or in median overall survival. The median overall survival times were 11 months in patients with EGFR wild-type tumors versus 8.3 months in patients with EGFR-mutant tumors, 11.6 months in smokers versus 10.0 months in never-smokers, 11.0 months in never-smokers with EGFR wild-type tumors versus 5.6 months in never-smokers with EGFR-mutant tumors, and 14.1 months in smokers with EGFR-mutant tumors versus 11.3 months in smokers with EGFR wild-type tumors. The data on the Italian expanded access program in populations with nonsquamous NSCLC suggest that subgroups of patients could benefit differently from nivolumab according to their EGFR mutational status and

Chemotherapy options for the elderly patient with advanced non-small cell lung cancer.

LENUS (Irish Health Repository)

Hennessy, B T

2012-02-03

Combination chemotherapy has been shown to improve overall survival compared with best supportive care in patients with advanced non-small cell lung cancer (NSCLC). The survival advantage is modest and was initially demonstrated with cisplatin-containing regimens in a large meta-analysis of randomized trials reported in 1995. Newer chemotherapy combinations have been shown to be better tolerated than older cisplatin-based combinations, and some trials have also shown greater efficacy and survival benefits with these newer combinations. Combination chemotherapy is, therefore, the currently accepted standard of care for patients with good performance statuses aged less than 70 years with advanced NSCLC. However, there are limited data from clinical trials to support the use of combination chemotherapy in elderly patients over 70 years of age with advanced NSCLC. Subgroup analyses of large randomized phase III trials suggest that elderly patients with good performance statuses do as well as younger patients treated with combination chemotherapy. There are few randomized trials reported that evaluate chemotherapy in patients aged greater than 70 years only. Based on data from trials performed by an Italian group, single-agent vinorelbine has been shown to have significant activity in elderly patients with advanced NSCLC and to be well tolerated by those patients with Eastern Cooperative Oncology Group performance statuses of two or less, with associated improvements in measures of global health.

PD-L1 Expression and Survival among Patients with Advanced Non-Small Cell Lung Cancer Treated with Chemotherapy

DEFF Research Database (Denmark)

Sørensen, Steffen Filskov; Zhou, Wei; Dolled-Filhart, Marisa

2016-01-01

with advanced non-small cell lung cancer (NSCLC) treated with chemotherapy are inconsistent. MATERIAL AND METHODS: We evaluated the relationship between PD-L1 expression and overall survival (OS) among 204 patients with advanced NSCLC treated at Aarhus University Hospital, Aarhus, Denmark, from 2007 to 2012. PD......-positive tumors, and 50% had PD-L1 weak-positive tumors. No statistically significant association was found between PD-L1 expression and survival; adjusted hazard ratio of 1.34 (95% confidence interval, 0.88-2.03; median OS, 9.0 months) for the PD-L1 strong-positive group and 1.07 (0.74-1.55; median OS, 9...... by immunohistochemistry to be frequently expressed in patients with advanced NSCLC. However, PD-L1 expression is not a strong prognostic marker in patients with advanced NSCLC treated with chemotherapy....

Protocol for the isotoxic intensity modulated radiotherapy (IMRT) in stage III non-small cell lung cancer (NSCLC): a feasibility study.

Science.gov (United States)

Haslett, Kate; Franks, Kevin; Hanna, Gerard G; Harden, Susan; Hatton, Matthew; Harrow, Stephen; McDonald, Fiona; Ashcroft, Linda; Falk, Sally; Groom, Nicki; Harris, Catherine; McCloskey, Paula; Whitehurst, Philip; Bayman, Neil; Faivre-Finn, Corinne

2016-04-15

The majority of stage III patients with non-small cell lung cancer (NSCLC) are unsuitable for concurrent chemoradiotherapy, the non-surgical gold standard of care. As the alternative treatment options of sequential chemoradiotherapy and radiotherapy alone are associated with high local failure rates, various intensification strategies have been employed. There is evidence to suggest that altered fractionation using hyperfractionation, acceleration, dose escalation, and individualisation may be of benefit. The MAASTRO group have pioneered the concept of 'isotoxic' radiotherapy allowing for individualised dose escalation using hyperfractionated accelerated radiotherapy based on predefined normal tissue constraints. This study aims to evaluate whether delivering isotoxic radiotherapy using intensity modulated radiotherapy (IMRT) is achievable. Isotoxic IMRT is a multicentre feasibility study. From June 2014, a total of 35 patients from 7 UK centres, with a proven histological or cytological diagnosis of inoperable NSCLC, unsuitable for concurrent chemoradiotherapy will be recruited. A minimum of 2 cycles of induction chemotherapy is mandated before starting isotoxic radiotherapy. The dose of radiation will be increased until one or more of the organs at risk tolerance or the maximum dose of 79.2 Gy is reached. The primary end point is feasibility, with accrual rates, local control and overall survival our secondary end points. Patients will be followed up for 5 years. The study has received ethical approval (REC reference: 13/NW/0480) from the National Research Ethics Service (NRES) Committee North West-Greater Manchester South. The trial is conducted in accordance with the Declaration of Helsinki and Good Clinical Practice (GCP). The trial results will be published in a peer-reviewed journal and presented internationally. NCT01836692; Pre-results. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence

Fluorescence In Situ Hybridization and Immunohistochemistry as Diagnostic Methods for ALK Positive Non-Small Cell Lung Cancer Patients

Science.gov (United States)

Martinez, Pablo; Hernández-Losa, Javier; Cedrés, Susana; Castellví, Josep; Martinez-Marti, Alex; Tallada, Natalia; Murtra-Garrell, Nuria; Navarro-Mendivill, Alejandro; Rodriguez-Freixinos, Victor; Canela, Mercedes; Ramon y Cajal, Santiago; Felip, Enriqueta

2013-01-01

Background Anaplastic Lymphoma Kinase (ALK) positivity represents a novel molecular target in a subset of Non-Small Cell Lung Cancers (NSCLC). We explore Fluorescence in situ Hybridization (FISH) and Immunohistochemistry (IHC) as diagnostic methods for ALK positive patients and to describe its prevalence and outcomes in a population of NSCLC patients. Methods NSCLC patients previously screened for Epidermal Growth Factor Receptor (EGFR) at our institution were selected. ALK positive patients were identified by FISH and the value of IHC (D5F3) was explored. Results ninety-nine patients were identified. Median age was 61.5 years (range 35–83), all were caucasians, eighty percent were adenocarcinomas, fifty-one percent were male and thirty-eight percent were current smokers. Seven (7.1%) patients were ALK positive by FISH, thirteen (13.1%) were EGFR mutant, and 65 (65.6%) were negative/Wild Type (WT) for both ALK and EGFR. ALK positivity and EGFR mutations were mutually exclusive. ALK positive patients tend to be younger than EGFR mutated or wt patients. ALK positive patients were predominantly never smokers (71.4%) and adenocarcinoma (71.4%). ALK positive and EGFR mutant patients have a better outcome than negative/WT. All patients with ALK FISH negative tumours were negative for ALK IHC. Out of 6 patients positive for ALK FISH with more tissue available, 5 were positive for ALK IHC and 1 negative. Conclusions ALK positive patients represent 7.1% of a population of selected NSCLC. ALK positive patients have different clinical features and a better outcome than EGFR WT and ALK negative patients. IHC is a promising method for detecting ALK positive NSCLC patients. PMID:23359795

Patient-specific dosimetric endpoints based treatment plan quality control in radiotherapy

International Nuclear Information System (INIS)

Song, Ting; Zhou, Linghong; Staub, David; Chen, Mingli; Lu, Weiguo; Tian, Zhen; Jia, Xun; Li, Yongbao; Jiang, Steve B; Gu, Xuejun

2015-01-01

In intensity modulated radiotherapy (IMRT), the optimal plan for each patient is specific due to unique patient anatomy. To achieve such a plan, patient-specific dosimetric goals reflecting each patient’s unique anatomy should be defined and adopted in the treatment planning procedure for plan quality control. This study is to develop such a personalized treatment plan quality control tool by predicting patient-specific dosimetric endpoints (DEs). The incorporation of patient specific DEs is realized by a multi-OAR geometry-dosimetry model, capable of predicting optimal DEs based on the individual patient’s geometry. The overall quality of a treatment plan is then judged with a numerical treatment plan quality indicator and characterized as optimal or suboptimal. Taking advantage of clinically available prostate volumetric modulated arc therapy (VMAT) treatment plans, we built and evaluated our proposed plan quality control tool. Using our developed tool, six of twenty evaluated plans were identified as sub-optimal plans. After plan re-optimization, these suboptimal plans achieved better OAR dose sparing without sacrificing the PTV coverage, and the dosimetric endpoints of the re-optimized plans agreed well with the model predicted values, which validate the predictability of the proposed tool. In conclusion, the developed tool is able to accurately predict optimally achievable DEs of multiple OARs, identify suboptimal plans, and guide plan optimization. It is a useful tool for achieving patient-specific treatment plan quality control. (paper)

FDG PET in monitoring response to neoadjuvant chemoradiotherapy in patients with locally advanced non-small lung carcinoma

International Nuclear Information System (INIS)

Berlangieri, S. U.; Lee, S. T.; Chan, A. M.; Mitchell, P. L.; Knight, S. R.; Feigen, M. M.; Scott, A. M.

2009-01-01

Full text:Aim: The aim of our study was to correlate 18F-FDG PET response to neoadjuvant chemoradiotherapy with histopathology in patients with locally advanced non-small cell lung carcinoma. Methods: All patients with stage III NSCLC planned for surgery following induction chemotherpay and/or radiotherapy who underwent pre- and post-treatment FDG-PET between 2004 and 2007 were retrospectively reviewed. The PET scans were performed according to standard protocol. The clinical FDG-PET TNM stage was correlated with the histopathology of the surgical specimens. Results: There were 9 patients (6 M :3 F ), median age 59.7 years (range 49 to 73 years). Post-treatment FDG-PET correctly predicted mediastinal pathological N stage in 8/9 patients, with one patient having microsopic disease in two nodes. The post-treatment FDG-PET correctly predicted pathological T stage in 7/9 patients, with 2 patients having small volume T4 disease not detected by PET. Post-treatment FDG-PET correctly downstaged 4 patients. Of the 5 patients, incorrectly staged on the post-treatment FDG-PET, one patient had microscopic pN 2 disease, 2 had pN 1 disease, and 2 had pT 4 disease. Conclusion: Post-treatment FDG-PET is predictive of pathological nodal stage within the mediastinum in patients with locally advanced NSCLC treated with neoadjuvant chemoradiotherapy. FDG-PET does not detect microscopic or small volume disease, nor is it able to define the boundaries of mediastinal tissue invasion.

Assessment of Referral and Chemotherapy Treatment Patterns for Elderly Patients With Non-small-Cell Lung Cancer.

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Dawe, David E; Pond, Gregory R; Ellis, Peter M

2016-11-01

Physiologic changes of aging in combination with greater comorbidity could lead to treatment nihilism for elderly patients (≥ 70 years old) with non-small-cell lung cancer (NSCLC). Randomized trials have shown improved survival with chemotherapy since 1999, but it remains unclear whether these data have translated into practice. We conducted a retrospective, population-based cohort study of NSCLC cases diagnosed in Ontario, Canada from 2000 to 2010. We compared referral and treatment patterns among patients aged treatment with chemotherapy. Of 61,646 patients with NSCLC, 32,131 (52.1%) were ≥ 70 years. Fewer adenocarcinomas were diagnosed in the elderly (29.8% vs. 44%), and more elderly patients lacked microscopic confirmation of malignancy (20.1% vs. 6.2%). Charlson co-morbidity scores ≥ 2 (14.0% vs. 7.4%) were higher in the elderly. Only 59.5% of elderly patients with NSCLC were referred to a medical oncologist, versus 78.5% of younger patients. Elderly patients were less likely to receive chemotherapy (18.3% vs. 46.7%), even among those referred to a medical oncologist (30.1% vs. 58.6%). Neither referral nor treatment changed substantially over time. The elderly also had a shorter median survival (5.8 vs. 9.6 months); however, there was less difference in median survival (13.6 vs. 14.9 months) among patients receiving chemotherapy. Elderly patients are less likely to be considered for systemic therapy for NSCLC, and evidence of benefit has had minimal impact on practice. We believe this disparity could be improved through systematically using tools to comprehensively assess elderly patients. Copyright © 2016 Elsevier Inc. All rights reserved.

Pemetrexed-carboplatin with intercalated icotinib in the treatment of patient with advanced EGFR wild-type lung adenocarcinoma: A case report.

Science.gov (United States)

Xu, Tongpeng; Wu, Hao; Jin, Shidai; Min, Huang; Zhang, Zhihong; Shu, Yongqian; Wen, Wei; Guo, Renhua

2017-08-01

Tyrosine kinase inhibitors (TKIs) are known to have greater efficacy in epidermal growth factor receptor (EGFR) mutation nonsmall cell lung cancer (NSCLC). However, about 10% of EGFR wild-type (wt) patients respond to TKIs. Several strategies to increase the efficacy of TKIs in wt NSCLC are the subjects of ongoing investigations. One of them is combining EGFR TKI with intercalated chemotherapy. We describe a patient with EGFR wt NSCLC, who was found with ovarian and lung metastasis, was treated with pemetrexed and intercalated icotinib. In this case, we reported the successful long-term maintenance treatment of a patient with EGFR wt NSCLC with pemetrexed and Icotinib. The patient (40-year-old female) was found with ovarian masses and lung masses. Pathological, immunohistochemical, and amplification refractory mutation system (ARMS) assay examinations of ovarian specimen suggested the expression of metastatic lung adenocarcinoma with wt EGFR. After failure treatment with paclitaxel-carboplatin, the patient received 4 cycles of pemetrexed plus platinum with intercalated icotinib and then remained on pemetrexed and icotinib. A partial response was achieved after the treatment. The patient's condition had remained stable on pemetrexed and icotinib for more than 20 months, with no evidence of progression. To our knowledge, this is the first report using the long-term maintenance treatment with pemetrexed and intercalated icotinib in EGFR wt patient. The therapeutic strategies warrant further exploration in selected populations of NSCLC.

Integrated Care Planning for Cancer Patients: A Scoping Review

Directory of Open Access Journals (Sweden)

Anum Irfan Khan

2017-11-01

Full Text Available Introduction: There has been a growing emphasis on the use of integrated care plans to deliver cancer care. However little is known about how integrated care plans for cancer patients are developed including featured core activities, facilitators for uptake and indicators for assessing impact. Methods: Given limited consensus around what constitutes an integrated care plan for cancer patients, a scoping review was conducted to explore the components of integrated care plans and contextual factors that influence design and uptake. Results: Five types of integrated care plans based on the stage of cancer care: surgical, systemic, survivorship, palliative and comprehensive (involving a transition between stages are described in current literature. Breast, esophageal and colorectal cancers were common disease sites. Multi-disciplinary teams, patient needs assessment and transitional planning emerged as key features. Provider buy-in and training alongside informational technology support served as important facilitators for plan uptake. Provider-level measurement was considerably less robust compared to patient and system-level indicators. Conclusions: Similarities in design features, components and facilitators across the various types of integrated care plans indicates opportunities to leverage shared features and enable a management lens that spans the trajectory of a patient’s journey rather than a phase-specific silo approach to care.

Using machine learning to predict radiation pneumonitis in patients with stage I non-small cell lung cancer treated with stereotactic body radiation therapy

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Valdes, Gilmer; Solberg, Timothy D.; Heskel, Marina; Ungar, Lyle; Simone, Charles B., II

2016-08-01

To develop a patient-specific ‘big data’ clinical decision tool to predict pneumonitis in stage I non-small cell lung cancer (NSCLC) patients after stereotactic body radiation therapy (SBRT). 61 features were recorded for 201 consecutive patients with stage I NSCLC treated with SBRT, in whom 8 (4.0%) developed radiation pneumonitis. Pneumonitis thresholds were found for each feature individually using decision stumps. The performance of three different algorithms (Decision Trees, Random Forests, RUSBoost) was evaluated. Learning curves were developed and the training error analyzed and compared to the testing error in order to evaluate the factors needed to obtain a cross-validated error smaller than 0.1. These included the addition of new features, increasing the complexity of the algorithm and enlarging the sample size and number of events. In the univariate analysis, the most important feature selected was the diffusion capacity of the lung for carbon monoxide (DLCO adj%). On multivariate analysis, the three most important features selected were the dose to 15 cc of the heart, dose to 4 cc of the trachea or bronchus, and race. Higher accuracy could be achieved if the RUSBoost algorithm was used with regularization. To predict radiation pneumonitis within an error smaller than 10%, we estimate that a sample size of 800 patients is required. Clinically relevant thresholds that put patients at risk of developing radiation pneumonitis were determined in a cohort of 201 stage I NSCLC patients treated with SBRT. The consistency of these thresholds can provide radiation oncologists with an estimate of their reliability and may inform treatment planning and patient counseling. The accuracy of the classification is limited by the number of patients in the study and not by the features gathered or the complexity of the algorithm.

Targeted erlotinib for first-line treatment of advanced non-small cell lung cancer: a budget impact analysis.

Science.gov (United States)

Bajaj, Preeti S; Veenstra, David L; Goertz, Hans-Peter; Carlson, Josh J

2014-08-01

A recent phase III trial showed that patients with advanced non-small cell lung cancer (NSCLC) whose tumors harbor specific EGFR mutations significantly benefit from first-line treatment with erlotinib compared to chemotherapy. This study sought to estimate the budget impact if coverage for EGFR testing and erlotinib as first-line therapy were provided in a hypothetical 500,000-member managed care plan. The budget impact model was developed from a US health plan perspective to evaluate administration of the EGFR test and treatment with erlotinib for EGFR-positive patients, compared to non-targeted treatment with chemotherapy. The eligible patient population was estimated from age-stratified SEER incidence data. Clinical data were derived from key randomized controlled trials. Costs related to drug, administration, and adverse events were included. Sensitivity analyses were conducted to assess uncertainty. In a plan of 500,000 members, it was estimated there would be 91 newly diagnosed advanced NSCLC patients annually; 11 are expected to be EGFR-positive. Based on the testing and treatment assumptions, it was estimated that 3 patients in Scenario 1 and 6 patients in Scenario 2 receive erlotinib. Overall health plan expenditures would increase by $0.013 per member per month (PMPM). This increase is largely attributable to erlotinib drug costs, in part due to lengthened progression-free survival and treatment periods experienced in erlotinib-treated patients. EGFR testing contributes slightly, whereas adverse event costs mitigate the budget impact. The budget impact did not exceed $0.019 PMPM in sensitivity analyses. Coverage for targeted first-line erlotinib therapy in NSCLC likely results in a small budget impact for US health plans. The estimated impact may vary by plan, or if second-line or maintenance therapy, dose changes/interruptions, or impact on patients' quality-of-life were included.

A potential to reduce pulmonary toxicity: The use of perfusion SPECT with IMRT for functional lung avoidance in radiotherapy of non-small cell lung cancer

International Nuclear Information System (INIS)

Lavrenkov, Konstantin; Christian, Judith A.; Partridge, Mike; Niotsikou, Elena; Cook, Gary; Parker, Michelle; Bedford, James L.; Brada, Michael

2007-01-01

Background and purpose: The study aimed to examine specific avoidance of functional lung (FL) defined by a single photon emission computerized tomography (SPECT) lung perfusion scan, using intensity modulated radiotherapy (IMRT) and three-dimensional conformal radiotherapy (3-DCRT) in patients with non-small cell lung cancer (NSCLC). Materials and methods: Patients with NSCLC underwent planning computerized tomography (CT) and lung perfusion SPECT scan in the treatment position using fiducial markers to allow co-registration in the treatment planning system. Radiotherapy (RT) volumes were delineated on the CT scan. FL was defined using co-registered SPECT images. Two inverse coplanar RT plans were generated for each patient: 4-field 3-DCRT and 5-field step-and-shoot IMRT. 3-DCRT plans were created using automated AutoPlan optimisation software, and IMRT plans were generated employing Pinnacle 3 treatment planning system (Philips Radiation Oncology Systems). All plans were prescribed to 64 Gy in 32 fractions using data for the 6 MV beam from an Elekta linear accelerator. The objectives for both plans were to minimize the volume of FL irradiated to 20 Gy (fV 20 ) and dose variation within the planning target volume (PTV). A spinal cord dose was constrained to 46 Gy. Volume of PTV receiving 90% of the prescribed dose (PTV 90 ), fV 20 , and functional mean lung dose (fMLD) were recorded. The PTV 90 /fV 20 ratio was used to account for variations in both measures, where a higher value represented a better plan. Results: Thirty-four RT plans of 17 patients with stage I-IIIB NSCLC suitable for radical RT were analysed. In 6 patients with stage I-II disease there was no improvement in PTV 90 , fV 20 , PTV/fV 20 ratio and fMLD using IMRT compared to 3-DCRT. In 11 patients with stage IIIA-B disease, the PTV was equally well covered with IMRT and 3-DCRT plans, with IMRT producing better PTV 90 /fV 20 ratio (mean ratio - 7.2 vs. 5.3, respectively, p = 0.001) and reduced f

Texture analysis of advanced non-small cell lung cancer (NSCLC) on contrast-enhanced computed tomography: prediction of the response to the first-line chemotherapy

International Nuclear Information System (INIS)

Farina, Davide; Morassi, Mauro; Maroldi, Roberto; Roca, Elisa; Tassi, Gianfranco; Cavalleri, Giuseppe

2013-01-01

To assess whether tumour heterogeneity, quantified by texture analysis (TA) on contrast-enhanced computed tomography (CECT), can predict response to chemotherapy in advanced non-small cell lung cancer (NSCLC). Fifty-three CECT studies of patients with advanced NSCLC who had undergone first-line chemotherapy were retrospectively reviewed. Response to chemotherapy was evaluated according to RECIST1.1. Tumour uniformity was assessed by a TA method based on Laplacian of Gaussian filtering. The resulting parameters were correlated with treatment response and overall survival by multivariate analysis. Thirty-one out of 53 patients were non-responders and 22 were responders. Average overall survival was 13 months (4-35), minimum follow-up was 12 months. In the adenocarcinoma group (n = 31), the product of tumour uniformity and grey level (GL*U) was the unique independent variable correlating with treatment response. Dividing the GL*U (range 8.5-46.6) into tertiles, lesions belonging to the second and the third tertiles had an 8.3-fold higher probability of treatment response compared with those in the first tertile. No association between texture features and response to treatment was observed in the non-adenocarcinoma group (n = 22). GL*U did not correlate with overall survival. TA on CECT images in advanced lung adenocarcinoma provides an independent predictive indicator of response to first-line chemotherapy. (orig.)

Subcarinal lymph node in upper lobe non-small cell lung cancer patients: is selective lymph node dissection valid?

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Aokage, Keiju; Yoshida, Junji; Ishii, Genichiro; Hishida, Tomoyuki; Nishimura, Mitsuyo; Nagai, Kanji

2010-11-01

Little is known about selective lymph node dissection in non-small cell lung cancer (NSCLC) patients. We sought to gain insight into subcarinal node involvement for its frequency and impact on outcome to evaluate whether it is valid to omit subcarinal lymph node dissection in upper lobe NSCLC patients. We reviewed node metastases distribution according to node region, tumor location, and histology among 1099 patients with upper lobe NSCLC. We paid special attention to subcarinal metastases patients without superior mediastinal node metastases, because their pathological stages would have been underdiagnosed if subcarinal node dissection had been omitted. We also assessed the outcome and the pattern of failure among subcarinal metastases patients. To identify subcarinal node involvement predictors, we analyzed 7 clinical factors. Subcarinal node metastases were found in 20 patients and were least frequent among squamous cell carcinoma patients (0.5%). Two of them were free from superior mediastinal metastases but died of the disease at 1 month and due to an unknown cause at 18 months, respectively. Seventeen of the 20 patients developed multi-site recurrence within 37 months. The 5-year survival rate of the 20 patients with subcarinal metastases was 9.0%, which was significantly lower than 32.0% of patients with only superior mediastinal metastases. Clinical diagnosis of node metastases was significantly predictive of subcarinal metastases. Subcarinal node metastases from upper lobe NSCLC were rare and predicted an extremely poor outcome. It appears valid to omit subcarinal node dissection in upper lobe NSCLC patients, especially in clinical N0 squamous cell carcinoma patients. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Split and Splice Approach for Highly Selective Targeting of Human NSCLC Tumors

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2014-10-01

development and implementation of the “split-and- spice ” approach required optimization of many independent parameters, which were addressed in parallel...verify the feasibility of the “split and splice” approach for targeting human NSCLC tumor cell lines in culture and prepare the optimized toxins for...for cultured cells (months 2- 8). 2B. To test the efficiency of cell targeting by the toxin variants reconstituted in vitro (months 3-6). 2C. To

Role of interim {sup 18}F-FDG-PET/CT for the early prediction of clinical outcomes of Non-Small Cell Lung Cancer (NSCLC) during radiotherapy or chemo-radiotherapy. A systematic review

Energy Technology Data Exchange (ETDEWEB)

Cremonesi, Marta; Garibaldi, Cristina [European Institute of Oncology, Radiation Research Unit, Milano (Italy); Gilardi, Laura; Travaini, Laura Lavinia; Grana, Chiara Maria [European Institute of Oncology, Division of Nuclear Medicine, Milano (Italy); Ferrari, Mahila Esmeralda; Botta, Francesca [Medical Physics Unit, European Institute of Oncology, Milano (Italy); Piperno, Gaia; Ronchi, Sara; Ciardo, Delia [European Institute of Oncology, Division of Radiation Oncology, Milano (Italy); Timmerman, Robert [University of Texas Southwestern Medical Center, Department of Radiation Oncology, Dallas, TX (United States); Baroni, Guido [Politecnico di Milano University, Department of Electronics, Information and Bioengineering, Milano (Italy); Jereczek-Fossa, Barbara Alicja [European Institute of Oncology, Division of Radiation Oncology, Milano (Italy); University of Milan, Department of Oncology and Hemato-Oncology, Milano (Italy); Orecchia, Roberto [University of Milan, Department of Oncology and Hemato-Oncology, Milano (Italy); European Institute of Oncology, Department of Medical Imaging and Radiation Sciences, Milano (Italy)

2017-10-15

Non-Small Cell Lung Cancer (NSCLC) is characterized by aggressiveness and includes the majority of thorax malignancies. The possibility of early stratification of patients as responsive and non-responsive to radiotherapy with a non-invasive method is extremely appealing. The distribution of the Fluorodeoxyglucose ({sup 18}F-FDG) in tumours, provided by Positron-Emission-Tomography (PET) images, has been proved to be useful to assess the initial staging of the disease, recurrence, and response to chemotherapy and chemo-radiotherapy (CRT). In the last years, particular efforts have been focused on the possibility of using ad interim {sup 18}F-FDG PET (FDG{sub int}) to evaluate response already in the course of radiotherapy. However, controversial findings have been reported for various malignancies, although several results would support the use of FDG{sub int} for individual therapeutic decisions, at least in some pathologies. The objective of the present review is to assemble comprehensively the literature concerning NSCLC, to evaluate where and whether FDG{sub int} may offer predictive potential. Several searches were completed on Medline and the Embase database, combining different keywords. Original papers published in the English language from 2005 to 2016 with studies involving FDG{sub int} in patients affected by NSCLC and treated with radiation therapy or chemo-radiotherapy only were chosen. Twenty-one studies out of 970 in Pubmed and 1256 in Embase were selected, reporting on 627 patients. Certainly, the lack of univocal PET parameters was identified as a major drawback, while standardization would be required for best practice. In any case, all these papers denoted FDG{sub int} as promising and a challenging examination for early assessment of outcomes during CRT, sustaining its predictivity in lung cancer. (orig.)

Use of PET and PET/CT for Radiation Therapy Planning: IAEA expert report 2006-2007

International Nuclear Information System (INIS)

MacManus, Michael; Nestle, Ursula; Rosenzweig, Kenneth E.; Carrio, Ignasi; Messa, Cristina; Belohlavek, Otakar; Danna, Massimo; Inoue, Tomio; Deniaud-Alexandre, Elizabeth; Schipani, Stefano; Watanabe, Naoyuki; Dondi, Maurizio; Jeremic, Branislav

2009-01-01

Positron Emission Tomography (PET) is a significant advance in cancer imaging with great potential for optimizing radiation therapy (RT) treatment planning and thereby improving outcomes for patients. The use of PET and PET/CT in RT planning was reviewed by an international panel. The International Atomic Energy Agency (IAEA) organized two synchronized and overlapping consultants' meetings with experts from different regions of the world in Vienna in July 2006. Nine experts and three IAEA staff evaluated the available data on the use of PET in RT planning, and considered practical methods for integrating it into routine practice. For RT planning, 18 F fluorodeoxyglucose (FDG) was the most valuable pharmaceutical. Numerous studies supported the routine use of FDG-PET for RT target volume determination in non-small cell lung cancer (NSCLC). There was also evidence for utility of PET in head and neck cancers, lymphoma and in esophageal cancers, with promising preliminary data in many other cancers. The best available approach employs integrated PET/CT images, acquired on a dual scanner in the radiotherapy treatment position after administration of tracer according to a standardized protocol, with careful optimization of images within the RT planning system and carefully considered rules for contouring tumor volumes. PET scans that are not recent or were acquired without proper patient positioning should be repeated for RT planning. PET will play an increasing valuable role in RT planning for a wide range of cancers. When requesting PET scans, physicians should be aware of their potential role in RT planning.

Pretreatment Pokemon Level as a Predictor of Response to Cisplatin and Paclitaxel in Patients with Unresectable Non-Small Cell Lung Cancer.

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Zhang, Quan-Le; Xing, Xi-Zhi; Li, Feng-Yan; Xing, Ya-Juan; Li, Jing

2015-01-01

We firstly investigated the expression of Pokemon in patients with non-small cell lung cancer (NSCLC), then characterized the role of Pokemon in evaluating the response to combined cisplatin and paclitaxel chemotherapy and prognosis. In this study, 61 patients with previously untreated locally advanced or metastatic NSCLC were treated with a combination chemotherapy comprising cisplatin and paclitaxel. The correlation between serum expression of Pokemon and effectiveness of chemotherapy was assessed. The expression level of Pokemon in NSCLC patients was higher than that in healthy controls (p = 0.000), and was correlated with tumor size and TNM stage (p Pokemon levels in excess of 135.09 ng/ml compared to those with Pokemon levels below 135.09 ng/ml (p = 0.013). Pokemon ≥ 135.09 ng/ml was an independent risk factor for survival time in NSCLC patients undergoing combination chemotherapy (p = 0.018). The serum level of Pokemon correlated with efficacy of cisplatin and paclitaxel combination chemotherapy and survival time, which indicated that Pokemon may be a potentially useful biomarker for predicting treatment effectiveness of first-line chemotherapy and prognosis in NSCLC. © 2015 S. Karger GmbH, Freiburg.

Characteristics of 49 patients who survived for 5 years following radical radiation therapy for non-small cell lung cancer: the potential for cure

International Nuclear Information System (INIS)

Mac Manus, Michael P.; Wada, Morikatsu; Matthews, Jane P.; Ball, David L.

2000-01-01

Purpose: To investigate the long-term curative potential of radical radiation therapy (RT) for non-small cell lung cancer (NSCLC) by studying characteristics of patients from a large prospective database who survived > 5 years after RT, and by analyzing survival beyond 5 years. Methods and Materials: Five-year survivors were identified from a database containing information on 488 patients given radical RT following presentation to the Peter MacCallum Cancer Institute with NSCLC between 1984 and 1990. Additional data were obtained from case notes of survivors. RT was computed tomography (CT)-planned, conventionally-fractionated, and given without chemotherapy. Results: Actuarial survival for 49 5-year survivors was 65% at 10 years. Five 5-year survivors had documented disease progression within the first 5 years and subsequently died. Of 44 patients free-from-progression (FFP) at 5 years, an estimated 81% remained FFP in the second 5 years. Age and histology were not significant prognostic factors, and only 22 patients (4.5%) had weight loss > 10%. For 277 patients who had not undergone thoracotomy, median RT dose was 60 Gy and survival at 5 and 10 years was 7% and 3%, respectively. For 207 patients who received radical RT post-thoracotomy, median dose was 60 Gy and survival at 5 and 10 years was 24% and 18%, respectively. Five-year survivors of post-thoracotomy RT had been treated for gross residual disease (n = 10), positive-margin (n = 6), or probable microscopic residual disease (n = 17). Failure to regain ECOG performance status = 0 post-thoracotomy was associated with reduced survival (p 5 years after radical RT for NSCLC remained FFP in the following 5 years and were apparently cured. RT alone can cure small but significant numbers of patients. Long-term results of combined chemotherapy/RT protocols, which are associated with increased median survival, are awaited for comparison

Emerging role of nivolumab in the management of patients with non-small-cell lung cancer: current data and future perspectives

Directory of Open Access Journals (Sweden)

Feld E

2017-07-01

Full Text Available Emily Feld, Leora Horn Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, TN, USA Abstract: Immune-checkpoint inhibitors have become valuable therapies in the treatment of patients with non-small-cell lung cancer (NSCLC. Recent clinical trials have shown promising results with regard to efficacy and toxicity profiles of these agents compared to cytotoxic chemotherapy. Nivolumab was one of the first immune-checkpoint inhibitors to demonstrate clinical activity in patients with NSCLC, and is currently approved in the US for treatment of patients with advanced squamous and nonsquamous NSCLC who have progressed on or after platinum-based chemotherapy. This review provides an update on nivolumab’s pharmacology, safety, and efficacy, as established by the CheckMate trials. We also discuss specific applications and strategies for the use of nivolumab in NSCLC patients, as well as predictive biomarkers and their role in treatment selection. Keywords: nivolumab, non-small-cell lung cancer, immune-checkpoint inhibitor, PD1 

Examination of 12-lipoxygenase (12-LOX) as a therapeutic target in non-small cell lung cancer (NSCLC): Mechanisms controlling survival and induction of apoptosis following selective inhibition

LENUS (Irish Health Repository)

Cathcart, Mary Clare

2011-06-01

Background: Platelet-type 12-LOX is an arachidonic acid metabolising enzyme resulting in the formation of 12(S)-HETE, which stimulates tumour cell adhesion, invasion and metastasis. This study aimed to examine the expression profile and role of this enzyme in NSCLC, and determine if it is a potential target for intervention. Methods: A panel of retrospective resected lung tumours was stained for 12-LOX expression by IHC. Levels of the 12-LOX metabolite, 12(S)-HETE, were examined in 50 NSCLC serum samples, and correlated with serum VEGF. A panel of NSCLC cell lines were treated with baicalein (10 uM), a selective inhibitor of 12-LOX, or 12(S)-HETE (100 ng\\/ml) and cell survival\\/proliferation examined by BrdU. Apoptosis following 12-LOX inhibition was examined by HCS and validated by FACS and DNA laddering. The effect of 12-LOX inhibition on NSCLC tumour growth and survival was examined in-vivo using an athymic nude mouse model. Gene alterations following 12-LOX inhibition in NSCLC cell lines were assessed by qPCR arrays and validated by RT-PCR. Transient transfection methods were used to examine the effects of 12-LOX overexpression in NSCLC cells. Results: 12-LOX expression was observed to a varying degree in human lung cancers of varying histological subtypes. 12(S)-HETE levels were correlated (p<0.05) with those of VEGF. Baicalein inhibited proliferation\\/survival in all cell lines, while 12(S)-HETE increased proliferation. 12-LOX inhibition increased apoptosis, indicated by a reduction in f-actin content and mitochondrial mass potential. Treatment with baicalein significantly reduced the growth of NSCLC tumours and increased overall survival in athymic nude mice. qPCR array data implicated a number of apoptosis\\/angiogenesis genes regulating these effects, including bcl-2, VEGF, integrin A2 and A4. 12-LOX overexpression resulted in an increase in VEGF secretion, confirming qPCR observations. Conclusions: 12-LOX is a survival factor\\/potential target in

Radio(chemotherapy in locally advanced nonsmall cell lung cancer

Directory of Open Access Journals (Sweden)

Markus Glatzer

2016-03-01

Full Text Available Definitive radiochemotherapy is the standard treatment for many patients with locally advanced nonsmall cell lung cancer (NSCLC. Treatment outcomes have improved over the last decades. Several treatment regimens have been shown effective and safe. This review summarises the results of significant studies between 1996 and 2015 on concomitant and sequential radiochemotherapy regimens and radiation dose per fraction. Beside therapy regimens, optimised radiotherapy planning is indispensable to improve outcome and minimise radiation-induced toxicity. An insight into the rationale of radiotherapy planning for stage III NSCLC is also provided.

Differences in practice patterns and costs between small cell and non-small cell lung cancer patients in Japan

International Nuclear Information System (INIS)

Kuwabara, Kazuaki; Matsuda, Shinya; Fushimi, Kiyohide; Anan, Makoto; Ishikawa, Koichi B.; Horiguchi, Hiromasa; Hayashida, Kenshi; Fujimori, Kenji

2009-01-01

Many reports exist regarding the economic evaluation of evolving chemotherapeutic regimens or diagnostic images for lung cancer (LC) patients. However, it is not clear whether clinical information, such as pathological diagnosis or cancer stage, should be considered as a risk adjustment in lung cancer. This study compared the cost and practice patterns between small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC) patients. 6,060 LC patients treated at 58 academic hospitals and 14,507 at 257 community hospitals were analyzed. Study variables included demographic variables, comorbid status, cancer stage, use of imaging and surgical procedures, type of adjuvant therapy (chemotherapy, radiation or chemoradiation), use of ten chemotherapeutic agents, length of stay (LOS), and total charges (TC; US$1=100 yen) in SCLC and NSCLC patients. The impact of pathological diagnosis on LOS and TC was investigated using multivariate analysis. We identified 3,571 SCLC and 16,996 NSCLC patients. The proportion of demographic and practice-process variables differed significantly between SCLC and NSCLC patients, including diagnostic imaging, adjuvant therapy and surgical procedures. Median LOS and TC were 20 days and US$6,015 for SCLC and 18 days and US$6,993 for NSCLC patients, respectively (p<0.001 for each variable). Regression analysis revealed that pathological diagnosis was not correlated with TC. Physicians should acknowledge that pathological diagnosis dose not accounts for any variation in cost of LC patients but that should remain as an indicator of appropriate care like selection of chemotherapeutic agents. (author)

Advance care planning: the impact of Ceiling of Treatment plans in patients with Coordinate My Care.

Science.gov (United States)

Broadhurst, Helen Lucy; Droney, Joanne; Callender, Tom; Shaw, Amanda; Riley, Julia

2018-03-22

The aim of this evaluation is to describe the components and results of urgent care planning in Coordinate My Care (CMC), a digital clinical service for patients with life-limiting illness, for use if a patient is unable to make or express choices. Ceiling of treatment (CoT) plans were created detailing where the patient would like to receive their care and how aggressive medical interventions should be. A retrospective service evaluation was completed of all CMC records created between December 2015 and September 2016 (n=6854). CMC records were divided into two cohorts: those with a CoT plan and those without. The factors associated with these cohorts were reviewed including age, diagnosis, resuscitation status and preferences for place of death (PPD). Analysis of the non-mandatory free text section was carried out. Two-thirds of patients had recorded decisions about CoT. Regardless of which CoT option was chosen, for most patients, PPD was home or care home. Patients with a CoT plan were more likely to have a documented resuscitation status.Patients with a CoT were more likely to die in their PPD (82%vs71%, OR 1.79, pcare planning. Three facets of urgent care planning identified include PPD, CoT and resuscitation status. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Inter-heterogeneity and intra-heterogeneity of α{sub v}β{sub 3} in non-small cell lung cancer and small cell lung cancer patients as revealed by {sup 68}Ga-RGD{sub 2} PET imaging

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Kang, Fei; Li, Guoquan; Wang, Shengjun; Liu, Daliang; Zhang, Mingru; Zhao, Mingxuan; Yang, Weidong; Wang, Jing [Fourth Military Medical University, Department of Nuclear Medicine, Xijing Hospital, Xi' an (China); Wang, Zhe [Fourth Military Medical University, Department of Nuclear Medicine, Xijing Hospital, Xi' an (China); Fourth Military Medical University, Department of Pathology, Xijing Hospital, Xi' an (China)

2017-08-15

Integrin α{sub v}β{sub 3} is the therapeutic target of the anti-angiogenic drug cilengitide. The objective of this study was to compare α{sub v}β{sub 3} levels in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) patients, by using the positron emission tomography (PET) tracer {sup 68}Ga-labeled dimerized-RGD ({sup 68}Ga-RGD{sub 2}). Thirty-one patients with pathologically confirmed lung cancer were enrolled (21 were NSCLC and 10 were SCLC). PET/CT images were acquired using {sup 68}Ga-RGD{sub 2}.{sup 18}F-FDG PET/CT images were also acquired on the consecutive day as reference. The standard uptake values (SUV) and the tumor/nontarget (T/NT) values were quantitatively compared. Expression of the angiogenesis marker α{sub v}β{sub 3} in NSCLC and SCLC lesions was analyzed by immunohistochemistry. The {sup 18}F-FDG SUVmax and the SUVmean were not significantly different between NSCLC and SCLC patients. The {sup 68}Ga-RGD{sub 2} uptake of SCLC patients was at background levels in both SUV and T/NT measurements and was significantly lower than that of NSCLC patients. The range value of {sup 68}Ga-RGD{sub 2} SUVmean was 4.5 in the NSCLC group and 2.2 in the SCLC group, while the variation coefficient was 36.2% and 39.3% in NSCLC and SCLC primary lesions, respectively. Heterogeneity between primary lesions and putative distant metastases was also observed in some NSCLC cases. Immunostaining showed that α{sub v}β{sub 3} integrin was expressed in the cells and neovasculature of NSCLC lesions, while SCLC samples had negative expression. The uptake of {sup 68}Ga-RGD{sub 2} in SCLC patients is significantly lower than that in NSCLC patients, indicating a lower α{sub v}β{sub 3} target level for cilengitide in SCLC. Apparent intra-tumor heterogeneities of α{sub v}β{sub 3} also exist in both NSCLC and SCLC. Such inter- and intra-heterogeneity of α{sub v}β{sub 3} may potentially improve current applications of α{sub v}β{sub 3}-targeted therapy

Variation in causes of death in patients with non-small cell lung cancer according to stage and time since diagnosis

NARCIS (Netherlands)

Janssen-Heijnen, M. L. G.; van Erning, F. N.; De Ruysscher, D. K.; Coebergh, J. W. W.; Groen, H. J. M.

Background: Many patients with non-small cell lung cancer (NSCLC) die within the first few years of diagnosis, and considerable excess mortality remains even after 5 years. We investigated the death rate and the distribution of causes of death for NSCLC patients by age and stage at diagnosis during

Real-life experience of ceritinib in crizotinib-pretreated ALK+ advanced non-small cell lung cancer patients

Directory of Open Access Journals (Sweden)

Jacques Cadranel

2018-02-01

Full Text Available Here we report our experience of ceritinib in crizotinib-pretreated patients with anaplastic lymphoma kinase (ALK positive (ALK+ non-small cell lung cancer (NSCLC in a French temporary authorisation for use (TAU study. The French TAU study included crizotinib-pretreated patients with advanced ALK+ or ROS proto-oncogene 1 positive (ROS1+ tumours. Patients received oral ceritinib (750 mg·day−1 as a starting dose and best tumour response (as evaluated by the investigator and safety were reported every 3 months. A total of 242 TAUs were granted from March 12, 2013 to August 05, 2015. Of the 242 patients, 228 had ALK+ NSCLC and 13 had ROS1+ NSCLC. The median age of ALK+ patients (n=214 was 58.5 years, 51.9% were female, 70.8% had an Eastern Cooperative Oncology Group (ECOG performance status (PS of 0–1 and 50.0% had brain metastases. Of the 149 efficacy evaluable ALK+ NSCLC patients, 5.4% had a complete response (CR, 47.0% had a partial response (PR and 22.8% had stable disease (SD. At September 05, 2015, the median duration of ceritinib treatment (n=182 was 3.9 months but 5.5 months for patients (n=71 with a follow-up of ≥12 months. Higher objective response rate (ORR was observed for patients with ECOG PS 0 to 1 (55.0% versus 42.4% and those receiving prior crizotinib for >5 months (51.6% versus 36.1%. Treatment-related adverse events (AEs were reported in 118 of 208 patients (56.7%, the most common being diarrhoea (22.1% and hepatic toxicity (19.7%. Ceritinib (750 mg·day−1 demonstrated efficacy similar efficacy to ASCEND-1, ASCEND-2 and phase 3 ASCEND-5 trials with manageable safety in crizotinib-pretreated patients with ALK+ NSCLC.

Functional cooperation between HIF-1α and c-Jun in mediating primary and acquired resistance to gefitinib in NSCLC cells with activating mutation of EGFR.

Science.gov (United States)

Meng, Shuyan; Wang, Guorui; Lu, Yang; Fan, Zhen

2018-07-01

Hypoxia-inducible factor 1 (HIF-1) and activator protein 1 (AP-1) are important transcription factors regulating expression of genes involved in cell survival. HIF-1α and c-Jun are key components of HIF-1 and AP-1, respectively, and are regulated by epidermal growth factor receptor (EGFR)-mediated cell signaling and tumor microenvironmental cues. The roles of HIF-1α and c-Jun in development of resistance to EGFR tyrosine kinase inhibitor (TKI) in non-small cell lung cancer (NSCLC) with activating mutation of EGFR have not been explored. In this study, we investigated the roles of HIF-1α and c-Jun in mediating primary and acquired resistance to gefitinib in NSCLC cells with activating mutation of EGFR. Changes in HIF-1α protein and in total and phosphorylated c-Jun levels in relation to changes in total and phosphorylated EGFR levels before and after gefitinib treatment were measured using Western blot analysis in NSCLC cells sensitive or resistant to gefitinib. The impact of overexpression of a constitutively expressed HIF-1α (HIF-1α/ΔODD) or a constitutively active c-Jun upstream regulator (SEK1 S220E/T224D mutant) on cell response to gefitinib was also examined. The effect of pharmacological inhibition of SEK1-JNK-c-Jun pathway on cell response to gefitinib was evaluated. Downregulation of HIF-1α and total and phosphorylated c-Jun levels correlated with cell inhibitory response to gefitinib better than decrease in phosphorylated EGFR did in NSCLC cells with intrinsic or acquired resistance to gefitinib. Overexpression of HIF-1α/ΔODD or SEK1 S220E/T224D mutant conferred resistance to gefitinib. There exists a positive feed-forward regulation loop between HIF-1 and c-Jun. The JNK inhibitor SP600125 sensitized gefitinib-resistant NSCLC cells to gefitinib. HIF-1α and c-Jun functionally cooperate in development of resistance to gefitinib in NSCLC cells. The translational value of inhibiting HIF-1α/c-Jun cooperation in overcoming resistance to EGFR TKI

The asphericity of the metabolic tumour volume in NSCLC: correlation with histopathology and molecular markers

International Nuclear Information System (INIS)

Apostolova, Ivayla; Ego, Kilian; Steffen, Ingo G.; Buchert, Ralph; Wertzel, Heinz; Achenbach, H.J.; Riedel, Sandra; Schreiber, Jens; Schultz, Meinald; Furth, Christian; Amthauer, Holger; Derlin, Thorsten; Hofheinz, Frank; Kalinski, Thomas

2016-01-01

Asphericity (ASP) is a tumour shape descriptor based on the PET image. It quantitates the deviation from spherical of the shape of the metabolic tumour volume (MTV). In order to identify its biological correlates, we investigated the relationship between ASP and clinically relevant histopathological and molecular signatures in non-small-cell lung cancer (NSCLC). The study included 83 consecutive patients (18 women, aged 66.4 ± 8.9 years) with newly diagnosed NSCLC in whom PET/CT with 18 F-FDG had been performed prior to therapy. Primary tumour resection specimens and core biopsies were used for basic histopathology and determination of the Ki-67 proliferation index. EGFR status, VEGF, p53 and ALK expression were obtained in a subgroup of 44 patients. The FDG PET images of the primary tumours were delineated using an automatic algorithm based on adaptive thresholding taking into account local background. In addition to ASP, SUVmax, MTV and some further descriptors of shape and intratumour heterogeneity were assessed as semiquantitative PET measures. SUVmax, MTV and ASP were associated with pathological T stage (Kruskal-Wallis, p = 0.001, p < 0.0005 and p < 0.0005, respectively) and N stage (p = 0.017, p = 0.003 and p = 0.002, respectively). Only ASP was associated with M stage (p = 0.026). SUVmax, MTV and ASP were correlated with Ki-67 index (Spearman's rho = 0.326/p = 0.003, rho = 0.302/p = 0.006 and rho = 0.271/p = 0.015, respectively). The latter correlations were considerably stronger in adenocarcinomas than in squamous cell carcinomas. ASP, but not SUVmax or MTV, showed a tendency for a significant association with the extent of VEGF expression (p = 0.058). In multivariate Cox regression analysis, ASP (p < 0.0005) and the presence of distant metastases (p = 0.023) were significantly associated with progression-free survival. ASP (p = 0.006), the presence of distant metastases (p = 0.010), and Ki-67 index (p = 0.062) were significantly associated with

The asphericity of the metabolic tumour volume in NSCLC: correlation with histopathology and molecular markers

Energy Technology Data Exchange (ETDEWEB)

Apostolova, Ivayla; Ego, Kilian; Steffen, Ingo G. [University Hospital, Otto-von-Guericke University Magdeburg, Clinic of Radiology and Nuclear Medicine, Magdeburg (Germany); Buchert, Ralph [University Medicine Charite, Clinic of Nuclear Medicine, Berlin (Germany); Wertzel, Heinz; Achenbach, H.J. [Lung Clinic Lostau GmbH, Lostau (Germany); Riedel, Sandra; Schreiber, Jens [University Hospital, Otto-von-Guericke University Magdeburg, Clinic of Pneumology, Magdeburg (Germany); Schultz, Meinald [Institute of Pathology Stendal, Stendal (Germany); Furth, Christian; Amthauer, Holger [University Hospital, Otto-von-Guericke University Magdeburg, Clinic of Radiology and Nuclear Medicine, Magdeburg (Germany); University Medicine Charite, Clinic of Nuclear Medicine, Berlin (Germany); Derlin, Thorsten [Hannover Medical School, Department of Nuclear Medicine, Hannover (Germany); Hofheinz, Frank [Helmholtz-Center Dresden-Rossendorf, Dresden (Germany); Kalinski, Thomas [University Hospital Magdeburg, Otto-von-Guericke University Magdeburg, Institute for Pathology, Magdeburg (Germany); Institute for Pathology Lademannbogen, Hamburg (Germany)

2016-12-15

Asphericity (ASP) is a tumour shape descriptor based on the PET image. It quantitates the deviation from spherical of the shape of the metabolic tumour volume (MTV). In order to identify its biological correlates, we investigated the relationship between ASP and clinically relevant histopathological and molecular signatures in non-small-cell lung cancer (NSCLC). The study included 83 consecutive patients (18 women, aged 66.4 ± 8.9 years) with newly diagnosed NSCLC in whom PET/CT with {sup 18}F-FDG had been performed prior to therapy. Primary tumour resection specimens and core biopsies were used for basic histopathology and determination of the Ki-67 proliferation index. EGFR status, VEGF, p53 and ALK expression were obtained in a subgroup of 44 patients. The FDG PET images of the primary tumours were delineated using an automatic algorithm based on adaptive thresholding taking into account local background. In addition to ASP, SUVmax, MTV and some further descriptors of shape and intratumour heterogeneity were assessed as semiquantitative PET measures. SUVmax, MTV and ASP were associated with pathological T stage (Kruskal-Wallis, p = 0.001, p < 0.0005 and p < 0.0005, respectively) and N stage (p = 0.017, p = 0.003 and p = 0.002, respectively). Only ASP was associated with M stage (p = 0.026). SUVmax, MTV and ASP were correlated with Ki-67 index (Spearman's rho = 0.326/p = 0.003, rho = 0.302/p = 0.006 and rho = 0.271/p = 0.015, respectively). The latter correlations were considerably stronger in adenocarcinomas than in squamous cell carcinomas. ASP, but not SUVmax or MTV, showed a tendency for a significant association with the extent of VEGF expression (p = 0.058). In multivariate Cox regression analysis, ASP (p < 0.0005) and the presence of distant metastases (p = 0.023) were significantly associated with progression-free survival. ASP (p = 0.006), the presence of distant metastases (p = 0.010), and Ki-67 index (p = 0.062) were significantly associated with

The use of fused PET/CT images for patient selection and radical radiotherapy target volume definition in patients with non-small cell lung cancer: Results of a prospective study with mature survival data

International Nuclear Information System (INIS)

Mac Manus, Michael P.; Everitt, Sarah; Bayne, Mike; Ball, David; Plumridge, Nikki; Binns, David; Herschtal, Alan; Cruickshank, Deborah; Bressel, Mathias; Hicks, Rodney J.

2013-01-01

Background and purpose: This prospective study investigated the impact of radiotherapy (RT)-planning FDG-PET/CT on management of non-small cell lung cancer (NSCLC). Materials and methods: Patients still eligible for radical RT after conventional staging underwent RT-planning PET/CT and, if disease was still treatable to 60 Gy, they entered our planning study, where visually-contoured tumour volumes derived with and without PET information were compared. If PET/CT detected advanced disease, palliative therapy was given. Overall survival (OS) for palliative and curative patients was compared. Results: Of 76 eligible patients, only 50 (66%) received radical chemoRT after PET/CT while 26 (34%) received palliative therapies because PET/CT detected advanced disease. Without PET, FDG-avid tumour would reside outside the planning target volume (PTV) in 36% of radical cases and in 25% 95% prescribed dose. OS for all patients was 56.8% and 24.9% at 1 and 4 years, respectively. OS for patients given chemoRT was 77.5% and 35.6% at 1 and 4 years, respectively and was 32% for stage IIIA patients at 4 years. OS for patients treated palliatively was inferior (P < 0.001); 16.3% and 4.1% at 1 and 4 years, respectively. Conclusions: Planning PET/CT frequently changed management and was associated with excellent survival. Survival data from this study were presented in part at the 2011 World Lung Cancer Conference, Amsterdam and planning data at the 2010 Annual Scientific Meeting of the American Society for Therapeutic Radiology and Oncology, Chicago

Health related quality of life in locally advanced NSCLC treated with high dose radiotherapy and concurrent chemotherapy or cetuximab – Pooled results from two prospective clinical trials

International Nuclear Information System (INIS)

Hallqvist, Andreas; Bergman, Bengt; Nyman, Jan

2012-01-01

Background: In non-small cell lung cancer (NSCLC) stage III, data on patient reported health-related quality of life (HRQL) are scarce, especially regarding concurrent chemoradiotherapy. Aims: To evaluate HRQL in patients treated with high dose radiotherapy combined with concurrent chemotherapy or the antibody cetuximab. Methods: The study population comprised all patients enroled in either of two phase II trials in locally advanced NSCLC performed in Sweden 2002–2007. The RAKET trial investigated three different ways of increasing local control (accelerated hyperfractionated treatment or concurrent daily or weekly chemotherapy). The Satellite trial evaluated the addition of cetuximab to thoracic irradiation. HRQL was measured at four time points: At baseline, before radiotherapy, 4–6 weeks after radiotherapy and at 3 months follow-up, using the EORTC QLQ-C30 and LC14 set of questionnaires. Results: 154/220 patients (65%) who completed HRQL assessments at all time points were included in the longitudinal study. There was a significant decline over time regarding most functioning measures. Dyspnoea and fatigue gradually deteriorated without recovery after completed treatment. Chemotherapy related symptoms showed a transient deterioration, whereas radiotherapy related esophagitis had not fully recovered at 3 months. Patients with stage IIIA disease tended to recover better regarding global QL, fatigue and dyspnoea compared to patients with stage IIIB. Patients with WHO performance status (PS) 0 reported improved global QL and less fatigue over time compared with PS 1. Concurrent chemotherapy was associated with more pronounced fatigue and dysphagia, and worse global QL compared with concurrent cetuximab. Baseline physical functioning was an independent predictor of overall survival. Conclusion: Patients undergoing high dose thoracic radiotherapy combined with chemotherapy or cetuximab reported a gradual deterioration in functioning, dyspnoea and fatigue, while

TH-CD-202-09: Free-Breathing Proton MRI Functional Lung Avoidance Maps to Guide Radiation Therapy

International Nuclear Information System (INIS)

Capaldi, D; Sheikh, K; Parraga, G; Hoover, D; Yaremko, B; Palma, D

2016-01-01

Purpose: Pulmonary functional MRI using inhaled gas contrast agents was previously investigated as a way to identify well-functioning lung in patients with NSCLC who are clinical candidates for radiotherapy. Hyperpolarized noble-gas ( 3 He and 129 Xe) MRI has also been optimized to measure functional lung information, but for a number of reasons, the clinical translation of this approach to guide radiotherapy planning has been limited. As an alternative, free-breathing pulmonary 1H MRI using clinically available MRI systems and pulse sequences provides a non-contrast-enhanced method to generate both ventilation and perfusion maps. Free-breathing 1 H MRI exploits non-rigid registration and Fourier decomposition of MRI signal intensity differences (Bauman et al., MRM, 2009) that may be generated during normal tidal breathing. Here, our objective was to generate free-breathing 1 H MRI ventilation and lung function avoidance maps in patients with NSCLC as a way to guide radiation therapy planning. Methods: Stage IIIA/IIIB NSCLC patients (n=8, 68±9yr) provided written informed consent to a randomized controlled clinical trial ( https://clinicaltrials.gov/ct2/show/NCT02002052 ) that aimed to compare outcomes related to image-guided versus conventional radiation therapy planning. Hyperpolarized 3 He/ 129 Xe and dynamic free tidal-breathing 1 H MRI were acquired as previously described (Capaldi et al., Acad Radiol, 2015). Non-rigid registration was performed using the modality-independent-neighbourhood-descriptor (MIND) deformable approach (Heinrich et al., Med Image Anal, 2012). Ventilation-defect-percent ( 3 He:VDP He , 129 Xe:VDP Xe , Free-breathing- 1 H:VDP FB ) and the corresponding ventilation maps were compared using Pearson correlation coefficients (r) and the Dice similarity coefficient (DSC). Results: VDP FB was significantly related to VDP He (r=.71; p=.04) and VDP Xe (r=.80; p=.01) and there were also strong spatial relationships (DSC He /DSC Xe =89±3%/77±11

Epithelial growth factor receptor (EGFR) mutation status and the treatment of non-small cell lung cancer (NSCLC): A population based quality assurance analysis

DEFF Research Database (Denmark)

Hansen, Niels-Chr. G.; Laursen, Christian B.; Hansen, Karin H.

2015-01-01

of adenocarcinoma or NSCLC not otherwise specified - diagnosed from July 2010 to June 2014. Chart review was updated in February 2015. The median age was 68 years (range 31 – 96 years), 6.4% were never-smokers and 37.5% ex-smokers. EGFR-mutation status has been determined for 683 patients (73.6%), but has not been...... possible from the available samples in 89 cases. For 156 patients the analysis has not been requested. The prevalence of EGFR-mutation has been 10.4% in women, 5.4% in men, and 39.2% in never-smokers (no gender difference). The EGFR mutations were proven in cytology samples in 75% of the 56 positive cases...

Dramatic response to high-dose icotinib in a lung adenocarcinoma patient after erlotinib failure.

Science.gov (United States)

Guan, Yin; Zhao, Hong; Meng, Jing; Yan, Xiang; Jiao, ShunChang

2014-02-01

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) retreatment is rarely administered for non-small cell lung cancer (NSCLC) patients who did not respond to previous TKI treatment. A high dose of TKI may overcome resistance to the standard dose of TKI and have different effectiveness toward cancer compared with the standard dose of TKI. This manuscript describes a dramatic and durable response to high-dose icotinib in a NSCLC patient who did not respond to a previous standard dose of erlotinib. The treatment extended the life of the patient for one additional year. A higher dose of icotinib deserves further study not only for patients whose therapy failed with the standard dose of TKI but also for newly diagnosed NSCLC patients with a sensitive mutation. Serial mutation testing during disease development is necessary for analysis and evaluation of EGFR TKI treatment. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

[Clinical Observation of Icotinib Hydrochloride for Advanced Non-small Cell Lung Cancer Patients with EGFR Status Identified].

Science.gov (United States)

Li, Xi; Qin, Na; Wang, Jinghui; Yang, Xinjie; Zhang, Xinyong; Lv, Jialin; Wu, Yuhua; Zhang, Hui; Nong, Jingying; Zhang, Quan; Zhang, Shucai

2015-12-01

Icotinib is the first self-developed small molecular drug in China for targeted therapy of lung cancer. Compared to the other two commercially available epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, gefitinib and erlotinib, icotinib is similar to them in chemical structure, mechanism of activity and therapeutic effects. To explore the efficacy and side effects of icotinib hydrochloride in the treatment of the advanced non-small cell lung cancer (NSCLC) patients with EGFR mutation and wild-type. Patients with advanced NSCLC who were treated with icotinib hydrochloride in Beijing Chest Hospital were retrospective analyzed from March 2009 to December 2014. The clinical data of 124 patients (99 with EGFR mutation and 25 with wild type) with advanced NSCLC were enrolled in this study. The patients' overall objective response rate (ORR) was 51.6 % and the disease control rate (DCR) was 79.8%; The patients with EGFR mutation, ORR was 63.6%, DCR was 93.9%. The ORR was 4.0% and the DCR was 24.0% in the wild-type patients. Median progression-free survival (PFS) with icotinib treatment in EGFR mutation patients was 10.5 months and 1.0 month in wild-type patients. The major adverse events were mild skin rash (30.6%) and diarrhea (16.1%). Monotherapy with icotinib hydrochloride is effective and tolerable for the advanced NSCLC EGFR mutation patients.


WE-AB-207B-02: A Bayesian Network Approach for Joint Prediction of Tumor Control and Radiation Pneumonitis (RP) in Non-Small-Cell Lung Cancer (NSCLC)

Energy Technology Data Exchange (ETDEWEB)

Luo, Y; McShan, D; Matuszak, M; Hobson, S; Jolly, S; Ten Haken, R; El Naqa, I [University of Michigan, Ann Arbor, MI (United States)

2016-06-15

Purpose: NSCLC radiotherapy treatment is a trade-off between controlling the tumor while limiting radiation-induced toxicities. Here we identify hierarchical biophysical relationships that could simultaneously influence both local control (LC) and RP by using an integrated Bayesian Networks (BN) approach. Methods: We studied 79 NSCLC patients treated on prospective protocol with 56 cases of LC and 21 events of RP. Beyond dosimetric information, each patient had 193 features including 12 clinical factors, 60 circulating blood cytokines before and during radiotherapy, 62 microRNAs, and 59 single-nucleotide polymorphisms (SNPs). The most relevant biophysical predictors for both LC and RP were identified using a Markov blanket local discovery algorithm and the corresponding BN was constructed using a score-learning algorithm. The area under the free-response receiver operating characteristics (AU-FROC) was used for performance evaluation. Cross-validation was employed to guard against overfitting pitfalls. Results: A BN revealing the biophysical interrelationships jointly in terms of LC and RP was developed and evaluated. The integrated BN included two SNPs, one microRNA, one clinical factor, three pre-treatment cytokines, relative changes of two cytokines between pre and during-treatment, and gEUDs of the GTV (a=-20) and lung (a=1). On cross-validation, the AUC prediction of independent LC was 0.85 (95% CI: 0.75–0.95) and RP was 0.83 (0.73–0.92). The AU-FROC of the integrated BN to predict both LC/RP was 0.81 (0.71–0.90) based on 2000 stratified bootstrap, indicating minimal loss in joint prediction power. Conclusions: We developed a new approach for multiple outcome utility application in radiotherapy based on integrated BN techniques. The BN developed from large-scale retrospective data is able to simultaneously predict LC and RP in NSCLC treatments based on individual patient characteristics. The joint prediction is only slightly compromised compared to

WE-AB-207B-02: A Bayesian Network Approach for Joint Prediction of Tumor Control and Radiation Pneumonitis (RP) in Non-Small-Cell Lung Cancer (NSCLC)

International Nuclear Information System (INIS)

Luo, Y; McShan, D; Matuszak, M; Hobson, S; Jolly, S; Ten Haken, R; El Naqa, I

2016-01-01

Purpose: NSCLC radiotherapy treatment is a trade-off between controlling the tumor while limiting radiation-induced toxicities. Here we identify hierarchical biophysical relationships that could simultaneously influence both local control (LC) and RP by using an integrated Bayesian Networks (BN) approach. Methods: We studied 79 NSCLC patients treated on prospective protocol with 56 cases of LC and 21 events of RP. Beyond dosimetric information, each patient had 193 features including 12 clinical factors, 60 circulating blood cytokines before and during radiotherapy, 62 microRNAs, and 59 single-nucleotide polymorphisms (SNPs). The most relevant biophysical predictors for both LC and RP were identified using a Markov blanket local discovery algorithm and the corresponding BN was constructed using a score-learning algorithm. The area under the free-response receiver operating characteristics (AU-FROC) was used for performance evaluation. Cross-validation was employed to guard against overfitting pitfalls. Results: A BN revealing the biophysical interrelationships jointly in terms of LC and RP was developed and evaluated. The integrated BN included two SNPs, one microRNA, one clinical factor, three pre-treatment cytokines, relative changes of two cytokines between pre and during-treatment, and gEUDs of the GTV (a=-20) and lung (a=1). On cross-validation, the AUC prediction of independent LC was 0.85 (95% CI: 0.75–0.95) and RP was 0.83 (0.73–0.92). The AU-FROC of the integrated BN to predict both LC/RP was 0.81 (0.71–0.90) based on 2000 stratified bootstrap, indicating minimal loss in joint prediction power. Conclusions: We developed a new approach for multiple outcome utility application in radiotherapy based on integrated BN techniques. The BN developed from large-scale retrospective data is able to simultaneously predict LC and RP in NSCLC treatments based on individual patient characteristics. The joint prediction is only slightly compromised compared to

Effects of multidisciplinary team care on the survival of patients with different stages of non-small cell lung cancer: a national cohort study.

Directory of Open Access Journals (Sweden)

Chien-Chou Pan

Full Text Available In Taiwan, cancer is the top cause of death, and the mortality rate of lung cancer is the highest of all cancers. Some studies have demonstrated that multidisciplinary team (MDT care can improve survival rates of non-small cell lung cancer (NSCLC patients. However, no study has discussed the effect of MDT care on different stages of NSCLC. The target population for this study consisted of patients with NSCLC newly diagnosed in the 2005-2010 Cancer Registry. The data was linked with the 2002-2011 National Health Insurance Research Database and the 2005-2011 Cause of Death Statistics Database. The multivariate Cox proportional hazards model was used to explore whether the involvement of MDT care had an effect on survival. This study applied the propensity score as a control variable to reduce selection bias between patients with and without involvement of MDT care. The adjusted hazard ratio (HR of death of MDT participants with stage III & IV NSCLC was significantly lower than that of MDT non-participants (adjusted HR = 0.87, 95% confidence interval = 0.84-0.90. This study revealed that MDT care are significantly associated with higher survival rate of patients with stage III and IV NSCLC, and thus MDT care should be used in the treatment of these patients.

Medical economics of whole-body FDG PET in patients suspected of having non-small cell lung carcinoma. Reassessment based on the revised Japanese national insurance reimbursement system

International Nuclear Information System (INIS)

Abe, Katsumi; Kosuda, Shigeru; Kusano, Shoichi

2003-01-01

Focusing on the savings expected from the revised Japanese national insurance reimbursement system in the management of patients suspected of having non-small cell lung carcinoma (NSCLC), cost-effectiveness was assessed using decision tree sensitivity analysis on the basis of the 2 competing strategies of whole-body FDG PET (WB-PET) and conventional imaging (CI). A WB-PET strategy that models dependence upon chest FDG PET scan, WB-PET scan, and brain MR imaging with contrast was designed. The cost of a FDG PET examination was updated and determined to be US$625.00. The CI strategy involves a combination of conventional examinations, such as abdominal CT with contrast, brain MR imaging with contrast, and a whole-body bone scan. A simulation of 1,000 patients suspected of having NSCLC (Stages I to IV) was created for each strategy using a decision tree and baselines of other relevant variables cited from published data. By using the WB-PET strategy in place of the CI strategy for the management of patients suspected of having NSCLC in hospitals with an NSCLC prevalence of 75%, the cost saving (CS) for each patient would be US$697.69 for an M1 prevalence of 20% and US$683.52 for an M1 prevalence of 40%, but the CS gradually decreases as the NSCLC prevalence increases. The break-even point requires less than an 80% prevalence in order for the WB-PET strategy to gain life expectancy (LE) per patient. By using the WB-PET strategy in place of the CI strategy for the management of patients suspected of having NSCLC in hospitals with an NSCLC prevalence of 75%, the gain in LE for each patient would be 0.04 years (11.06 vs. 11.02 years) for an M1 prevalence of 20% and 0.10 years (10.13 vs. 10.03 years) for an M1 prevalence of 40%. The maximum cost of a PET study without losing LE would be US$1322.68 per patient for prevalences of 75% NSCLC and 20% M1 disease. The present study quantitatively showed WB-PET, employed in place of CI for managing NSCLC patients, to be cost

Automatic treatment planning implementation using a database of previously treated patients

International Nuclear Information System (INIS)

Moore, J A; Evans, K; Yang, W; Herman, J; McNutt, T

2014-01-01

Purpose: Using a database of prior treated patients, it is possible to predict the dose to critical structures for future patients. Automatic treatment planning speeds the planning process by generating a good initial plan from predicted dose values. Methods: A SQL relational database of previously approved treatment plans is populated via an automated export from Pinnacle 3 . This script outputs dose and machine information and selected Regions of Interests as well as its associated Dose-Volume Histogram (DVH) and Overlap Volume Histograms (OVHs) with respect to the target structures. Toxicity information is exported from Mosaiq and added to the database for each patient. The SQL query is designed to ask the system for the lowest achievable dose for a specified region of interest (ROI) for each patient with a given volume of that ROI being as close or closer to the target than the current patient. Results: The additional time needed to calculate OVHs is approximately 1.5 minutes for a typical patient. Database lookup of planning objectives takes approximately 4 seconds. The combined additional time is less than that of a typical single plan optimization (2.5 mins). Conclusions: An automatic treatment planning interface has been successfully used by dosimetrists to quickly produce a number of SBRT pancreas treatment plans. The database can be used to compare dose to individual structures with the toxicity experienced and predict toxicities before planning for future patients.

Interstitial lung abnormalities in treatment-naïve advanced non-small-cell lung cancer patients are associated with shorter survival

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Nishino, Mizuki, E-mail: Mizuki_Nishino@DFCI.HARVARD.EDU [Department of Radiology, Brigham and Women' s Hospital, 75 Francis St., Boston, MA 02115 (United States); Department of Imaging, Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02215 (United States); Cardarella, Stephanie [Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02215, (United States); Dahlberg, Suzanne E. [Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02215 (United States); Araki, Tetsuro [Department of Radiology, Brigham and Women' s Hospital, 75 Francis St., Boston, MA 02115 (United States); Lydon, Christine; Jackman, David M.; Rabin, Michael S. [Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02215, (United States); Hatabu, Hiroto [Department of Radiology, Brigham and Women' s Hospital, 75 Francis St., Boston, MA 02115 (United States); Johnson, Bruce E. [Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02215, (United States)

2015-05-15

Highlights: • Interstitial lung abnormalities were present in 14% of stage IV NSCLC patients. • ILA was more common in older patients with heavier smoking history. • ILA was associated with shorter survival after adjusting for smoking and therapy. • ILA could be an additional independent marker for survival in advanced NSCLC. - Abstract: Objective: Interstitial lung diseases are associated with increased risk of lung cancer. The prevalence of ILA at diagnosis of advanced non-small-cell lung cancer (NSCLC) and its impact on overall survival (OS) remain to be investigated. Materials and method: The study included 120 treatment-naïve stage IV NSCLC patients (53 males, 67 females). ILA was scored on CT prior to any systemic therapy using a 4-point scale [0 = no evidence of ILA, 1 = equivocal for ILA, 2 = suspicious for ILA, 3 = ILA] by a sequential reading method previously reported. ILA scores of 2 or 3 indicated the presence of ILA. Results: ILA was present in 17 patients (14%) with advanced NSCLC prior to any treatment (score3: n = 2, score2: n = 15). These 17 patients were significantly older (median age: 69 vs. 63, p = 0.04) and had a heavier smoking history (median: 40 vs. 15.5 pack-year, p = 0.003) than those with ILA score 0 or 1. Higher ILA scores were associated with shorter OS (p = 0.001). Median OS of the 17 patients with ILA was 7.2 months [95%CI: 2.9–9.4] compared to 14.8 months [95%CI: 11.1–18.4] in patients with ILA score 0 or 1 (p = 0.002). In a multivariate model, the presence of ILA remained significant for increased risk for death (HR = 2.09, p = 0.028) after adjusting for first-line systemic therapy (chemotherapy, p < 0.001; TKI, p < 0.001; each compared to no therapy) and pack years of smoking (p = 0.40). Conclusion: Radiographic ILA was present in 14% of treatment-naïve advanced NSCLC patients. Higher ILA scores were associated with shorter OS, indicating that ILA could be a marker of shorter survival in advanced NSCLC.

Spectrum of EGFR gene mutations in Vietnamese patients with non-small cell lung cancer.

Science.gov (United States)

Vu, Hoang Anh; Xinh, Phan Thi; Ha, Hua Thi Ngoc; Hanh, Ngo Thi Tuyet; Bach, Nguyen Duc; Thao, Doan Thi Phuong; Dat, Ngo Quoc; Trung, Nguyen Sao

2016-03-01

Epidermal growth factor receptor (EGFR) mutational status is a crucial biomarker for prediction of response to tyrosine kinase inhibitors in patients with non-small cell lung cancer (NSCLC). Although these mutations have been well characterized in other countries, little is known about the frequency or spectrum of EGFR mutations in Vietnamese NSCLC patients. Using Sanger DNA sequencing, we investigated mutations in EGFR exons 18-21 from 332 patients diagnosed with NSCLC at University of Medicine and Pharmacy, Ho Chi Minh City, Vietnam. DNA was extracted from formalin-fixed, paraffin-embedded tissues, followed by PCR amplification and sequencing. EGFR mutations were detected in 135 samples (40.7%), of which eight samples carried double mutations. In total, 46 different types of EGFR mutations were found, including six novel mutations (p.K713E, p.K714R, p.P794S, p.R803W, p.P848S, and p.K867E). Among the four exons investigated, exon 19 was most frequently mutated (63 out of 332 patients, 19%), with the p.E746_A750del appearing in 43 samples. Exon 21 was mutated in 56 samples (16.9%), of which 47 were p.L858R. Each of exons 18 and 20 was mutated in 12 samples (3.6%). The frequency of EGFR mutations was higher in females than in males (48.9% vs 35%, P = 0.012), but not statistically different between adenocarcinomas and other histological types of NSCLC (41.3% vs 34.5%, P = 0.478). DNA sequencing detected EGFR mutations with high frequency and revealed a broad spectrum of mutation type in Vietnamese patients with NSCLC. © 2015 Wiley Publishing Asia Pty Ltd.

cMET in NSCLC: Can We Cut off the Head of the Hydra? From the Pathway to the Resistance

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Van Der Steen, Nele [Center for Oncological Research Antwerp, University of Antwerp, Universiteitsplein 1, Wilrijk 2610 (Belgium); Pauwels, Patrick [Center for Oncological Research Antwerp, University of Antwerp, Universiteitsplein 1, Wilrijk 2610 (Belgium); Molecular Pathology Unit, Pathology Department, Antwerp University Hospital, Wilrijkstraat 10, Edegem 2650 (Belgium); Gil-Bazo, Ignacio [Department of Oncology, Clínica Universidad de Navarra, Pamplona 31008 (Spain); Castañon, Eduardo [Department of Oncology, Clínica Universidad de Navarra, Pamplona 31008 (Spain); Phase I-Early Clinical Trials Unit, Oncology Department, Antwerp University Hospital, Wilrijkstraat 10, Edegem 2650 (Belgium); Raez, Luis [Thoracic Oncology Program, Memorial Cancer Institute, Memorial Health Care System, Pembroke Pines, FL 33024 (United States); Cappuzzo, Federico [4Thoracic Oncology Program, Memorial Cancer Institute, Memorial Health Care System, Pembroke Pines, FL 33024 (United States); Rolfo, Christian, E-mail: Christian.Rolfo@uza.be [Center for Oncological Research Antwerp, University of Antwerp, Universiteitsplein 1, Wilrijk 2610 (Belgium); Phase I-Early Clinical Trials Unit, Oncology Department, Antwerp University Hospital, Wilrijkstraat 10, Edegem 2650 (Belgium)

2015-03-25

In the last decade, the tyrosine kinase receptor cMET, together with its ligand hepatocyte growth factor (HGF), has become a target in non-small cell lung cancer (NSCLC). Signalization via cMET stimulates several oncological processes amongst which are cell motility, invasion and metastasis. It also confers resistance against several currently used targeted therapies, e.g., epidermal growth factor receptor (EGFR) inhibitors. In this review, we will discuss the basic structure of cMET and the most important signaling pathways. We will also look into aberrations in the signaling and the effects thereof in cancer growth, with the focus on NSCLC. Finally, we will discuss the role of cMET as resistance mechanism.

Efficacy and Safety of rh-Endostatin Combined with Chemotherapy 
versus Chemotherapy Alone for Advanced NSCLC: A Meta-analysis Review

Directory of Open Access Journals (Sweden)

Jinzhong ZHANG

2011-05-01

Full Text Available Background and objective In recent years, there has been a large number of studies and reports about the efficacy and safety of recombinant human endostatin (rh-endostatin, an anti-angiogenic drug, in treatment of advanced lung cancer. Authentic assessment of rh-endostatin treatment in lung cancer is important. The aim of this study is to assess the clinical efficacy and safety of rh-endostatin combined with chemotherapy in the treatment of patients with non-small cell lung cancer (NSCLC. Methods Cochrane systematic review methods were used in the data selection, and data were selected from the Cochrane Library, EMBASE, Medline, SCI, CBM, CNKI, and etc electronic database to get all clinical controlled trials. The retrieval time was March 2010. The objects of these randomized controlled trials were advanced NSCLC patients and in the experimental group was rh-endostatin combination chemotherapy, in the control group was chemotherapy alone to compare the efficacy of two groups. The quality of included trials were evaluated by two reviewers independently. The software RevMan 5.0 was used for meta-analyses. Results Fifteen trials with 1,326 patients were included according to the including criterion. All trials were randomized controlled trials, and two trials were adequate in reporting randomization. Thirteen trials didn’t mention the blinding methods. Meta analysis indicated that the NPE arm (Vinorelbine+cisplatin+rh-endostatin had a different response rate compared with NP (Vinorelbine+cisplatin arm (OR=2.16, 95%CI: 1.57-2.99. The incidences of severe leukopenia (OR=0.94, 95%CI: 0.66-1.32 and severe thrombocytopenia (OR=1.00, 95%CI: 0.64-1.57 and nausea and vomiting (OR=0.85, 95%CI: 0.61-1.20 were similar in the NPE arm compared with those in the NP arm. The NPE plus radiotherapy (RT arm had a similar response rate compared with NP plus RT arm (OR=2.39, 95%CI: 0.99-5.79. The incidences of leukopenia (OR=0.83, 95%CI: 0.35-1.94 and

The impact of time between staging PET/CT and definitive chemo-radiation on target volumes and survival in patients with non-small cell lung cancer

International Nuclear Information System (INIS)

Everitt, Sarah; Plumridge, Nikki; Herschtal, Alan; Bressel, Mathias; Ball, David; Callahan, Jason; Kron, Tomas; Schneider-Kolsky, Michal; Binns, David; Hicks, Rodney J.

2013-01-01

Background and purpose: To investigate the impact of treatment delays on radiation therapy (RT) target volumes and overall survival (OS) in patients with non-small cell lung cancer (NSCLC) who underwent two baseline FDG PET/CT scans. Material and methods: Patients underwent a staging (PET1) and RT planning (PET2) FDG PET/CT scan. At PET1 all patients were eligible for radical chemo-RT. OS and progression-free survival (PFS) were compared for patients remaining eligible for radical RT and those treated palliatively because PET2 showed progression. RT target volumes were contoured using PET1 and PET2. Normal tissue doses were compared for patients remaining eligible for radical RT. Results: Eighty-two patients underwent PET2 scans between October 2004 and February 2007. Of these, 21 had a prior PET1 scan, median 23 days apart (range 8–176 days). Six patients (29%) were unsuitable for radical RT after PET2; five received palliative treatment and one received no treatment. Patients treated palliatively had significantly worse OS and PFS than patients treated radically p < 0.001. Mean RT tumour volume increased from 105cc to 198cc (p < 0.005) between scans. Conclusions: Disease progression while awaiting initiation of curative RT in NSCLC is associated with larger treatment volumes and worse survival

Failure patterns by prognostic group as determined by recursive partitioning analysis (RPA) of 1547 on four radiation therapy oncology group studies in operable non-small cell lung cancer (NSCLC)

International Nuclear Information System (INIS)

Komaki, Ritsuko; Scott, Charles B.; Byhardt, Roger W.; Emami, Bahman; Asbell, Sucha O.; Russell, Anthony H.; Roach, Mack; Urtasun, Raul C.; Gaspar, Laurie E.

1997-01-01

Purpose: To identify groups of patients who might benefit from more aggressive systemic or local treatment based on failure patterns when unresectable NSCLC was treated by radiation therapy alone. Methods: 1547 patients from 4 RTOG trials treated by RT alone were analyzed for the patterns of first failure by PRA class which was defined by prognostic factors, e.g., stage, KPS, weight loss, pleural effusion, age. All patients were AJCC stage II, IIIA or IIIB with KPS of at least 50 and n previous radiotherapy or chemotherapy for their NSCLC. Progressions in the primary (within irradiated fields), thorax (outside irradiated area), brain and distant metastasis other than brain were compared (two-sided) for each failure category by RPA. Results: The RPA classes are four distinct subgroups that had significantly different median survivals of 12.6, 8.3, 6.2 and 3.3 months for classes I, II, III and IV respectively (all groups p=0.0002). Pair comparison showed that RPA I vs IV p<0.0001, I vs III p=0.006, II vs IV p<0.0001, and III vs IV p=0.06. Conclusions: These results suggest the burden of disease and physiologic compromise in class IV patients are sufficient to cause death before specific sites of failure can be discerned. Site specific treatment strategies (intensive local therapy, combination chemotherapy, prophylactic cranial irradiation) may lead to improved outcome in class I and II, but are unlikely to alter outcome in class III and IV

Inhibition of PDGFR by CP-673451 induces apoptosis and increases cisplatin cytotoxicity in NSCLC cells via inhibiting the Nrf2-mediated defense mechanism.

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Yang, Yang; Deng, Yanchao; Chen, Xiangcui; Zhang, Jiahao; Chen, Yueming; Li, Huachao; Wu, Qipeng; Yang, Zhicheng; Zhang, Luyong; Liu, Bing

2018-05-29

Platelet-derived growth factor receptors (PDGFRs) are abundantly expressed by stromal cells in the non-small cell lung cancer (NSCLC) microenvironment, and in a subset of cancer cells, usually with their overexpression and/or activating mutation. However, the effect of PDGFR inhibition on lung cancer cells themselves has been largely neglected. In this study, we investigated the anticancer activity of CP-673451, a potent and selective inhibitor of PDGFRβ, on NSCLC cell lines (A549 and H358) and the potential mechanism. The results showed that inhibition of PDGFRβ by CP-673451 induced a significant increase in cell apoptosis, accompanied by ROS accumulation. However, CP-673451 exerted less cytotoxicity in normal lung epithelial cell line BEAS-2B cells determined by MTT and apoptosis assay. Elimination of ROS by NAC reversed the CP-673451-induced apoptosis in NSCLC cells. Furthermore, CP-673451 down-regulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) probably through inhibition of PI3K/Akt pathway. Rescue of Nrf2 activity counteracted the effects of CP-673451 on cell apoptosis and ROS accumulation. Silencing PDGFRβ expression by PDGFRβ siRNA exerted similar effects with CP-673451 in A549 cells, and when PDGFRβ was knockdowned by PDGFRβ siRNA, CP-673451 produced no additional effects on cell viability, ROS and GSH production, Nrf2 expression as well as PI3K/Akt pathway activity. Specifically, Nrf2 plays an indispensable role in NSCLC cell sensitivity to platinum-based treatments and we found that combination of CP-673451 and cisplatin produced a synergistic anticancer effect and substantial ROS production in vitro. Therefore, these results clearly demonstrate the effectiveness of inhibition of PDGFRβ against NSCLC cells and strongly suggest that CP-673451 may be a promising adjuvant chemotherapeutic drug. Copyright © 2018 Elsevier B.V. All rights reserved.

Phase I/II study of gefitinib (Iressa(®)) and vorinostat (IVORI) in previously treated patients with advanced non-small cell lung cancer.

Science.gov (United States)

Han, Ji-Youn; Lee, Soo Hyun; Lee, Geon Kook; Yun, Tak; Lee, Young Joo; Hwang, Kum Hui; Kim, Jin Young; Kim, Heung Tae

2015-03-01

Vorinostat has been shown to overcome resistance to gefitinib. We performed a phase I/II study combining gefitinib with vorinostat in previously treated non-small cell lung cancer (NSCLC). A 3 + 3 dose-escalation design was used to determine maximum tolerated dose (MTD) and recommended phase II dose (RP2D). Three dose levels were tested: 250 mg/day gefitinib on days 1-28 and 200, 300 or 400 mg/day vorinostat on days 1-7, and 15-21 out of every 28 days. The primary endpoint was median progression-free survival (PFS). Fifty-two patients were enrolled and treated (43 in phase II). The median age was 59 years, 28 patients were male, 44 had adenocarcinoma, 29 had never smoked, and 36 had undergone one prior treatment. Twenty-two patients exhibited sensitive EGFR mutations. Planned dose escalation was completed without reaching the MTD. The RP2D was 250 mg gefitinib and 400 mg vorinostat. In 43 assessable patients in phase II, the median PFS was 3.2 months; the overall survival (OS) was 19.0 months. There were 16 partial responses and six cases of stable disease. In EGFR-mutant NSCLC, response rate was 77 %, median PFS was 9.1 months, and median OS was 24.1 months. The most common adverse events were anorexia and diarrhea. Treatment with 250 mg gefitinib daily with biweekly 400 mg/day vorinostat was feasible and well tolerated. In an unselected patient population, this combination dose did not improve PFS. However, this combination showed a potential for improving efficacy of gefitinib in EGFR-mutant NSCLC (NCT01027676).

Health care resource use among patients with advanced non-small cell lung cancer: the PIvOTAL retrospective observational study.

Science.gov (United States)

Lee, Dae Ho; Isobe, Hiroshi; Wirtz, Hubert; Aleixo, Sabina Bandeira; Parente, Phillip; de Marinis, Filippo; Huang, Min; Arunachalam, Ashwini; Kothari, Smita; Cao, Xiting; Donnini, Nello; Woodgate, Ann-Marie; de Castro, Javier

2018-03-01

Data are scarce regarding real-world health care resource use (HCRU) for non-small cell lung cancer (NSCLC). An understanding of current clinical practices and HCRU is needed to provide a benchmark for rapidly evolving NSCLC management recommendations and therapeutic options. The objective of this study was to describe real-world HCRU for patients with advanced NSCLC. This multinational, retrospective chart review study was conducted at academic and community oncology sites in Italy, Spain, Germany, Australia, Japan, South Korea, Taiwan, and Brazil. Deidentified data were drawn from medical records of 1440 adults (≥18 years old) who initiated systemic therapy (2011 to mid-2013) for a new, confirmed diagnosis of advanced or metastatic (stage IIIB or IV) NSCLC. We summarized HCRU associated with first and subsequent lines of systemic therapy for advanced/metastatic NSCLC. The proportion of patients who were hospitalized at least once varied by country from 24% in Italy to 81% in Japan during first-line therapy and from 22% in Italy to 84% in Japan during second-line therapy; overall hospitalization frequency was 2.5-11.1 per 100 patient-weeks, depending on country. Emergency visit frequency also varied among countries (overall from 0.3-5.9 per 100 patient-weeks), increasing consistently from first- through third-line therapy in each country. The outpatient setting was the most common setting of resource use. Most patients in the study had multiple outpatient visits in association with each line of therapy (overall from 21.1 to 59.0 outpatient visits per 100 patient-weeks, depending on country). The use of health care resources showed no regular pattern associated with results of tests for activating mutations of the epidermal growth factor receptor (EGFR) gene or anaplastic lymphoma kinase (ALK) gene rearrangements. HCRU varied across countries. These findings suggest differing approaches to the clinical management of advanced NSCLC among the eight countries

Patient outcomes of monotherapy with hypofractionated three-dimensional conformal radiation therapy for stage T2 or T3 non-small cell lung cancer: a retrospective study

International Nuclear Information System (INIS)

Sakaguchi, Masakuni; Maebayashi, Toshiya; Aizawa, Takuya; Ishibashi, Naoya; Fukushima, Shoko; Abe, Osamu; Saito, Tsutomu

2016-01-01

Hypofractionated three-dimensional conformal radiation therapy (3D-CRT) is a treatment option for patients with early-stage non-small cell lung cancer (NSCLC) who are medically unable to tolerate surgery and who are not amenable to treatment with stereotactic body radiotherapy. This study assessed the efficacy and safety of 3D-CRT as a monotherapy in patients with localized stage T2 or T3 NSCLC. This retrospective study consisted of 29 patients (20 males) aged 56–89 years (median, 76 years) with histologically confirmed NSCLC who underwent 3D-CRT between 2005 and 2014. The median duration of patient observation was 17.0 months (range, 1.0–64.0 months). Complete and partial responses occurred in 13.8 and 44.8 % of patients, respectively, and the overall response rate was 58.2 %. Meanwhile, the 1- and 3-year survival rates were 65.8 and 33.8 %, respectively. In T2 NSCLC, the median survival time (MST) was 12 months, and the 1- and 3-year survival rates were 62.4 and 21.4 %, respectively. In T3 NSCLC, the MST was 17 months, and the 1- and 3-year survival rates were 72.9 and 48.6 %, respectively. Severe toxicities (Common Terminology Criteria Grade 3) were not observed. The mean biologically effective dose required to improve local control exceeded 80 Gy (range, 67.2–96.0 Gy). These findings support a role for 3D-CRT as a treatment option for patients who refuse or could not tolerate surgical therapy with early-stage NSCLC. Although this was a small, retrospective study, it may form the basis for future, larger controlled studies on 3D-CRT as a monotherapy for NSCLC

SU-F-R-20: Image Texture Features Correlate with Time to Local Failure in Lung SBRT Patients

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Andrews, M; Abazeed, M; Woody, N; Stephans, K; Videtic, G; Xia, P; Zhuang, T [The Cleveland Clinic Foundation, Cleveland, OH (United States)

2016-06-15

Purpose: To explore possible correlation between CT image-based texture and histogram features and time-to-local-failure in early stage non-small cell lung cancer (NSCLC) patients treated with stereotactic body radiotherapy (SBRT).Methods and Materials: From an IRB-approved lung SBRT registry for patients treated between 2009–2013 we selected 48 (20 male, 28 female) patients with local failure. Median patient age was 72.3±10.3 years. Mean time to local failure was 15 ± 7.1 months. Physician-contoured gross tumor volumes (GTV) on the planning CT images were processed and 3D gray-level co-occurrence matrix (GLCM) based texture and histogram features were calculated in Matlab. Data were exported to R and a multiple linear regression model was used to examine the relationship between texture features and time-to-local-failure. Results: Multiple linear regression revealed that entropy (p=0.0233, multiple R2=0.60) from GLCM-based texture analysis and the standard deviation (p=0.0194, multiple R2=0.60) from the histogram-based features were statistically significantly correlated with the time-to-local-failure. Conclusion: Image-based texture analysis can be used to predict certain aspects of treatment outcomes of NSCLC patients treated with SBRT. We found entropy and standard deviation calculated for the GTV on the CT images displayed a statistically significant correlation with and time-to-local-failure in lung SBRT patients.

SU-F-R-20: Image Texture Features Correlate with Time to Local Failure in Lung SBRT Patients

International Nuclear Information System (INIS)

Andrews, M; Abazeed, M; Woody, N; Stephans, K; Videtic, G; Xia, P; Zhuang, T

2016-01-01

Purpose: To explore possible correlation between CT image-based texture and histogram features and time-to-local-failure in early stage non-small cell lung cancer (NSCLC) patients treated with stereotactic body radiotherapy (SBRT).Methods and Materials: From an IRB-approved lung SBRT registry for patients treated between 2009–2013 we selected 48 (20 male, 28 female) patients with local failure. Median patient age was 72.3±10.3 years. Mean time to local failure was 15 ± 7.1 months. Physician-contoured gross tumor volumes (GTV) on the planning CT images were processed and 3D gray-level co-occurrence matrix (GLCM) based texture and histogram features were calculated in Matlab. Data were exported to R and a multiple linear regression model was used to examine the relationship between texture features and time-to-local-failure. Results: Multiple linear regression revealed that entropy (p=0.0233, multiple R2=0.60) from GLCM-based texture analysis and the standard deviation (p=0.0194, multiple R2=0.60) from the histogram-based features were statistically significantly correlated with the time-to-local-failure. Conclusion: Image-based texture analysis can be used to predict certain aspects of treatment outcomes of NSCLC patients treated with SBRT. We found entropy and standard deviation calculated for the GTV on the CT images displayed a statistically significant correlation with and time-to-local-failure in lung SBRT patients.

Relationship Between Preoperative Sarcopenia Status and Immuno-nutritional Parameters in Patients with Early-stage Non-small Cell Lung Cancer.

Science.gov (United States)

Shoji, Fumihiro; Matsubara, Taichi; Kozuma, Yuka; Haratake, Naoki; Akamine, Takaki; Takamori, Shinkichi; Katsura, Masakazu; Toyokawa, Gouji; Okamoto, Tatsuro; Maehara, Yoshihiko

2017-12-01

Although the skeletal muscle in the region of the third lumbar vertebra (L3) is generally assessed in order to judge sarcopenia, not every patient with non-small cell lung cancer (NSCLC) undergoes computed tomography including the L3 region. We hypothesized that immuno-nutritional parameters could predict the existence of sarcopenia in patients with NSCLC. The aim of this study was to retrospectively investigate the correlation between preoperative sarcopenia and immuno-nutritional parameters in patients with early-stage NSCLC. We selected 147 of patients with pathological stage I NSCLC who underwent preoperative measurement of immuno-nutritional parameters and CT including the L3 region. Preoperative sarcopenia was significantly associated with female gender (p=0.0003) and poor prognosis (p=0.0322). In Kaplan-Meier analysis of overall survival (OS) by preoperative sarcopenia status, the sarcopenic group had significantly shorter OS than the non-sarcopenic group (5-year OS: 87.27% vs. 77.37%, p=0.0131, log-rank test). In multivariate analysis, the preoperative sarcopenia status (hazard ratio=5.138; 95% confidence interval=2.305-11.676; psarcopenia status was significantly related to controlling nutritional status score (p=0.0071) and Geriatric Nutritional Risk Index (GNRI) (psarcopenia status and GNRI (r=0.348, psarcopenia which was associated with poor outcome in patients with early-stage NSCLC. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Decision-tree sensitivity analysis for cost-effectiveness of whole-body FDG PET in the management of patients with non-small-cell lung carcinoma in Japan

International Nuclear Information System (INIS)

Kosuda, Shigeru; Kobayashi, Hideo; Kusano, Shoichi; Ichihara, Kiyoshi; Watanabe, Masazumi

2002-01-01

Whole-body 2-fluoro-2-D-[ 18 F]deoxyglucose[FDG] positron emission tomography (WB-PET) may be more cost-effective than chest PET because WB-PET does not require conventional imaging (CI) for extrathoracic staging. The cost-effectiveness of WB-PET for the management of Japanese patients with non-small-cell lung carcinoma (NSCLC) was assessed. Decision-tree sensitivity analysis was designed, based on the two competing strategies of WB-PET vs. CI. WB-PET was assumed to have a sensitivity and specificity for detecting metastases, of 90% to 100% and CI of 80% to 90%. The prevalences of M1 disease were 34% and 20%. On thousand patients suspected of having NSCLC were simulated in each strategy. We surveyed the relevant literature for the choice of variables. Expected cost saving (CS) and expected life expectancy (LE) for NSCLC patients were calculated. The WB-PET strategy yielded an expected CS of $951 US to $1,493 US per patient and an expected LE of minus 0.0246 years to minus 0.0136 years per patient for the 71.4% NSCLC and 34% M1 disease prevalence at our hospital. PET avoided unnecessary bronchoscopies and thoracotomies for incurable and benign disease. Overall, the CS for each patient was $833 US to $2,010 US at NSCLC prevalences ranging from 10% to 90%. The LE of the WB-PET strategy was similar to that of the CI strategy. The CS and LE minimally varied in the two situations of 34% and 20% M1 disease prevalence. The introduction of a WB-PET strategy in place of CI for managing NSCLC patients is potentially cost-effective in Japan. (author)

Reducing dose to the lungs through loosing target dose homogeneity requirement for radiotherapy of non small cell lung cancer.

Science.gov (United States)

Miao, Junjie; Yan, Hui; Tian, Yuan; Ma, Pan; Liu, Zhiqiang; Li, Minghui; Ren, Wenting; Chen, Jiayun; Zhang, Ye; Dai, Jianrong

2017-11-01

It is important to minimize lung dose during intensity-modulated radiation therapy (IMRT) of nonsmall cell lung cancer (NSCLC). In this study, an approach was proposed to reduce lung dose by relaxing the constraint of target dose homogeneity during treatment planning of IMRT. Ten NSCLC patients with lung tumor on the right side were selected. The total dose for planning target volume (PTV) was 60 Gy (2 Gy/fraction). For each patient, two IMRT plans with six beams were created in Pinnacle treatment planning system. The dose homogeneity of target was controlled by constraints on the maximum and uniform doses of target volume. One IMRT plan was made with homogeneous target dose (the resulting target dose was within 95%-107% of the prescribed dose), while another IMRT plan was made with inhomogeneous target dose (the resulting target dose was more than 95% of the prescribed dose). During plan optimization, the dose of cord and heart in two types of IMRT plans were kept nearly the same. The doses of lungs, PTV and organs at risk (OARs) between two types of IMRT plans were compared and analyzed quantitatively. For all patients, the lung dose was decreased in the IMRT plans with inhomogeneous target dose. On average, the mean dose, V5, V20, and V30 of lung were reduced by 1.4 Gy, 4.8%, 3.7%, and 1.7%, respectively, and the dose to normal tissue was also reduced. These reductions in DVH values were all statistically significant (P target dose could protect lungs better and may be considered as a choice for treating NSCLC. © 2017 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.

Successful Chemotherapy with Nab-Paclitaxel in a Heavily Treated Non-Small Cell Lung Cancer Patient: A Case Report

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Mikiko Ishihara

2014-06-01

Full Text Available Non-small cell lung cancer (NSCLC accounts for the majority of all lung cancers. A 69-year-old female with postoperatively recurrent NSCLC was treated weekly with nanoparticle-albumin-bound paclitaxel (nab-paclitaxel monotherapy every 4 weeks as a tenth line chemotherapy, and stable disease was achieved by seven cycles of this regimen. The patient developed grade 4 neutropenia and grade 3 leukopenia, but none of the other toxicities, including febrile neutropenia and peripheral neuropathy, were severe, and thus she was able to tolerate this salvage chemotherapy. To our knowledge this is the first report of the efficacy of nab-paclitaxel monotherapy in a heavily treated NSCLC patient.

The Analysis of Predictive Factors for the Identification of Patients Who Could Benefit from Respiratory-Gated Radiotherapy in Non-Small Cell Lung Cancer

International Nuclear Information System (INIS)

Jang, Seong Soon; Park, Ji Chan

2009-01-01

4DCT scans performed for radiotherapy were retrospectively analyzed to assess the possible benefits of respiratory gating in non-small cell lung cancer (NSCLC) and established the predictive factors for identifying patients who could benefit from this approach. Three treatment planning was performed for 15 patients with stage I∼III NSCLC using different planning target volumes (PTVs) as follows: 1) PTVroutine, derived from the addition of conventional uniform margins to gross tumor volume (GTV) of a single bin, 2) PTVall phases (patient-specific PTV), derived from the composite GTV of all 6 bins of the 4DCT, and 3) PTVgating, derived from the composite GTV of 3 consecutive bins at end-exhalation. The reductions in PTV were 43.2% and 9.5%, respectively, for the PTVall phases vs. PTVroutine and PTVgating vs. PTVall phases. Compared to PTVroutine, the use of PTVall phases and PTVgating reduced the mean lung dose (MLD) by 18.1% and 21.6%, and V20 by 18.2% and 22.0%, respectively. Significant correlations were seen between certain predictive factors selected from the tumor mobility and volume analysis, such as the 3D mobility vector, the reduction in 3D mobility and PTV with gating, and the ratio of GTV overlap between 2 extreme bins and additional reductions in both MLD and V20 with gating. The additional benefits with gating compared to the use of patient-specific PTV were modest; however, there were distinct correlations and differences according to the predictive factors. Therefore, these predictive factors might be useful for identifying patients who could benefit from respiratory-gated radiotherapy

Early tumor shrinkage served as a prognostic factor for patients with stage III non-small cell lung cancer treated with concurrent chemoradiotherapy.

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Wei, Min; Ye, Qingqing; Wang, Xuan; Wang, Men; Hu, Yan; Yang, Yonghua; Yang, Jiyuan; Cai, Jun

2018-05-01

Lung cancer is the most common cause of cancer death. About 80% of patients are diagnosed at stage III in the non-small cell lung cancer (NSCLC). It is extremely important to understand the progression of this disease which has low survival times despite the advancing treatment modalities. We aimed to investigate the relationship between early tumor shrinkage (ETS) after initial concurrent chemoradiotherapy (C-CRT) and survival outcome in patients with stage III (NSCLC). A retrospective review of 103 patients with stage III NSCLC who had received C-CRT from January 2006 to October 2011 was performed. Patients were treated with systemic chemotherapy regimen of Cisplatin/Vp-16 and concurrent thoracic radiotherapy at a median dose of 66 Gy (range 60-70 Gy). All patients received a computed tomography (CT) examination before treatment. Also subsequently, chest CT scans were performed with the same imaging parameters at approximately 5 weeks after the initiation of treatment. ETS is here stratified by a decrease in tumor size ≥30% and cancer-related death (P < .05) in stage IIINSCLC. ETS may be served as a useful prognostic factor to predict the outcome of stage III NSCLC patients treated with CCRT.

Three-dimensional conformal radiation may deliver considerable dose of incidental nodal irradiation in patients with early stage node-negative non-small cell lung cancer when the tumor is large and centrally located

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Zhao Lujun; Chen Ming; Haken, Randall ten; Chetty, Indrin; Chapet, Olivier; Hayman, James A.; Kong Fengming

2007-01-01

Background and purpose: To determine the dose to regional nodal stations in patients with T 1-3 N 0 M 0 non-small cell lung cancer (NSCLC) treated with three-dimensional conformal radiation therapy (3DCRT) without intentional elective nodal irradiation (ENI). Materials and methods: Twenty-three patients with medically inoperable T 1-3 N 0 M 0 NSCLC were treated with 3DCRT without ENI. Hilar and mediastinal nodal regions were contoured on planning CT. The prescription dose was normalized to 70 Gy. Equivalent uniform dose (EUD) and other dosimetric parameters (e.g., V 40 ) were calculated for each nodal station. Results: The median EUD for the whole group ranged from 0.4 to 4.4 Gy for all elective nodal regions. Gross tumor volume (GTV) and the relationship between GTV and hilum were significantly correlated with irradiation dose to ipsilateral hilar nodal regions (P 3 (diameter ∼ 4 cm) and or having any overlap with hilum, the median EUDs were 9.6, 22.6, and 62.9 Gy for ipsilateral lower paratracheal, subcarinal, and ipsilateral hilar regions, respectively. The corresponding median V 40 were 32.5%, 39.3%, and 97.6%, respectively. Conclusions: Although incidental nodal irradiation dose is low in the whole group, the dose to high-risk nodal regions is considerable in patients with T 1-3 N 0 NSCLC when the primary is large and/or centrally located

CMS proposes prioritizing patient preferences, linking patients to follow-up care in discharge planning process.

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2016-03-01

Hospital providers voice concerns about a proposed rule by the Centers for Medicare and Medicaid Services (CMS) that would require providers to devote more resources to discharge planning. The rule would apply to inpatients as well as emergency patients requiring comprehensive discharge plans as opposed to discharge instructions. CMS states that the rule would ensure the prioritization of patient preferences and goals in the discharge planning process, and also would prevent avoidable complications and readmissions. However, hospital and emergency medicine leaders worry that community resources are not yet in place to facilitate the links and follow-up required in the proposed rule, and that the costs associated with implementation would be prohibitive. The proposed rule would apply to acute care hospitals, EDs, long-term care facilities, inpatient rehabilitation centers, and home health agencies. Regardless of the setting, though, CMS is driving home the message that patient preferences should be given more weight during the discharge planning process. Under the rule, hospitals or EDs would need to develop a patient-centered discharge plan within 24 hours of admission or registration, and complete the plan prior to discharge or transfer to another facility. Under the rule, emergency physicians would determine which patients require a comprehensive discharge plan. Both the American Hospital Association and the American College of Emergency Physicians worry that hospitals will have to take on more staff, invest in training, and make changes to their electronic medical record systems to implement the provisions in the proposed rule.

Subcarinal Lymph Nodes Should be Dissected in All Lobectomies for Non-Small Cell Lung Cancer

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Eckardt, Jens; Jakobsen, Erik; Licht, Peter B

2017-01-01

BACKGROUND: Mediastinal staging is of paramount importance for planning of treatment in non-small cell lung cancer (NSCLC). Single institution reports recently claimed that subcarinal lymph node dissection during resection of upper lobe NSCLC could be spared. We used a complete national lung cancer...... registry to investigate patterns of unsuspected mediastinal lymph node involvement after lobectomy. METHODS: During an 11-year period (2004 to 2014) 5,577 consecutive patients who underwent operations for NSCLC were investigated for unsuspected mediastinal lymph node involvement (N2 disease) discovered......: Mediastinal lymph node dissection was performed in 5,577 patients during the operation, and unsuspected N2 disease was discovered in 612 (11.0%), and 193 (3.5%) had subcarinal metastasis. Subcarinal N2 disease was significantly more common in patients with lower-lobe or middle-lobe cancers compared with upper...

Can Laws Be a Potential PET Image Texture Analysis Approach for Evaluation of Tumor Heterogeneity and Histopathological Characteristics in NSCLC?

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Karacavus, Seyhan; Yılmaz, Bülent; Tasdemir, Arzu; Kayaaltı, Ömer; Kaya, Eser; İçer, Semra; Ayyıldız, Oguzhan

2018-04-01

We investigated the association between the textural features obtained from 18 F-FDG images, metabolic parameters (SUVmax , SUVmean, MTV, TLG), and tumor histopathological characteristics (stage and Ki-67 proliferation index) in non-small cell lung cancer (NSCLC). The FDG-PET images of 67 patients with NSCLC were evaluated. MATLAB technical computing language was employed in the extraction of 137 features by using first order statistics (FOS), gray-level co-occurrence matrix (GLCM), gray-level run length matrix (GLRLM), and Laws' texture filters. Textural features and metabolic parameters were statistically analyzed in terms of good discrimination power between tumor stages, and selected features/parameters were used in the automatic classification by k-nearest neighbors (k-NN) and support vector machines (SVM). We showed that one textural feature (gray-level nonuniformity, GLN) obtained using GLRLM approach and nine textural features using Laws' approach were successful in discriminating all tumor stages, unlike metabolic parameters. There were significant correlations between Ki-67 index and some of the textural features computed using Laws' method (r = 0.6, p = 0.013). In terms of automatic classification of tumor stage, the accuracy was approximately 84% with k-NN classifier (k = 3) and SVM, using selected five features. Texture analysis of FDG-PET images has a potential to be an objective tool to assess tumor histopathological characteristics. The textural features obtained using Laws' approach could be useful in the discrimination of tumor stage.

First-line single agent treatment with gefitinib in patients with advanced non-small-cell lung cancer

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Shu Yong-Qian

2010-09-01

Full Text Available Abstract Background Lung cancer is a malignant carcinoma which has the highest morbidity and mortality in Chinese population. Gefitinib, a tyrosine kinase (TK inhibitor of epidermal growth factor receptor (EGFR, displays anti-tumor activity. The present data regarding first-line treatment with single agent gefitinib against non-small-cell lung cancer (NSCLC in Chinese population are not sufficient. Purpose To assess the efficacy and toxicity of gefitinib in Chinese patients with advanced non-small-cell lung cancer (NSCLC, a study of single agent treatment with gefitinib in Chinese patients was conducted. Methods 45 patients with advanced NSCLC were treated with gefitinib (250 mg daily until the disease progression or intolerable toxicity. Results Among the 45 patients, 15 patients achieved partial response (PR, 17 patients experienced stable disease (SD, and 13 patients developed progression disease (PD. None of the patients achieved complete response (CR. The tumor response rate and disease control rate was 33% and 71.1%, respectively. Symptom remission rate was 72.5%, and median remission time was 8 days. Median overall survival and median progression-free survival was 15.3 months and 6.0 months, respectively. The main induced toxicities by gefitinib were skin rash and diarrhea (53.3% and 33.3%, respectively. The minor induced toxicities included dehydration and pruritus of skin (26.7% and 22.2%, respectively. In addition, hepatic toxicity and oral ulceration occurred in few patients (6.7% and 4.4%2, respectively. Conclusions Single agent treatment with gefitinib is effective and well tolerated in Chinese patients with advanced NSCLC.

Complete resection of the primary lesion improves survival of certain patients with stage IV non-small cell lung cancer.

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Chikaishi, Yasuhiro; Shinohara, Shinji; Kuwata, Taiji; Takenaka, Masaru; Oka, Soichi; Hirai, Ayako; Yoneda, Kazue; Kuroda, Kouji; Imanishi, Naoko; Ichiki, Yoshinobu; Tanaka, Fumihiro

2017-12-01

The standard treatment for patients with stage IV non-small cell lung cancer (NSCLC) is systemic chemotherapy. However, certain patients, such as those with oligometastasis or M1a disease undergo resection of the primary lesion. We conducted a retrospective review of the records of 1,471 consecutive patients with NSCLC who underwent resection of the primary lesion for between June 2005 and May 2016. The present study included 38 patients with stage IV NSCLC who underwent complete resection of the primary lesion as first-line treatment. The median follow-up duration for the 38 patients (27 men) was 17.7 months (range, 1-82.3 months). The T factors were T1/T2/T3/T4 in 4/16/12/6 patients, respectively. The N factors were N0/N1/N2/N3 in 16/8/12/2 patients, respectively. The M factors were M1a/M1b/M1c in 19/13/6 patients, respectively. Of the 19 M1a patients, 11 were classified as cM0. We introduced the novel classification M-better/M-worse. M-better includes cM0 patients and M1b and M1c patients in whom all lesions have been locally controlled. M-worse includes cM1a patients and M1b and M1c patients in whom lesions cannot be locally controlled. The new M-better/M-worse statuses were 24/14 patients, respectively. The histology of NSCLC was adenocarcinoma/squamous cell carcinoma/others in 30/5/3 patients, respectively. The 5-year overall survival rate was 29%, and the median survival time was 725 days. Squamous cell carcinoma and M-worse were significant factors predicting poor outcomes (P=0.0017, P=0.0007, respectively). Even for stage IV NSCLC patients, resection of the primary lesion may be beneficial, especially for those with M-better status and those not diagnosed with squamous-cell carcinoma (SCC).

Mutational profiling of non-small-cell lung cancer patients resistant to first-generation EGFR tyrosine kinase inhibitors using next generation sequencing

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Jin, Ying; Shao, Yang; Shi, Xun; Lou, Guangyuan; Zhang, Yiping; Wu, Xue; Tong, Xiaoling; Yu, Xinmin

2016-01-01

Patients with advanced non-small-cell lung cancer (NSCLC) harboring sensitive epithelial growth factor receptor (EGFR) mutations invariably develop acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). Identification of actionable genetic alterations conferring drug-resistance can be helpful for guiding the subsequent treatment decision. One of the major resistant mechanisms is secondary EGFR-T790M mutation. Other mechanisms, such as HER2 and MET amplifications, and PIK3CA mutations, were also reported. However, the mechanisms in the remaining patients are still unknown. In this study, we performed mutational profiling in a cohort of 83 NSCLC patients with TKI-sensitizing EGFR mutations at diagnosis and acquired resistance to three different first-generation EGFR TKIs using targeted next generation sequencing (NGS) of 416 cancer-related genes. In total, we identified 322 genetic alterations with a median of 3 mutations per patient. 61% of patients still exhibit TKI-sensitizing EGFR mutations, and 36% of patients acquired EGFR-T790M. Besides other known resistance mechanisms, we identified TET2 mutations in 12% of patients. Interestingly, we also observed SOX2 amplification in EGFR-T790M negative patients, which are restricted to Icotinib treatment resistance, a drug widely used in Chinese NSCLC patients. Our study uncovered mutational profiles of NSCLC patients with first-generation EGFR TKIs resistance with potential therapeutic implications. PMID:27528220

Prognostic Significance of N-Glycolyl GM3 Ganglioside Expression in Non-Small Cell Lung Carcinoma Patients: New Evidences

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Blanco, Rancés; Domínguez, Elizabeth; Morales, Orlando; Blanco, Damián; Martínez, Darel; Rengifo, Charles E.; Viada, Carmen; Cedeño, Mercedes; Rengifo, Enrique; Carr, Adriana

2015-01-01

The prognostic role of N-glycolyl GM3 ganglioside (NeuGcGM3) expression in non-small cell lung carcinoma (NSCLC) still remains controversial. In this study, the NeuGcGM3 expression was reevaluated using an increased number of NSCLC cases and the 14F7 Mab (a highly specific IgG1 raised against NeuGcGM3). An immunohistochemical score integrating the percentage of 14F7-positive cells and the intensity of reaction was applied to reassess the relationship between NeuGcGM3 expression, some clinicopathological features, and the overall survival (OS) of NSCLC patients. The double and the triple expression of NeuGcGM3 with the epidermal growth factor receptor (EGFR) and/or its ligand, the epidermal growth factor (EGF), were also evaluated. NeuGcGM3 expression correlates with both S-Phase fraction (p = 0.006) and proliferation index (p = 0.000). Additionally, NeuGcGM3 expression was associated with a poor OS of patients in both univariate (p = 0.020) and multivariate (p = 0.010) analysis. Moreover, the double and/or the triple positivity of tumors to NeuGcGM3, EGFR, and/or EGF permitted us to identify phenotypes of NSCLC with a more aggressive biological behavior. Our results are in agreement with the negative prognostic significance of NeuGcGM3 expression in NSCLC patients. However, standardization of techniques to determine the expression of NeuGcGM3 in NSCLC as well as the implementation of a universal scoring system is recommended. PMID:26634172

Clinical Observation of Icotinib Hydrochloride for Advanced Non-small Cell Lung Cancer Patients with EGFR Status Identified

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Xi LI

2015-12-01

Full Text Available Background and objective Icotinib is the first self-developed small molecular drug in China for targeted therapy of lung cancer. Compared to the other two commercially available epidermal growth factor receptor (EGFR tyrosine kinase inhibitors, gefitinib and erlotinib, icotinib is similar to them in chemical structure, mechanism of activity and therapeutic effects. To explore the efficacy and side effects of icotinib hydrochloride in the treatment of the advanced non-small cell lung cancer (NSCLC patients with EGFR mutation and wild-type. Methods Patients with advanced NSCLC who were treated with icotinib hydrochloride in Beijing Chest Hospital were retrospective analyzed from March 2009 to December 2014. Results The clinical data of 124 patients (99 with EGFR mutation and 25 with wild type with advanced NSCLC were enrolled in this study. The patients’ overall objective response rate (ORR was 51.6 % and the disease control rate (DCR was 79.8%; The patients with EGFR mutation, ORR was 63.6%, DCR was 93.9%. The ORR was 4.0% and the DCR was 24.0% in the wild-type patients. Median progression-free survival (PFS with icotinib treatment in EGFR mutation patients was 10.5 months and 1.0 month in wild-type patients. The major adverse events were mild skin rash (30.6% and diarrhea (16.1%. Conclusion Monotherapy with icotinib hydrochloride is effective and tolerable for the advanced NSCLC EGFR mutation patients.

Molecular prediction of adjuvant cisplatin efficacy in Non-Small Cell Lung Cancer (NSCLC)—validation in two independent cohorts

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Buhl, Ida Kappel; Santoni Rugiu, Eric; Ravn, Jesper

2018-01-01

Introduction Effective predictive biomarkers for selection of patients benefiting from adjuvant platinum-based chemotherapy in non-small cell lung cancer (NSCLC) are needed. Based on a previously validated methodology, molecular profiles of predicted sensitivity in two patient cohorts are presented....... Methods The profiles are correlations between in vitro sensitivity to cisplatin and vinorelbine and baseline mRNA expression of the 60 cell lines in the National Cancer Institute panel. An applied clinical samples filter focused the profiles to clinically relevant genes. The profiles were tested on 1......) univariate HR of 0.37 (95% CI:0.12–1.15, p = 0.09) in the ACV cohort and 2) univariate HR of 0.14 (95% CI:0.03–0.59, p = 0.0076) to three years. Functional analysis on the cisplatin profile revealed a group of upregulated genes related to RNA splicing as a part of DNA damage repair and apoptosis. Conclusions...

Co-activation of STAT3 and YES-Associated Protein 1 (YAP1) Pathway in EGFR-Mutant NSCLC

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Chaib, Imane; Karachaliou, Niki; Pilotto, Sara

2017-01-01

Background: The efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC) is limited by adaptive activation of cell survival signals. We hypothesized that both signal transducer and activator of transcription 3 (STAT3) ...

Keratin 34betaE12/keratin7 expression is a prognostic factor of cancer-specific and overall survival in patients with early stage non-small cell lung cancer

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Pøhl, Mette; Olsen, Karen Ege; Holst, Rene

2016-01-01

proliferation, migration, and possibly cancer invasion, factors impacting prognosis in early stage non-small cell lung cancer (NSCLC). MATERIAL AND METHODS: Tumor tissue from a retrospective Danish cohort of 177 patients with completely resected NSCLC, stage I-IIIA tumors, were analyzed for keratin 7 (K7...... that stage II-IIIA (HR 2.3), 34βE12+/K7+ (HR 1.6), and 34βE12-/K7+ (HR 2.0) were prognostic factors of poor CSS (p overall survival (p ...: Keratin 34βE12/K7 expression is a prognostic parameter in resected early stage NSCLC that allows identification of high-risk NSCLC patients with poor cancer-specific and overall survival....

Pretreatment advanced lung cancer inflammation index (ALI) for predicting early progression in nivolumab-treated patients with advanced non-small cell lung cancer.

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Shiroyama, Takayuki; Suzuki, Hidekazu; Tamiya, Motohiro; Tamiya, Akihiro; Tanaka, Ayako; Okamoto, Norio; Nakahama, Kenji; Taniguchi, Yoshihiko; Isa, Shun-Ichi; Inoue, Takako; Imamura, Fumio; Atagi, Shinji; Hirashima, Tomonori

2018-01-01

Programmed death-ligand 1 (PD-L1) expression status is inadequate for indicating nivolumab in patients with non-small cell lung cancer (NSCLC). Because the baseline advanced lung cancer inflammation index (ALI) is reportedly associated with patient outcomes, we investigated whether the pretreatment ALI is prognostic in NSCLC patients treated with nivolumab. We retrospectively reviewed the medical records of all patients treated with nivolumab for advanced NSCLC between December 2015 and May 2016 at three Japanese institutes. Multivariate logistic regression and Cox proportional hazards models were used to assess the impact of the pretreatment ALI (and other inflammation-related parameters) on progression-free survival (PFS) and early progression (i.e., within 8 weeks after starting nivolumab). A total of 201 patients were analyzed; their median age was 68 years (range, 27-87 years), 67% were men, and 24% had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or higher. An ECOG performance status ≥2, serum albumin ALI ALI ALI was found to be a significant independent predictor of early progression in patients with advanced NSCLC receiving nivolumab, and may help identify patients likely to benefit from continued nivolumab treatment in routine clinical practice. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Tactical resource allocation and elective patient admission planning in care pathways

NARCIS (Netherlands)

Hulshof, P.J.H.; Boucherie, Richardus J.; Hans, Elias W.; Hurink, Johann L.

Tactical planning of resources in hospitals concerns elective patient admission planning and the intermediate term allocation of resource capacities. Its main objectives are to achieve equitable access for patients, to meet production targets/to serve the strategically agreed number of patients, and

Tactical resource allocation and elective patient admission planning in care processes

NARCIS (Netherlands)

Hulshof, P.J.H.; Boucherie, Richardus J.; Hans, Elias W.; Hurink, Johann L.

2013-01-01

Tactical planning of resources in hospitals concerns elective patient admission planning and the intermediate term allocation of resource capacities. Its main objectives are to achieve equitable access for patients, to meet production targets/to serve the strategically agreed number of patients, and

Interaction between hypoxia, AKT and HIF-1 signaling in HNSCC and NSCLC: implications for future treatment strategies

NARCIS (Netherlands)

Stegeman, H.; Span, P.N.; Peeters, W.J.M.; Verheijen, M.M.; Grenman, R.; Meijer, T.W.H.; Kaanders, J.H.A.M.; Bussink, J.

2016-01-01

BACKGROUND: Hypoxia is a negative prognostic factor and this study investigated the relationship between hypoxia, hypoxia inducible factor 1 (HIF-1) and AKT signaling in head and neck squamous cell carcinoma (HNSCC) and non-small-cell lung cancer (NSCLC). RESULTS/METHODOLOGY: pAKT was induced by

Patient geometry-driven information retrieval for IMRT treatment plan quality control

International Nuclear Information System (INIS)

Wu Binbin; Ricchetti, Francesco; Sanguineti, Giuseppe; Kazhdan, Misha; Simari, Patricio; Chuang Ming; Taylor, Russell; Jacques, Robert; McNutt, Todd

2009-01-01

Purpose: Intensity modulated radiation therapy (IMRT) treatment plan quality depends on the planner's level of experience and the amount of time the planner invests in developing the plan. Planners often unwittingly accept plans when further sparing of the organs at risk (OARs) is possible. The authors propose a method of IMRT treatment plan quality control that helps planners to evaluate the doses of the OARs upon completion of a new plan. Methods: It is achieved by comparing the geometric configurations of the OARs and targets of a new patient with those of prior patients, whose plans are maintained in a database. They introduce the concept of a shape relationship descriptor and, specifically, the overlap volume histogram (OVH) to describe the spatial configuration of an OAR with respect to a target. The OVH provides a way to infer the likely DVHs of the OARs by comparing the relative spatial configurations between patients. A database of prior patients is built to serve as an external reference. At the conclusion of a new plan, planners search through the database and identify related patients by comparing the OAR-target geometric relationships of the new patient with those of prior patients. The treatment plans of these related patients are retrieved from the database and guide planners in determining whether lower doses delivered to the OARs in the new plan are feasible. Results: Preliminary evaluation is promising. In this evaluation, they applied the analysis to the parotid DVHs of 32 prior head-and-neck patients, whose plans are maintained in a database. Each parotid was queried against the other 63 parotids to determine whether a lower dose was possible. The 17 parotids that promised the greatest reduction in D 50 (DVH dose at 50% volume) were flagged. These 17 parotids came from 13 patients. The method also indicated that the doses of the other nine parotids of the 13 patients could not be reduced, so they were included in the replanning process as

Impact of Symptomatic Metastatic Spinal Cord Compression on Survival of Patients with Non-Small-Cell Lung Cancer.

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da Silva, Gustavo Telles; Bergmann, Anke; Thuler, Luiz Claudio Santos

2017-12-01

Non-small-cell lung cancer (NSCLC) is one of the most common primary tumor sites among patients with metastatic spinal cord compression (MSCC). This disorder is related to neurologic dysfunction and can reduce the quality of life, but the association between MSCC and death is unclear. The aim of this study was to analyze the impact of the occurrence of symptomatic MSCC on overall survival of patients with NSCLC. A cohort study was carried out involving 1112 patients with NSCLC who were enrolled between 2006 and 2014 in a single cancer center. Clinical and sociodemographic data were extracted from the physical and electronic records. Survival analysis of patients with NSCLC was conducted using the Kaplan-Meier method. A log-rank test was used to assess differences between survival curves. Cox proportional hazards regression analyses were carried out to quantify the relationship between the independent variable (MSCC) and the outcome (overall survival). During the study period, the incidence of MSCC was 4.1%. Patients who presented with MSCC were 1.43 times more likely to die than were those with no history of MSCC (hazard ratio, 1.43; 95% confidence interval [CI], 1.03-2.00; P = 0.031). The median survival time was 8.04 months (95% CI, 6.13-9.96) for those who presented MSCC and 11.95 months (95% CI, 10.80-13.11) for those who did not presented MSCC during the course of disease (P = 0.002). MSCC is an important and independent predictor of NSCLC worse survival. This effect was not influenced by sociodemographic and clinical factors. Copyright © 2017 Elsevier Inc. All rights reserved.

Changes of Brain Glucose Metabolism in the Pretreatment Patients with Non-Small Cell Lung Cancer: A Retrospective PET/CT Study.

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Zhang, Weishan; Ning, Ning; Li, Xianjun; Niu, Gang; Bai, Lijun; Guo, Youmin; Yang, Jian

2016-01-01

The tumor-to-brain communication has been emphasized by recent converging evidences. This study aimed to compare the difference of brain glucose metabolism between patients with non-small cell lung cancer (NSCLC) and control subjects. NSCLC patients prior to oncotherapy and control subjects without malignancy confirmed by 6 months follow-up were collected and underwent the resting state 18F-fluoro-D-glucose (FDG) PET/CT. Normalized FDG metabolism was calculated by a signal intensity ratio of each brain region to whole brain. Brain glucose metabolism was compared between NSCLC patients and control group using two samples t-test and multivariate test by statistical parametric maps (SPM) software. Compared with the control subjects (n = 76), both brain glucose hyper- and hypometabolism regions with significant statistical differences (Pbrain signal transduction pathways, and the hypometabolism regions (the left superior parietal lobule, bilateral inferior parietal lobule and left fusiform gyrus) lied in dorsal attention network and visuospatial function areas. The changes of brain glucose metabolism exist in NSCLC patients prior to oncotherapy, which might be attributed to lung-cancer related visceral sympathetic activation and decrease of dorsal attention network function.

Treatment Choice for Advanced Non-small Cell Lung Cancer Patients Who Had Gradual Progression After EGFR-TKIs: 32 Cases Report

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Lin LIN

2013-10-01

Full Text Available Background and objective The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs have been widely used in the treatment of the advanced non-small cell lung cancer (NSCLC, especially in the adenocarcinoma patients with activating EGFR mutations. But there is no published overview of the following treatment. This report through observing the efficacy, toxicity and overall survival of different treatments to the advanced NSCLC patients who had gradual progression after EGFR-TKIs, evaluates the influence of the continued treatment and switching chemotherapy. Methods Retrospective review is conducted on 32 cases of advanced NSCLC patients who experienced treatment failure of EGFR-TKIs. One group accepted the continued treatment and the other group accepted the switching chemotherapy. Results The median overall survival of the continued treatment group is 36.0 months. The respose rate of the switching chemotherapy group is 43.75%, and clinical benefit rate (complete and partial response and stable disease is 87.5%. The median overall survival is 15.5 months. The main toxicities are nausea, vomiting and hematological toxicities. Conclusion For the advanced NSCLC patients who had gradual progression after EGFR-TKIs, the continued treatment is one of the acceptable choices.

Longitudinal assessment of TUBB3 expression in non-small cell lung cancer patients

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Jakobsen, Jan Nyrop; Santoni-Rugiu, Eric; Sørensen, Jens Benn

2014-01-01

INTRODUCTION: Class-III-beta-tubulin (TUBB3) expression may be a potential predictive factor for treatment with microtubule interfering cytotoxic drugs in non-small cell lung cancer (NSCLC). Potential changes in TUBB3 expression during chemotherapy may be of interest if future choice...... NSCLC patients stage T1-4N0-1 was treated with surgery alone without preceding chemotherapy (OP-group). Paired repeated samples were compared in order to evaluate for changes in TUBB3 expression. RESULTS: No statistically significant change in TUBB3 expression was observed between initial diagnostic...... during chemotherapy. MATERIALS AND METHODS: TUBB3 expression was investigated by immunohistochemistry performed on diagnostic biopsies and on available subsequent resection specimens in 65 NSCLC patients stage T1-3N0-2 who received neoadjuvant carboplatin and paclitaxel (NAC-group). Another group of 53...

Evaluation of plan quality assurance models for prostate cancer patients based on fully automatically generated Pareto-optimal treatment plans.

Science.gov (United States)

Wang, Yibing; Breedveld, Sebastiaan; Heijmen, Ben; Petit, Steven F

2016-06-07

IMRT planning with commercial Treatment Planning Systems (TPSs) is a trial-and-error process. Consequently, the quality of treatment plans may not be consistent among patients, planners and institutions. Recently, different plan quality assurance (QA) models have been proposed, that could flag and guide improvement of suboptimal treatment plans. However, the performance of these models was validated using plans that were created using the conventional trail-and-error treatment planning process. Consequently, it is challenging to assess and compare quantitatively the accuracy of different treatment planning QA models. Therefore, we created a golden standard dataset of consistently planned Pareto-optimal IMRT plans for 115 prostate patients. Next, the dataset was used to assess the performance of a treatment planning QA model that uses the overlap volume histogram (OVH). 115 prostate IMRT plans were fully automatically planned using our in-house developed TPS Erasmus-iCycle. An existing OVH model was trained on the plans of 58 of the patients. Next it was applied to predict DVHs of the rectum, bladder and anus of the remaining 57 patients. The predictions were compared with the achieved values of the golden standard plans for the rectum D mean, V 65, and V 75, and D mean of the anus and the bladder. For the rectum, the prediction errors (predicted-achieved) were only  -0.2  ±  0.9 Gy (mean  ±  1 SD) for D mean,-1.0  ±  1.6% for V 65, and  -0.4  ±  1.1% for V 75. For D mean of the anus and the bladder, the prediction error was 0.1  ±  1.6 Gy and 4.8  ±  4.1 Gy, respectively. Increasing the training cohort to 114 patients only led to minor improvements. A dataset of consistently planned Pareto-optimal prostate IMRT plans was generated. This dataset can be used to train new, and validate and compare existing treatment planning QA models, and has been made publicly available. The OVH model was highly accurate

Fully Automated Volumetric Modulated Arc Therapy Plan Generation for Prostate Cancer Patients

International Nuclear Information System (INIS)

Voet, Peter W.J.; Dirkx, Maarten L.P.; Breedveld, Sebastiaan; Al-Mamgani, Abrahim; Incrocci, Luca; Heijmen, Ben J.M.

2014-01-01

Purpose: To develop and evaluate fully automated volumetric modulated arc therapy (VMAT) treatment planning for prostate cancer patients, avoiding manual trial-and-error tweaking of plan parameters by dosimetrists. Methods and Materials: A system was developed for fully automated generation of VMAT plans with our commercial clinical treatment planning system (TPS), linked to the in-house developed Erasmus-iCycle multicriterial optimizer for preoptimization. For 30 randomly selected patients, automatically generated VMAT plans (VMAT auto ) were compared with VMAT plans generated manually by 1 expert dosimetrist in the absence of time pressure (VMAT man ). For all treatment plans, planning target volume (PTV) coverage and sparing of organs-at-risk were quantified. Results: All generated plans were clinically acceptable and had similar PTV coverage (V 95%  > 99%). For VMAT auto and VMAT man plans, the organ-at-risk sparing was similar as well, although only the former plans were generated without any planning workload. Conclusions: Fully automated generation of high-quality VMAT plans for prostate cancer patients is feasible and has recently been implemented in our clinic

Diagnostic utility of neuron specific enolase (NSE) in serum and pleural fluids from patients with lung cancer and tuberculosis

International Nuclear Information System (INIS)

Alam, J.M.; Baig, J.A.; Asghar, S.S.; Mahmood, S.R.; Ansari, M.A.; Jamil, S.

2010-01-01

Several past and recent investigations have focused on the determination of tumor markers in pleural fluids to assess their Usefulness as less invasive replacement method of diagnosis. In this regard, few studies have dealt with the determination of the tumor marker, neuron specific enolase (NSE), in pleural fluids of patients suffering from both benign and malignant diseases such as non small cell lung carcinoma( NSCLC), small cell lung carcinoma( SCLC) and tuberculosis. Therefore, the present study was undertaken to establish the diagnostic utility of NSE in malignant condition by assessing levels in serum and pleural fluids of patients with lung cancer and by comparing it with a benign pulmonary disease of tuberculosis. Pleural fluids were obtained from 22 patients with carcinomatous pleurisy due to SCLC, 11 patients with carcinomatous pleurisy due to non-small cell lung cancer, and 30 patients with tuberculosis pleurisy for comparison purpose. Determination of NSE levels was performed by ECL technology according to the manufacturer's instructions. NSE levels of pleural fluids from SCLC patients were significantly elevated( P<0.0001) when compared with pleural fluids from NSCLC and tuberculosis patients. Moreover, pleural fluids of all 30 tuberculosis patients and 11 NSCLC patients showed moderate significance ( P< O.05 and P < 0.01, respectively) when compared with each other. In addition, cumulative results of NSE levels from SCLC and NSCLC combined also showed high significance (P<0.001) as compared to pleural fluids of tuberculosis patients and moderate significance (P<0.01) when compared with serum levels of both malignant and benign groups. It is concluded that determination of NSE levels in pleural fluids of lung cancer patients noted to be an effective diagnostic tool to differentiate carcinomatous pleurisy due to SCLC from those occurring due to NSCLC and tuberculosis. Further studies with larger group of patients are under progress to further establish

Smoking Cessation in Cardiac Patients: The Influence of Action Plans, Coping Plans and Self-Efficacy on Quitting Smoking

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de Hoog, Natascha; Bolman, Catherine; Berndt, Nadine; Kers, Esther; Mudde, Aart; de Vries, Hein; Lechner, Lilian

2016-01-01

Smoking cessation is the most effective action for cardiac patients who smoke to improve their prognosis, yet more than one-half of cardiac patients continue to smoke after hospital admission. This study examined the influence of action plans, coping plans and self-efficacy on intention to quit and smoking cessation in cardiac patients. Cardiac…

Chemotherapy Treatment of Elderly Patients (≥70 Years) with Non-Small Cell Lung Cancer: A Seven-Year Retrospective Study of Real-Life Clinical Practice at Karolinska University Hospital, Sweden.

Science.gov (United States)

Koyi, Hirsh; Hillerdal, Gunnar; Andersson, Olov; Kölbeck, Karl-Gustav; Liv, Per; Brandén, Eva

2015-01-01

An increasing proportion of cancer patients are aged >65 years and many are aged >70 years. Treatment of the elderly with lung cancer has, therefore, become an important issue; so we performed a retrospective study of our patients to demonstrate how elderly patients with NSCLC are treated in real-life, clinical practice. All patients aged ≥70 years with NSCLC at our department were reviewed retrospectively. In total, 1059 patients (50.8% of all NSCLC patients). Of these patients, 243 (22.9%) received chemotherapy, 164 (70.4%) of whom were treated with a platinum doublet using carboplatin. Second- and third-line chemotherapy were given to 31.4% and 13.9% of patients, respectively. Median overall survival was 289 and 320 days for male and female patients, respectively. Patients with performance status (PS) 0 experienced significantly better survival than patients with PS1 or PS 2: 410, 314, and 204 days, respectively. Age was of less importance, with patients aged 70-79 years versus those aged ≥80 years. Treatment of elderly NSCLC patients with chemotherapy is feasible if they have a good PS and appears to prolong survival. In this study, we found no significant differences in survival either between age groups or genders.

The CT Findings and the Peak SUV on PET/CT according to the Levels of Cyfra 21-1 and CEA in Patients with Non-Small Cell Lung Carcinoma

International Nuclear Information System (INIS)

Jou, Sung Shick; Kim, Young Tong; Han, Jong Kyu; Kim, Hyung Hwan; Park, Jeong Mi; Park, Jai Soung; Hwang, Jung Hwa

2009-01-01

We wanted to evaluate the CT findings and the peak SUV according to the levels of cyfra 21-1 and CEA in patients with non-small cell lung carcinoma (NSCLC). We evaluated the TNM staging, cell types, the CT findings and peak SUV of the NSCLC in 234 patients with NSCLC according to the tumor marker levels. The correlations of the CT findings and the peak SUV with the tumor markers were evaluated in 35 patients with stage I disease. The sensitivities of the combined tumor markers cyfra 21-1 and CEA in the NSCLC for each TNM staging (I-IV) were 48.5%, 66.7%, 78.3% and 84.3%, respectively (p<0.05). Cyfra 21-1 was more sensitive for squamous cell carcinoma and CEA was more sensitive for adenocarcinoma. The tumor size, tumor necrosis and peak SUV were greater in the NSCLC with an elevated cyfra 21-1 level than that in the NSCLC without an elevated cyfra 21-1 level (p<0.05). For stage I disease, the level of cyfra 21-1 was linearly correlated with the tumor size (r=0.54) and the peak SUV (r=0.46), and the level of CEA was high in the spiculated masses (p<0.05). The NSCLC with an elevated cyfra 21-1 level shows larger, more frequently necrosis and a higher peak SUV than the NSCLC without an elevated Cyfra 21-1 level. For stage 1 disease, the tumor size and peak SUV correlate with the level of cyfra 21-1, and spiculated masses show an elevated level of CEA

The CT Findings and the Peak SUV on PET/CT according to the Levels of Cyfra 21-1 and CEA in Patients with Non-Small Cell Lung Carcinoma

Energy Technology Data Exchange (ETDEWEB)

Jou, Sung Shick; Kim, Young Tong; Han, Jong Kyu; Kim, Hyung Hwan [Soonchunhyang University Cheonan Hospital, Cheonan (Korea, Republic of); Park, Jeong Mi; Park, Jai Soung [Soonchunhyang University Bucheon Hospital, Bucheon (Korea, Republic of); Hwang, Jung Hwa [Soonchunhyang University Hospital, Seoul (Korea, Republic of)

2009-10-15

We wanted to evaluate the CT findings and the peak SUV according to the levels of cyfra 21-1 and CEA in patients with non-small cell lung carcinoma (NSCLC). We evaluated the TNM staging, cell types, the CT findings and peak SUV of the NSCLC in 234 patients with NSCLC according to the tumor marker levels. The correlations of the CT findings and the peak SUV with the tumor markers were evaluated in 35 patients with stage I disease. The sensitivities of the combined tumor markers cyfra 21-1 and CEA in the NSCLC for each TNM staging (I-IV) were 48.5%, 66.7%, 78.3% and 84.3%, respectively (p<0.05). Cyfra 21-1 was more sensitive for squamous cell carcinoma and CEA was more sensitive for adenocarcinoma. The tumor size, tumor necrosis and peak SUV were greater in the NSCLC with an elevated cyfra 21-1 level than that in the NSCLC without an elevated cyfra 21-1 level (p<0.05). For stage I disease, the level of cyfra 21-1 was linearly correlated with the tumor size (r=0.54) and the peak SUV (r=0.46), and the level of CEA was high in the spiculated masses (p<0.05). The NSCLC with an elevated cyfra 21-1 level shows larger, more frequently necrosis and a higher peak SUV than the NSCLC without an elevated Cyfra 21-1 level. For stage 1 disease, the tumor size and peak SUV correlate with the level of cyfra 21-1, and spiculated masses show an elevated level of CEA.

TH-CD-202-09: Free-Breathing Proton MRI Functional Lung Avoidance Maps to Guide Radiation Therapy

Energy Technology Data Exchange (ETDEWEB)

Capaldi, D; Sheikh, K; Parraga, G [Robarts Research Institute, The University of Western Ontario, London, Ontario, CA (United States); Department of Medical Biophysics, The University of Western Ontario, London, Ontario, CA (United States); Hoover, D; Yaremko, B; Palma, D [Department of Medical Biophysics, The University of Western Ontario, London, Ontario, CA (United States); Department of Oncology, The University of Western Ontario, London, Ontario, CA (United States)

2016-06-15

Purpose: Pulmonary functional MRI using inhaled gas contrast agents was previously investigated as a way to identify well-functioning lung in patients with NSCLC who are clinical candidates for radiotherapy. Hyperpolarized noble-gas ({sup 3}He and {sup 129}Xe) MRI has also been optimized to measure functional lung information, but for a number of reasons, the clinical translation of this approach to guide radiotherapy planning has been limited. As an alternative, free-breathing pulmonary 1H MRI using clinically available MRI systems and pulse sequences provides a non-contrast-enhanced method to generate both ventilation and perfusion maps. Free-breathing {sup 1}H MRI exploits non-rigid registration and Fourier decomposition of MRI signal intensity differences (Bauman et al., MRM, 2009) that may be generated during normal tidal breathing. Here, our objective was to generate free-breathing {sup 1}H MRI ventilation and lung function avoidance maps in patients with NSCLC as a way to guide radiation therapy planning. Methods: Stage IIIA/IIIB NSCLC patients (n=8, 68±9yr) provided written informed consent to a randomized controlled clinical trial ( https://clinicaltrials.gov/ct2/show/NCT02002052 ) that aimed to compare outcomes related to image-guided versus conventional radiation therapy planning. Hyperpolarized {sup 3}He/{sup 129}Xe and dynamic free tidal-breathing {sup 1}H MRI were acquired as previously described (Capaldi et al., Acad Radiol, 2015). Non-rigid registration was performed using the modality-independent-neighbourhood-descriptor (MIND) deformable approach (Heinrich et al., Med Image Anal, 2012). Ventilation-defect-percent ({sup 3}He:VDP{sub He}, {sup 129}Xe:VDP{sub Xe}, Free-breathing-{sup 1}H:VDP{sub FB}) and the corresponding ventilation maps were compared using Pearson correlation coefficients (r) and the Dice similarity coefficient (DSC). Results: VDP{sub FB} was significantly related to VDP{sub He} (r=.71; p=.04) and VDP{sub Xe} (r=.80; p=.01) and

CyberKnife with Tumor Tracking: An Effective Treatment for High-Risk Surgical Patients with Stage I Non-Small Cell Lung Cancer