Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer

NARCIS (Netherlands)

Tol, J.; Koopman, M.; Cats, A.; Rodenburg, C.J.; Creemers, G.J.M.; Schrama, J.G.; Erdkamp, F.L.G.; Vos, A.H.; van Groeningen, C.J.; Sinnige, H.A.M.; Richel, D.J.; Voest, E.E.; Dijkstra, J.R.; Vink-Börger, M.E.; Antonini, N.F.; Mol, L.; van Krieken, J.H.J.M.; Dalesio, O.; Punt, C.J.A.

2009-01-01

Background: Fluoropyrimidine- based chemotherapy plus the anti - vascular endothelial growth factor (VEGF) antibody bevacizumab is standard first- line treatment for metastatic colorectal cancer. We studied the effect of adding the anti - epidermal growth factor receptor (EGFR) antibody cetuximab to

Factors influencing choice of chemotherapy in metastatic colorectal cancer (mCRC)

International Nuclear Information System (INIS)

Rossi, Luigi; Vakiarou, Foteini; Zoratto, Federica; Bianchi, Loredana; Papa, Anselmo; Basso, Enrico; Verrico, Monica; Lo Russo, Giuseppe; Evangelista, Salvatore; Rinaldi, Guilia; Perrone-Congedi, Francesca; Spinelli, Gian Paolo; Stati, Valeria; Caruso, Davide; Prete, Alessandra; Tomao, Silverio

2013-01-01

Management of metastatic colorectal cancer requires a multimodal approach and must be performed by an experienced, multidisciplinary expert team. The optimal choice of the individual treatment modality, according to disease localization and extent, tumor biology, and patient clinical characteristics, will be one that can maintain quality of life and long-term survival, and even cure selected patients. This review is an overview of the different therapeutic approaches available in metastatic colorectal cancer, for the purpose of defining personalized therapeutic algorithms according to tumor biology and patient clinical features

Outcomes in Patients with Obstructive Jaundice from Metastatic Colorectal Cancer and Implications for Management

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Nichols, Shawnn D.; Albert, Scott; Shirley, Lawrence; Schmidt, Carl; Abdel-Misih, Sherif; El-Dika, Samer; Groce, J. Royce; Wu, Christina; Goldberg, Richard M.; Bekaii-Saab, Tanios; Bloomston, Mark

2016-01-01

Introduction Patients with metastatic colorectal cancer can develop jaundice from intrahepatic or extrahepatic causes. Currently, there is little data on the underlying causes and overall survival after onset of jaundice. The purpose of this study was to characterize the causes of jaundice and determine outcomes. Methods Six hundred twenty-nine patients treated for metastatic colorectal cancer between 2004 and 2010 were retrospectively reviewed. Those developing jaundice were grouped as having intrahepatic or extrahepatic obstruction. Demographics, clinicopathologic, and outcome data were analyzed. Results Sixty-two patients with metastatic colorectal cancer developed jaundice. Intrahepatic biliary obstruction was most common, occurring in younger patients. Time from metastatic diagnosis to presentation of jaundice was similar between groups, as was the mean number of prior lines of chemotherapy. Biliary decompression was successful 41.7 % of the time and was attempted more commonly for extrahepatic causes. Median overall survival after onset of jaundice was 1.5 months and it was similar between groups, but improved to 9.6 months in patients who were able to receive further chemotherapy. Conclusions Jaundice due to metastatic colorectal cancer is an ominous finding, representing aggressive tumor biology or exhaustion of therapies. Biliary decompression is often difficult and should only be pursued when additional treatment options are available. PMID:25300799

Concomitant parenteral nutrition and systemic cytotoxic therapy in a metastatic colorectal cancer patient

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A. A. Popov

2012-01-01

Full Text Available Pathologic nutrients metabolism presents a severe problem in metastatic colorectal cancer patients, especially those with canceromatosis. A hypermetabolism-catabolism syndrome frequently develops in in patients with progressing canceromatosis. This leads to cachexia anorexia syndrome, which significantly impedes available treatment options. Artificial nutrition allows to improve available treatment in such patients. We present a successful case of concomitant parenteral nutrition and systemic cytotoxic therapy in metastatic colorectal cancer patient with peritoneal canceromatosis.

Travel distance and use of salvage palliative chemotherapy in patients with metastatic colorectal cancer.

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Ahmed, Shahid; Iqbal, Mahjabeen; Le, Duc; Iqbal, Nayyer; Pahwa, Punam

2018-04-01

Salvage palliative chemotherapy in metastatic colorectal cancer has been associated with significant improvement in survival. However, not all patients receive all available therapies. Travel burden can affect patient access and use of future therapy. The present study aims to determine relationship between travel distance (TD) and salvage palliative chemotherapy in patients with metastatic colorectal cancer. A patient cohort diagnosed with metastatic colorectal cancer during 2006-2010 in the province of Saskatchewan, Canada was studied. Logistic regression analyses were performed to assess relationship between travel distance and subsequent line therapies. The median age of 264 eligible patients was 62 years [interquartile range (IQR): 53-72]. The patients who received salvage systemic therapy had a median distance to travel of 60.0 km (IQR: 4.7-144) compared with 88.1 km (IQR: 4.8-189) if they did not receive second- or third-line therapy (P=0.06). In multivariate analysis distance to the cancer center therapies. Our result revealed that travel distance to the cancer center greater than 100 km was associated less frequent use of second or subsequent line therapies in patients with metastatic colorectal cancer.

Visualising and quantifying angiogenesis in metastatic colorectal cancer

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Hansen, Torben Frøstrup; Nielsen, Boye Schnack; Jakobsen, Anders

2013-01-01

Angiogenesis plays an important role in tumour growth and dissemination. We have recently shown that blood vessel density, determined by image analysis based on microRNA-126 (miRNA-126) in situ hybridization (ISH) in the primary tumours of metastatic colorectal cancers (mCRC), is predictive...

Third-line therapy for metastatic colorectal cancer

DEFF Research Database (Denmark)

Gundgaard, M.G.; Ehrnrooth, E.; Sørensen, Jens Benn

2008-01-01

BACKGROUND: The past years' therapy for colorectal cancer has evolved rapidly with the introduction of novel cytotoxic agents such as irinotecan, capecitabine and oxaliplatin. Further advances have been achieved with the integration of targeted agents such as bevacizumab, cetuximab and recently......, panitumumab. As a result, third-line treatment is now a necessary step in the optimal treatment of patients with metastatic colorectal cancer (MCRC). MATERIALS AND METHODS: We conducted a literature review of English language publications on third-line therapy for MCRC from January 2000 to April 2007. Data......OS of 16 months. With irinotecan and 5-FU, mOS around 8 months were reported and with cetuximab combined with irinotecan, the highest mOS was 9.8 months. CONCLUSION: Third-line therapy in advanced colorectal cancer may improve mOS for patients with MCRC. Therefore, randomized studies should be conducted...

Decline in peripheral blood NKG2D+CD3+CD56+ NKT cells in metastatic colorectal cancer patients.

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Gharagozloo, M; Rezaei, A; Kalantari, H; Bahador, A; Hassannejad, N; Maracy, M; Nouri, N; Sedghi, M; Ghazanfari, H; Bayat, B

2018-01-01

Colorectal cancer (CRC) is one of the main causes of cancer deaths in the world. This cancer can be divided into non-metastatic and metastatic CRC stages. CD3+CD56+ NKT cell subsets are a minor T cell subset in peripheral blood and conduct the killing of tumor cells in direct manner. Little is obvious about levels and surface markers of these cells such as NKG2D in different cancers, especially in CRC. We included 15 non-metastatic (low-grade), 11 non-metastatic (high-grade), 10 metastatic colorectal cancer patients and 18 healthy controls. The percentages of CD3+CD56+ NKT cells and NKG2D+CD56+ NKT cells from samples were analyzed by flow cytometry in peripheral blood mononuclear cells (PBMCs) of samples. We found that there was a significantly lower number of NKG2D+CD3+CD56+ cells in peripheral blood of patients with metastatic colorectal cancer compared with normal controls (77.53 ± 5.79 % vs 90.74 ± 9.84 %; pNKT cells was significantly lower in patients with metastatic colorectal cancer compared to healthy controls strengthens the hypothesis that NKT cells can play a substantial role in the protection against human colorectal cancer, and this opens up avenues for novel studies about elucidating the other aspects of tumor surveillance in CRC progression and immunotherapy (Tab. 2, Fig. 2, Ref. 46).

Pre-treatment inflammatory indexes as predictors of survival and cetuximab efficacy in metastatic colorectal cancer patients with wild-type RAS.

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Yang, Jing; Guo, Xinli; Wang, Manni; Ma, Xuelei; Ye, Xiaoyang; Lin, Panpan

2017-12-07

This study aims at evaluating the prognostic significance of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and systemic immune-inflammation indexes (SII) in metastatic colorectal cancer (mCRC) patients treated with cetuximab. Ninety-five patients receiving cetuximab for mCRC were categorized into the high or low NLR, PLR, LMR, and SII groups based on their median index values. Univariate and multivariate survival analysis were performed to identify the indexes' correlation with progression-free survival (PFS) and overall survival (OS). In the univariate analysis, ECOG performance status, neutrphil counts, lymphocyte counts, monocyte counts, NLR, PLR, and LDH were associated with survival. Multivariate analysis showed that ECOG performance status of 0 (hazard ratio [HR] 3.608, p < 0.001; HR 5.030, p < 0.001, respectively), high absolute neutrophil counts (HR 2.837, p < 0.001; HR 1.922, p = 0.026, respectively), low lymphocyte counts (HR 0.352, p < 0.001; HR 0.440, p = 0.001, respectively), elevated NLR (HR 3.837, p < 0.001; HR 2.467, p = 0.006) were independent predictors of shorter PFS and OS. In conclusion, pre-treatment inflammatory indexes, especially NLR were potential biomarkers to predict the survival of mCRC patients with cetuximab therapy.

Arctigenin Inhibits Lung Metastasis of Colorectal Cancer by Regulating Cell Viability and Metastatic Phenotypes.

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Han, Yo-Han; Kee, Ji-Ye; Kim, Dae-Seung; Mun, Jeong-Geon; Jeong, Mi-Young; Park, Sang-Hyun; Choi, Byung-Min; Park, Sung-Joo; Kim, Hyun-Jung; Um, Jae-Young; Hong, Seung-Heon

2016-08-27

Arctigenin (ARC) has been shown to have an anti-cancer effect in various cell types and tissues. However, there have been no studies concerning metastatic colorectal cancer (CRC). In this study, we investigated the anti-metastatic properties of ARC on colorectal metastasis and present a potential candidate drug. ARC induced cell cycle arrest and apoptosis in CT26 cells through the intrinsic apoptotic pathway via MAPKs signaling. In several metastatic phenotypes, ARC controlled epithelial-mesenchymal transition (EMT) through increasing the expression of epithelial marker E-cadherin and decreasing the expressions of mesenchymal markers; N-cadherin, vimentin, β-catenin, and Snail. Moreover, ARC inhibited migration and invasion through reducing of matrix metalloproteinase-2 (MMP-2) and MMP-9 expressions. In an experimental metastasis model, ARC significantly inhibited lung metastasis of CT26 cells. Taken together, our study demonstrates the inhibitory effects of ARC on colorectal metastasis.

Arctigenin Inhibits Lung Metastasis of Colorectal Cancer by Regulating Cell Viability and Metastatic Phenotypes

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Yo-Han Han

2016-08-01

Full Text Available Arctigenin (ARC has been shown to have an anti-cancer effect in various cell types and tissues. However, there have been no studies concerning metastatic colorectal cancer (CRC. In this study, we investigated the anti-metastatic properties of ARC on colorectal metastasis and present a potential candidate drug. ARC induced cell cycle arrest and apoptosis in CT26 cells through the intrinsic apoptotic pathway via MAPKs signaling. In several metastatic phenotypes, ARC controlled epithelial-mesenchymal transition (EMT through increasing the expression of epithelial marker E-cadherin and decreasing the expressions of mesenchymal markers; N-cadherin, vimentin, β-catenin, and Snail. Moreover, ARC inhibited migration and invasion through reducing of matrix metalloproteinase-2 (MMP-2 and MMP-9 expressions. In an experimental metastasis model, ARC significantly inhibited lung metastasis of CT26 cells. Taken together, our study demonstrates the inhibitory effects of ARC on colorectal metastasis.

Targeting metastatic colorectal cancer – present and emerging treatment options

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Ciombor KK

2014-07-01

Full Text Available Kristen K Ciombor,1 Jordan Berlin21Division of Medical Oncology, Department of Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA; 2Division of Hematology/Oncology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, TN, USAAbstract: Metastatic colorectal cancer is a significant cause of morbidity and mortality in the US and around the world. While several novel cytotoxic and biologic therapies have been developed and proven efficacious in the past two decades, their optimal use in terms of patient selection, drug combinations, and regimen sequences has yet to be defined. Recent investigations regarding anti-epidermal growth factor receptor therapies include the comparison of single-agent panitumumab and cetuximab, the benefit of adding cetuximab to chemotherapy in the conversion therapy setting, the comparison of cetuximab and bevacizumab when added to first-line chemotherapy, and predictive biomarkers beyond KRAS exon 2 (codons 12 and 13 mutations. With respect to anti-vascular endothelial growth factor therapies, new data on continuing bevacizumab beyond disease progression on a bevacizumab-containing chemotherapy regimen, the addition of bevacizumab to triplet chemotherapy in the first-line setting, maintenance therapy with bevacizumab plus either capecitabine or erlotinib, the addition of aflibercept to chemotherapy, and regorafenib as monotherapy have emerged. Recent scientific and technologic advances in the field of metastatic colorectal cancer promise to elucidate the biological underpinnings of this disease and its therapies for the goal of improving personalized treatments for patients with metastatic colorectal cancer.Keywords: cetuximab, panitumumab, bevacizumab, aflibercept, regorafenib, biomarker

CLINICAL CASE OF A MASSIVE ISOLA TED METASTATIC ADRENAL LESION IN COLORECT AL CANCER

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I. P. Moshurov

2015-01-01

Full Text Available AbstractThe liver, lungs, parietal and visceral peritoneum have traditionally been considered to be the main target organs of metastatic colorectal cancer. The isolated adrenal metastasis in colorectal cancer is rare, in the literature there are single observations of clinical cases of successful surgical treatment of such patients. This article presents the clinical observation of successful surgical treatment of patients with colorectal cancer with massive isolated adrenal metastases.

Monoclonal antibodies in the treatment of metastatic colorectal cancer: a review

NARCIS (Netherlands)

Tol, Jolien; Punt, Cornelis J. A.

2010-01-01

Two groups of agents targeting either the vascular endothelial growth factor (VEGF) receptor or the epidermal growth factor receptor (EGFR) have been added to the therapeutic arsenal against metastatic colorectal cancer (mCRC). Currently available agents in these groups are the anti-VEGF antibody

Monoclonal antibodies in the treatment of metastatic colorectal cancer: a review.

NARCIS (Netherlands)

Tol, J.; Punt, C.J.A.

2010-01-01

BACKGROUND: Two groups of agents targeting either the vascular endothelial growth factor (VEGF) receptor or the epidermal growth factor receptor (EGFR) have been added to the therapeutic arsenal against metastatic colorectal cancer (mCRC). Currently available agents in these groups are the anti-VEGF

Correlation of bevacizumab-induced hypertension and outcomes of metastatic colorectal cancer patients treated with bevacizumab: a systematic review and meta-analysis.

Science.gov (United States)

Cai, Jun; Ma, Hong; Huang, Fang; Zhu, Dichao; Bi, Jianping; Ke, Yang; Zhang, Tao

2013-11-28

With the wide application of targeted drug therapies, the relevance of prognostic and predictive markers in patient selection has become increasingly important. Bevacizumab is commonly used in combination with chemotherapy in the treatment of metastatic colorectal cancer. However, there are currently no predictive or prognostic biomarkers for bevacizumab. Several clinical studies have evaluated bevacizumab-induced hypertension in patients with metastatic colorectal cancer. This meta-analysis was performed to better determine the association of bevacizumab-induced hypertension with outcome in patients with metastatic colorectal cancer, and to assess whether bevacizumab-induced hypertension can be used as a prognostic factor in these patients. We performed a systematic review and meta-analysis on seven published studies to investigate the relationship between hypertension and outcome of patients with metastatic colorectal cancer treated with bevacizumab. Our primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS) and overall response rate (ORR). Hazard ratios (HRs) for PFS and OS were extracted from each trial, and the log of the relative risk ratio (RR) was estimated for ORR. The occurrence of bevacizumab-induced hypertension in patients was highly associated with improvements in PFS (HR = 0.57, 95% CI: 0.46-0.72; P hypertension. Bevacizumab-induced hypertension may represent a prognostic factor in patients with metastatic colorectal cancer.

Role of capecitabine in treating metastatic colorectal cancer in Chinese patients

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Wang F

2014-04-01

Full Text Available Feng Wang,* Feng-Hua Wang,* Long Bai, Rui-Hua XuDepartment of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China *These authors contributed equally to this workAbstract: The China Food and Drug Administration approved the use of capecitabine in patients with metastatic colorectal cancer (mCRC in 2004. This paper reviews the available information of capecitabine in Chinese patients with mCRC, focusing on its effectiveness and safety against mCRC. Identification of all eligible studies was made by searching the PubMed and Wanfang database from 2000 to 2013. Published data examining various aspects of clinical response and tolerability with capecitabine alone or in combination with other chemotherapeutic or biological agents for first- and second-line mCRC were examined. Capecitabine and its combination displayed high efficacy in Chinese patients with mCRC. Toxicities are generally manageable, and elderly patients can tolerate capecitabine well.Keywords: capecitabine, metastatic colorectal cancer, Chinese

Cell-Free DNA in Metastatic Colorectal Cancer

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Spindler, Karen-Lise G.; Boysen, Anders K.; Pallisgard, Niels

2017-01-01

-analysis of the prognostic value of total cfDNA in patients with metastatic colorectal cancer (mCRC) treated with chemotherapy. In addition, we report on the overall performance of cfDNA as source for KRAS mutation detection. MATERIALS AND METHODS: A systematic literature search of PubMed and Embase was performed by two......BACKGROUND: Circulating DNA can be detected and quantified in the blood of cancer patients and used for detection of tumor-specific genetic alterations. The clinical utility has been intensively investigated for the past 10 years. The majority of reports focus on analyzing the clinical potential...

Metastatic Colorectal Cancer in Young Adults: A Study From the South Australian Population-Based Registry.

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Vatandoust, Sina; Price, Timothy J; Ullah, Shahid; Roy, Amitesh C; Beeke, Carole; Young, Joanne P; Townsend, Amanda; Padbury, Robert; Roder, David; Karapetis, Christos S

2016-03-01

Colorectal cancer (CRC) is a common malignancy. There is growing evidence that CRC incidence is increasing in the younger population. There is controversy surrounding the prognosis of young patients with CRC. In this study we reviewed Australian patients with metastatic CRC (mCRC) who were younger than 40 years of age at the time of diagnosis of metastatic disease. To our knowledge this is the first study to focus on this age group with mCRC. This was a retrospective study using data from the South Australian Metastatic Colorectal Cancer database. We compared patient and disease characteristics, management approaches, and outcomes for age groups Young-onset mCRC patients, when defined as aged younger than 40 years, have equivalent survival compared with their older counterparts. This is despite differences in disease characteristics and management approach between the 2 groups. Copyright © 2016 Elsevier Inc. All rights reserved.

Molecularly targeted drugs for metastatic colorectal cancer

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Cheng YD

2013-11-01

Full Text Available Ying-dong Cheng, Hua Yang, Guo-qing Chen, Zhi-cao Zhang Department of General Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, People's Republic of China Abstract: The survival rate of patients with metastatic colorectal cancer (mCRC has significantly improved with applications of molecularly targeted drugs, such as bevacizumab, and led to a substantial improvement in the overall survival rate. These drugs are capable of specifically targeting the inherent abnormal pathways in cancer cells, which are potentially less toxic than traditional nonselective chemotherapeutics. In this review, the recent clinical information about molecularly targeted therapy for mCRC is summarized, with specific focus on several of the US Food and Drug Administration-approved molecularly targeted drugs for the treatment of mCRC in the clinic. Progression-free and overall survival in patients with mCRC was improved greatly by the addition of bevacizumab and/or cetuximab to standard chemotherapy, in either first- or second-line treatment. Aflibercept has been used in combination with folinic acid (leucovorin–fluorouracil–irinotecan (FOLFIRI chemotherapy in mCRC patients and among patients with mCRC with wild-type KRAS, the outcomes were significantly improved by panitumumab in combination with folinic acid (leucovorin–fluorouracil–oxaliplatin (FOLFOX or FOLFIRI. Because of the new preliminary studies, it has been recommended that regorafenib be used with FOLFOX or FOLFIRI as first- or second-line treatment of mCRC chemotherapy. In summary, an era of new opportunities has been opened for treatment of mCRC and/or other malignancies, resulting from the discovery of new selective targeting drugs. Keywords: metastatic colorectal cancer (mCRC, antiangiogenic drug, bevacizumab, aflibercept, regorafenib, cetuximab, panitumumab, clinical trial, molecularly targeted therapy

Clinical implementation of KRAS testing in metastatic colorectal carcinoma: the pathologist's perspective.

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Ross, Jeffrey S

2012-10-01

Mutation status of the KRAS gene identifies a distinct disease subtype of metastatic colorectal carcinoma that does not respond to antibody therapeutics targeting the epidermal growth factor receptor. This is currently the only validated marker in metastatic colorectal carcinoma with a clear implication in treatment selection. KRAS testing is widely accepted in clinical practice to guide metastatic colorectal carcinoma therapeutic decisions, and there are many commercially available platforms to perform the test. To evaluate the critical role of pathologists in the full implementation of KRAS testing by optimizing tumor tissue collection and fixation procedures and by choosing testing technologies and reliable Clinical Laboratory Improvement Amendments of 1988-certified laboratories to perform the tests. Prospective clinical trials, retrospective studies, and quality assessment and survey reports were identified in the following databases: PubMed, American Society of Clinical Oncology Proceedings (American Society of Clinical Oncology Annual Meeting and Gastrointestinal Cancer Symposium) and European Society for Medical Oncology Proceedings (Annals of Oncology European Society for Medical Oncology Congress and Annals of Oncology World Congress on Gastrointestinal Cancers). More bona fide standards are needed to address the variety of available test methods, which have different performance characteristics including speed, sensitivity to detect rare mutations, and technical requirements. Refined standards addressing timing of KRAS testing, laboratory performance and accuracy, quality assurance and control, proper tissue collection, and appropriate result reporting would also be greatly beneficial. Pathologists should be aware that the amount of information they need to manage will increase, because future trends and technological advances will enhance the predictive power of diagnostic tests or the scope of the biomarker panels tested routinely across tumor types.

Hope, optimism and survival in a randomised trial of chemotherapy for metastatic colorectal cancer.

Science.gov (United States)

Schofield, Penelope E; Stockler, M R; Zannino, D; Tebbutt, N C; Price, T J; Simes, R J; Wong, N; Pavlakis, N; Ransom, D; Moylan, E; Underhill, C; Wyld, D; Burns, I; Ward, R; Wilcken, N; Jefford, M

2016-01-01

Psychological responses to cancer are widely believed to affect survival. We investigated associations between hope, optimism, anxiety, depression, health utility and survival in patients starting first-line chemotherapy for metastatic colorectal cancer. Four hundred twenty-nine subjects with metastatic colorectal cancer in a randomised controlled trial of chemotherapy completed baseline questionnaires assessing the following: hopefulness, optimism, anxiety and depression and health utility. Hazard ratios (HRs) and P values were calculated with Cox models for overall survival (OS) and progression-free survival (PFS) in univariable and multivariable analyses. Median follow-up was 31 months. Univariable analyses showed that OS was associated negatively with depression (HR 2.04, P optimism, anxiety or hopefulness. PFS was not associated with hope, optimism, anxiety or depression in any analyses. Depression and health utility, but not optimism, hope or anxiety, were associated with survival after controlling for known prognostic factors in patients with advanced colorectal cancer. Further research is required to understand the nature of the relationship between depression and survival. If a causal mechanism is identified, this may lead to interventional possibilities.

Critical appraisal of the use of regorafenib in the management of colorectal cancer

International Nuclear Information System (INIS)

Festino, Lucia; Fabozzi, Alessio; Manzo, Anna; Gambardella, Valentina; Martinelli, Erika; Troiani, Teresa; De Vita, Ferdinando; Orditura, Michele; Ciardiello, Fortunato; Morgillo, Floriana

2013-01-01

The lack of valid clinical management options for patients affected by metastatic colorectal cancer, which has progressed after all approved standard treatments, has lead to research into new active molecules. Regorafenib is an oral small-molecule multi kinase inhibitor, binding to several intracellular kinases, with powerful inhibitory activity against vascular endothelial growth factor receptors (VEGFR-1,VEGFR-2, and VEGFR-3), platelet-derived growth factor receptor, fibroblast growth factor receptor 1, Raf, TIE-2, and the kinases KIT, RET, and BRAF. The antitumor activity of regorafenib has been tested in vitro and in vivo, and inhibition of tumor growth has been observed in several cancer models, particularly colorectal cancer and gastrointestinal stromal tumors. The most frequent adverse events of grade 3 or higher related to regorafenib were hand-foot skin reaction, fatigue, diarrhea, hypertension, and rash or desquamation. Only a few Phase I–II trials, and most recently a Phase III trial in pretreated colorectal cancer, have been carried out to date. Several ongoing trials are testing the efficacy of regorafenib in combination with chemotherapy. At this point in time, regorafenib is the first small-molecule tyrosine kinase inhibitor to gain approval by the US Food and Drug Administration for pretreated metastatic colorectal cancer patients

Treatment of metastatic colorectal cancer: focus on panitumumab

International Nuclear Information System (INIS)

Tay, Rebecca Y; Wong, Rachel; Hawkes, Eliza A

2015-01-01

Targeted agents are an important therapeutic option in the treatment of metastatic colorectal cancer (mCRC). Panitumumab is a recombinant, fully humanized, immunoglobulin G2 monoclonal antibody that targets the epidermal growth factor receptor (EGFR) with efficacy in mCRC as monotherapy and in combination with chemotherapy. Kirsten rat sarcoma (KRAS) mutation status has emerged as an important biomarker to predict response to anti-EGFR therapy. Optimal timing for panitumumab use in the mCRC treatment algorithm has not been established. This review discusses the mechanism of action, predictive biomarkers, and role of panitumumab in the treatment of mCRC

Adverse prognostic impact of the CpG island methylator phenotype in metastatic colorectal cancer.

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Cha, Yongjun; Kim, Kyung-Ju; Han, Sae-Won; Rhee, Ye Young; Bae, Jeong Mo; Wen, Xianyu; Cho, Nam-Yun; Lee, Dae-Won; Lee, Kyung-Hun; Kim, Tae-Yong; Oh, Do-Youn; Im, Seock-Ah; Bang, Yung-Jue; Jeong, Seung-Yong; Park, Kyu Joo; Kang, Gyeong Hoon; Kim, Tae-You

2016-07-12

The association between the CpG island methylator phenotype (CIMP) and clinical outcomes in metastatic colorectal cancer remains unclear. We investigated the prognostic impact of CIMP in patients with metastatic colorectal cancer treated with systemic chemotherapy. Eight CIMP-specific promoters (CACNA1G, IGF2, NEUROG1, RUNX3, SOCS1, CDKN2A, CRABP1, and MLH1) were examined. The CIMP status was determined by the number of methylated promoters as high (⩾5), low (1-4), and negative (0). A total of 153 patients were included (men/women, 103/50; median age, 61 years; range, 22-80 years). The CIMP status was negative/low/high in 77/ 69/7 patients, respectively. Overall survival (OS) was significantly different among the three CIMP groups, with median values of 35.7, 22.2, and 9.77 months for the negative, low, and high groups, respectively (PCIMP groups; the median OS was 37.9, 23.8, and 6.77 months for the negative, low, and high groups, respectively (PCIMP groups (53.4% vs 45.1% vs 16.7%, respectively; P=0.107). For patients treated with fluoropyrimidine and irinotecan second-line chemotherapy (N=86), only OS showed a difference according to the CIMP status, with median values of 20.4, 13.4, and 2.90 months for the negative, low, and high groups, respectively (PCIMP status is a negative prognostic factor for patients with metastatic colorectal cancer treated with chemotherapy.

Durable response using regorafenib in an elderly patient with metastatic colorectal cancer: case report

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Tang R

2015-11-01

Full Text Available Ronald Tang,1 Tatiana Kain,2 June Herman,2 Tara Seery1 1Division of Hematology-Oncology, 2Division of Nuclear Medicine and Molecular Imaging, University of California, Irvine, Orange, CA, USA Abstract: Regorafenib, an oral multikinase inhibitor, was approved in September 2012 by the US Food and Drug Administration for the treatment of patients with metastatic colorectal cancer. Since this time, however, few case reports outlining real-world usage have been published in the literature. Here, we detail the clinical history of an elderly woman with KRAS wild-type colon cancer who received regorafenib after prior treatment with other agents. We show that by employing dose modification strategies to address adverse events, this patient was able to remain on therapy for 11 months and achieve stable disease. Keywords: regorafenib, metastatic colorectal cancer, oral multikinase inhibitor

Bevacizumab increases the incidence of cardiovascular events in patients with metastatic breast or colorectal cancer

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Ioannis Kapelakis

2017-05-01

Conclusions: The addition of bevacizumab to conventional chemotherapy for metastatic breast or colorectal cancer increases the incidence of cardiovascular events, which is mainly due to the increased prevalence of myocardial infarction and thromboembolic events.

miR-345 in metastatic colorectal cancer: a non-invasive biomarker for clinical outcome in non-KRAS mutant patients treated with 3rd line cetuximab and irinotecan

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Schou, Jakob V; Rossi, Simona; Jensen, Benny V

2014-01-01

for overall survival (OS) in patients with metastatic colorectal cancer (mCRC) treated with cetuximab and irinotecan. METHODS: From 138 patients with mCRC in 3rd line therapy with cetuximab and irinotecan in a prospective phase II study, 738 pretreatment miRNAs were isolated and profiled from whole blood...... to treatment with cetuximab and irinotecan. CONCLUSION: We identified miR-345 in whole blood as a potential biomarker for clinical outcome. MiR-345 was a single prognostic biomarker for both OS and PFS in all patients and also in the non-KRAS mutant population....

TIMP-1 and CEA as biomarkers in third-line treatment with irinotecan and cetuximab for metastatic colorectal cancer

DEFF Research Database (Denmark)

Spindler, Karen-Lise Garm; Christensen, Ib Jarle; Nielsen, Hans Jørgen

2015-01-01

in colorectal cancer (CRC). The aim of the present study was to investigate the clinical value of TIMP-1 in patients with metastatic colorectal cancer (mCRC) treated with cetuximab and irinotecan. Patients with chemotherapy-resistant mCRC referred to third-line treatment with cetuximab (initial 400 mg/m(2...

A Systematic Review and Meta-analysis of Retrospective Series of Regorafenib for Treatment of Metastatic Colorectal Cancer.

Science.gov (United States)

Mercier, Joey; Voutsadakis, Ioannis A

2017-11-01

Metastatic colorectal cancer is a common disease encountered in oncology practice and treatment options beyond fluoropyrimidines, irinotecan, oxaliplatin and monoclonal antibodies against epidermal growth factor receptor and vascular endothelium growth factor (VEGF) are limited. Regorafenib, a new drug that targets tyrosine kinases such as VEGF receptor as well as others, has been added recently to the armamentarium for metastatic colorectal cancer. This report analyzes the published experience with this drug in clinical practice outside of clinical trials. A literature search of major databases was performed for the identification of studies of regorafenib in metastatic colorectal cancer. Studies retained for further analysis were in English or French, describing 20 or more patients treated with regorafenib monotherapy and not part of a phase I, II or III trial. Results of the pooled analysis of retrospective studies were compared with results of the published phase III trials and a phase IIIb prospective study. Twelve publications including a total of 702 patients were included in the meta-analysis. Summary response rate was 2% [95% confidence interval (CI) =0.8-3.2%] and the disease control rate 38.14% (95% CI=32.35-43.93%). Summary survival rates were 3.34 months (95% CI=2.71-3.97 months) for progression-free and 7.27 months (95% CI=6.23-8.3 months) for overall survival. These were similar to the phase III and IIIb studies. Most common adverse effects were also consistent with those of the published phase III experience. This systematic review and meta-analysis confirmed a moderate efficacy of regorafenib in later-stage metastatic colorectal cancer in the everyday clinical practice setting outside of clinical trials. Future identification of biomarkers may aid in further tailoring of this treatment in order to obtain maximum clinical benefit. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Cell-Free DNA in Metastatic Colorectal Cancer: A Systematic Review and Meta-Analysis.

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Spindler, Karen-Lise G; Boysen, Anders K; Pallisgård, Niels; Johansen, Julia S; Tabernero, Josep; Sørensen, Morten M; Jensen, Benny V; Hansen, Torben F; Sefrioui, David; Andersen, Rikke F; Brandslund, Ivan; Jakobsen, Anders

2017-09-01

systemic therapy. Small fragments of circulating cell-free DNA (cfDNA) can be measured in a simple blood sample. This report presents the first meta-analysis of the prognostic value of total cfDNA measurement in patients with metastatic colorectal cancer. Data from 1,076 patients confirmed that patients with the lowest pre-treatment levels of cfDNA had a significantly higher chance of longer survival than those with higher levels. Cell-free DNA analysis can also be used for detection of tumor-specific mutations, and hold potential as a valuable tool in colorectal cancer treatment. © AlphaMed Press 2017.

Cetuximab in the management of colorectal cancer

OpenAIRE

Lenz, Heinz-Josef

2007-01-01

Cetuximab, a chimeric IgG1 monoclonal antibody that targets the ligand-binding domain of the epidermal growth factor receptor (EGFR), is active in metastatic colorectal cancer (mCRC). As an IgG1 antibody, cetuximab may exert its antitumor efficacy through both EGFR antagonism and antibody-dependent cell-mediated cytotoxicity. Clinical trials established the role of cetuximab, particularly with irinotecan, in irinotecan-refractory/heavily pretreated patients. More recent studies show promising...

A Comparison of Regorafenib and TAS-102 for Metastatic Colorectal Cancer: A Systematic Review and Network Meta-analysis.

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Abrahao, Ana B K; Ko, Yoo-Joung; Berry, Scott; Chan, Kelvin K W

2017-11-21

Regorafenib and TAS-102 have shown to be superior to placebo in refractory metastatic colorectal cancer. However, no studies have directly compared both drugs. Giving the lack of standard options in this scenario, a systematic review to compare the efficacy and safety of regorafenib and TAS-102 was performed. A systematic review using the PubMed, Medline, Embase, Scopus, and Cochrane databases to identify published and unpublished studies up to November 2015 for randomized controlled trials for patients with metastatic colorectal cancer, involving regorafenib or TAS-102, was performed. Data including overall survival, progression-free survival, and toxicity were extracted. Pairwise direct meta-analyses (regorafenib vs. placebo and TAS-102 vs. placebo) and indirect comparison (regorafenib vs. TAS-102) using network meta-analyses methods to preserve randomization were performed using random effects. Three randomized controlled trials fulfilled eligibility criteria (regorafenib monotherapy for previously treated metastatic colorectal cancer [CORRECT]: an international, multicentre, randomised, pacebo-controlled, phase 3 trial, regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer [CONCUR]: a randomised, double-blind, placebo-controlled, phase 3 trial, and randomized trial of TAS-102 for refractory metastatic colorectal cancer [RECOURSE] trials) involving 1764 patients (regorafenib, 641; TAS-102, 534; placebo, 589). Subgroups of patients (1659) who had not received prior regorafenib or TAS-102 were used to perform meta-analyses for efficacy. In the indirect comparison, no statistically significant differences were observed between regorafenib and TAS-102 in overall survival (hazard ratio, 0.96; 95% confidence interval [CI], 0.57-1.66; P = .91) or progression-free survival (hazard ratio, 0.85; 95% CI, 0.40-1.81; P = .67). However, regorafenib has statistically more all

Multicenter retrospective analysis of metastatic colorectal cancer (CRC) with high-level microsatellite instability (MSI-H).

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Goldstein, J; Tran, B; Ensor, J; Gibbs, P; Wong, H L; Wong, S F; Vilar, E; Tie, J; Broaddus, R; Kopetz, S; Desai, J; Overman, M J

2014-05-01

The microsatellite instability-high (MSI-H) phenotype, present in 15% of early colorectal cancer (CRC), confers good prognosis. MSI-H metastatic CRC is rare and its impact on outcomes is unknown. We describe survival outcomes and the impact of chemotherapy, metastatectomy, and BRAF V600E mutation status in the largest reported cohort of MSI-H metastatic colorectal cancer (CRC). A retrospective review of 55 MSI-H metastatic CRC patients from two institutions, Royal Melbourne Hospital (Australia) and The University of Texas MD Anderson Cancer Center (United States), was conducted. Statistical analyses utilized Kaplan-Meier method, Log-rank test, and Cox proportional hazards models. Median age was 67 years (20-90), 58% had poor differentiation, and 45% had stage IV disease at presentation. Median overall survival (OS) from metastatic disease was 15.4 months. Thirteen patients underwent R0/R1 metastatectomies, with median OS from metastatectomy 33.8 months. Thirty-one patients received first-line systemic chemotherapy for metastatic disease with median OS from the start of chemotherapy 11.5 months. No statistically significant difference in progression-free survival or OS was seen between fluoropyrimidine, oxaliplatin, or irinotecan based chemotherapy. BRAF V600E mutation was present in 14 of 47 patients (30%). BRAF V600E patients demonstrated significantly worse median OS; 10.1 versus 17.3 months, P = 0.03. In multivariate analyses, BRAF V600E mutants had worse OS (HR 4.04; P = 0.005), while patients undergoing metastatectomy (HR 0.11; P = CRC do not appear to have improved outcomes. BRAF V600E mutation is a poor prognostic factor in MSI-H metastatic CRC.

Palliative radiotherapy in patients with a symptomatic pelvic mass of metastatic colorectal cancer

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Chun Ho Kyung

2011-05-01

Full Text Available Abstract Background To evaluate the palliative role of radiotherapy (RT and define the effectiveness of chemotherapy combined with palliative RT (CCRT in patients with a symptomatic pelvic mass of metastatic colorectal cancer. Methods From August 1995 to December 2007, 80 patients with a symptomatic pelvic mass of metastatic colorectal cancer were treated with palliative RT at Samsung Medical Center. Initial presenting symptoms were pain (68 cases, bleeding (18 cases, and obstruction (nine cases. The pelvic mass originated from rectal cancer in 58 patients (73% and from colon cancer in 22 patients (27%. Initially 72 patients (90% were treated with surgery, including 64 complete local excisions; 77% in colon cancer and 81% in rectal cancer. The total RT dose ranged 8-60 Gy (median: 36 Gy with 1.8-8 Gy per fraction. When the α/β for the tumor was assumed to be 10 Gy for the biologically equivalent dose (BED, the median RT dose was 46.8 Gy10 (14.4-78. Twenty one patients (26% were treated with CCRT. Symptom palliation was assessed one month after the completion of RT. Results Symptom palliation was achieved in 80% of the cases. During the median follow-up period of five months (1-44 months, 45% of the cases experienced reappearance of symptoms; the median symptom control duration was five months. Median survival after RT was six months. On univariate analysis, the only significant prognostic factor for symptom control duration was BED ≥40 Gy10 (p Conclusions RT was an effective palliation method in patients with a symptomatic pelvic mass of metastatic colorectal cancer. For improvement of symptom control rate and duration, a BED ≥ 40 Gy10 is recommended when possible. Considering the low morbidity and improved symptom palliation, CCRT might be considered in patients with good performance status.

STUDY ON ADHERENCE TO CAPECITABINE AMONG PATIENTS WITH COLORECTAL CANCER AND METASTATIC BREAST CANCER

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Adiel Goes de FIGUEIREDO JUNIOR

2014-09-01

Full Text Available Context Capecitabine, an oral drug, is as effective as traditional chemotherapy drugs. Objectives To investigate the adhesion to treatment with oral capecitabine in breast and colorectal cancer, and to determine any correlation with changes in patient’s quality of life. Methods Patients with colorectal cancer or breast cancer using capecitabine were included. The patients were asked to bring any medication left at the time of scheduled visits. The QLQ-C30 questionnaire was applied at the first visit and 8-12 weeks after treatment. Results Thirty patients were evaluated. Adherence was 88.3% for metastatic colon cancer, 90.4% for non-metastatic colon cancer, 94.3% for rectal cancer and 96.2% for metastatic breast cancer. No strong correlation between adherence and European Organisation for Research and Treatment of Cancer QLQ-C30 functional or symptom scale rates had been found. There was no statistically significant correlation between compliance and the functional and symptom scales of the questionnaire before and after chemotherapy, with the exception of dyspnea. Conclusions Although no absolute adherence to oral capecitabine treatment had been observed, the level of adherence was good. Health professionals therefore need a greater focus in the monitoring the involvement of patients with oral treatment regimens. Patients with lesser degrees of dyspnea had greater compliance.

Molecular Events in Primary and Metastatic Colorectal Carcinoma: A Review

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Rani Kanthan

2012-01-01

Full Text Available Colorectal cancer (CRC is a heterogeneous disease, developing through a multipathway sequence of events guided by clonal selections. Pathways included in the development of CRC may be broadly categorized into (a genomic instability, including chromosomal instability (CIN, microsatellite instability (MSI, and CpG island methylator phenotype (CIMP, (b genomic mutations including suppression of tumour suppressor genes and activation of tumour oncogenes, (c microRNA, and (d epigenetic changes. As cancer becomes more advanced, invasion and metastases are facilitated through the epithelial-mesenchymal transition (EMT, with additional genetic alterations. Despite ongoing identification of genetic and epigenetic markers and the understanding of alternative pathways involved in the development and progression of this disease, CRC remains the second highest cause of malignancy-related mortality in Canada. The molecular events that underlie the tumorigenesis of primary and metastatic colorectal carcinoma are detailed in this manuscript.

Regorafenib with a fluoropyrimidine for metastatic colorectal cancer after progression on multiple 5-FU-containing combination therapies and regorafenib monotherapy.

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Marks, Eric I; Tan, Carlyn; Zhang, Jun; Zhou, Lanlan; Yang, Zhaohai; Scicchitano, Angelique; El-Deiry, Wafik S

2015-01-01

We present 2 patients with metastatic colorectal cancer who had progressed despite treatment with first-line FOLFOX and second-line FOLFIRI combination chemotherapy regimens. After failing these fluoropyrimidine-based regimens, both patients received additional cytotoxic and targeted therapies with eventual disease progression. These therapies included capecitabine plus dabrafenib and trametinib, regorafenib monotherapy, and regorafenib with panitumumab. After exhausting available options, both patients were offered regorafenib with either 5-fluorouracil (5-FU) or capecitabine. These therapies are individually approved for the treatment of colorectal cancer but have not yet been studied in combination. This regimen produced stable disease in both patients with acceptable toxicity. One patient continued therapy for 17 months. Although these patients previously progressed during treatment with regorafenib, capecitabine or 5-FU, the combination had some activity in both cases of refractory metastatic colorectal cancer and may be considered in the palliative setting. In bedside-to-bench cell culture experiments performed after the clinical observations, we observed sensitivity of human colorectal cancer cell lines (N = 4) to single agent regorafenib or 5-FU and evidence of synergy with the combination therapy. Synergistic effects were noted in colorectal cancer cells with KRAS mutation, BRAF mutation, and p53 mutation, as well as mismatch repair deficient cells. Regorafenib suppressed Mcl-1 and Bcl-XL in treated cancer cells that may have contributed to the anticancer efficacy including in combination with 5-FU. The safety and efficacy of regorafenib with 5-FU or capecitabine in combination should be further investigated as a therapy for patients with refractory metastatic colorectal cancer, including individuals who had progressed on regorafenib monotherapy.

Virilisation during Pregnancy in a Patient with Metastatic Colorectal Cancer

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F. Conway

2012-01-01

Full Text Available This paper describes the case of a 25-year-old woman with virilisation occurring during pregnancy in the presence of metastatic colorectal cancer. Virilisation during pregnancy is rare. The potential causes include adrenal, foetal, or ovarian pathologies. The most common causes during pregnancy are pregnancy luteoma and hyperreactio luteinalis. The incidence of cancer during pregnancy is rare and the incidence of colorectal cancer (CRC in pregnancy is even rarer. The presenting signs and symptoms of CRC can be confused with symptoms commonly encountered during pregnancy, thereby delaying diagnosis and commencement of treatment. Diagnosis and staging also proves more problematic in the pregnant patient as the usual modalities of colonoscopy with biopsy and imaging with CT are relatively contraindicated. Treatment is dependent on gestational age of the foetus. There is currently no agreed best practice as to the role of prophylactic oophorectomy in the prevention of metachronous ovarian metastases. Surgical and adjuvant treatments have implications for females of child-bearing age.

Cetuximab in treatment of metastatic colorectal cancer

DEFF Research Database (Denmark)

Guren, Tormod Kyrre; Thomsen, Maria Morandi; Kure, Elin H

2017-01-01

BACKGROUND: The NORDIC-VII study is a randomised phase III trial of cetuximab plus continuous or intermittent fluorouracil, folinic acid, and oxaliplatin (Nordic FLOX) vs FLOX alone in first-line treatment of metastatic colorectal cancer. The present report presents an updated and final survival...... population). RAS was mutated in 46% and BRAF in 12% of the tumours. RAS and BRAF, if mutated, were negative prognostic factors. The updated analyses confirmed the finding of the primary report that cetuximab did not provide any additional benefit when added to FLOX in patients with RAS/BRAF wild-type tumours......, neither on progression-free nor overall survival. However, the outcomes in a subset of patients, which, after the first eight treatment cycles, received cetuximab alone, suggested a beneficial effect of cetuximab monotherapy. CONCLUSIONS: Adding cetuximab to Nordic FLOX did not provide any clinical...

Emerging combination therapies for metastatic colorectal cancer – impact of trifluridine/tipiracil

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Puthiamadathil JM

2017-10-01

Full Text Available Jeevan M Puthiamadathil,1 Benjamin A Weinberg1,2 1Department of Medicine, 2Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA Abstract: Patients with metastatic colorectal cancer (mCRC are surviving longer now than ever before, but mortality rates are still high and more effective therapies are clearly needed. For patients with disease that is refractory to fluoropyrimidines, oxaliplatin, irinotecan, and biologic agents targeting the vascular endothelial growth factor and epidermal growth factor receptor pathways, novel treatment options trifluridine/tipiracil (TAS-102 and regorafenib can be effective disease stabilizers. However, objective clinical responses are rare and toxicities are manageable but common. In order to tackle poor clinical responses to TAS-102, there is an ongoing effort to effectively combine this drug with other agents, particularly those targeting angiogenesis. Certain subpopulations appear to benefit more than others from TAS-102; those that benefit often have underlying genetic defects in DNA repair pathways and/or develop neutropenia. In this review, we focus on the role of TAS-102 in the treatment of mCRC, including its use in combination with other agents, potential predictive biomarkers of response to TAS-102, and possible future directions. Keywords: metastatic colorectal cancer, trifluridine, tipiracil, TAS-102, regorafenib

The predictive value of KRAS, NRAS, BRAF, PIK3CA and PTEN for anti-EGFR treatment in metastatic colorectal cancer

DEFF Research Database (Denmark)

Therkildsen, Christina; Bergmann, Troels K; Henrichsen-Schnack, Tine

2014-01-01

BACKGROUND: In metastatic colorectal cancer, mutation testing for KRAS exon 2 is widely implemented to select patients with wild-type tumors for treatment with the monocloncal anti-EGFR antibodies cetuximab and panitumumab. The added predictive value of additional biomarkers in the RAS-RAF-MAPK a......BACKGROUND: In metastatic colorectal cancer, mutation testing for KRAS exon 2 is widely implemented to select patients with wild-type tumors for treatment with the monocloncal anti-EGFR antibodies cetuximab and panitumumab. The added predictive value of additional biomarkers in the RAS...

FCGR polymorphisms and cetuximab efficacy in chemorefractory metastatic colorectal cancer: an international consortium study

DEFF Research Database (Denmark)

Geva, Ravit; Vecchione, Loredana; Kalogeras, Konstantinos T

2015-01-01

OBJECTIVE: We aimed to better clarify the role of germline variants of the FCG2 receptor, FCGR2A-H131R and FCGR3A-V158F, on the therapeutic efficacy of cetuximab in metastatic colorectal cancer (mCRC). A large cohort with sufficient statistical power was assembled. DESIGN: To show a HR advantage ...

Palliative radiotherapy in patients with a symptomatic pelvic mass of metastatic colorectal cancer

International Nuclear Information System (INIS)

Bae, Sun Hyun; Yun, Seong Hyeon; Kim, Hee Cheol; Park, Won; Choi, Doo Ho; Nam, Heerim; Kang, Won Ki; Park, Young Suk; Park, Joon Oh; Chun, Ho Kyung; Lee, Woo Yong

2011-01-01

To evaluate the palliative role of radiotherapy (RT) and define the effectiveness of chemotherapy combined with palliative RT (CCRT) in patients with a symptomatic pelvic mass of metastatic colorectal cancer. From August 1995 to December 2007, 80 patients with a symptomatic pelvic mass of metastatic colorectal cancer were treated with palliative RT at Samsung Medical Center. Initial presenting symptoms were pain (68 cases), bleeding (18 cases), and obstruction (nine cases). The pelvic mass originated from rectal cancer in 58 patients (73%) and from colon cancer in 22 patients (27%). Initially 72 patients (90%) were treated with surgery, including 64 complete local excisions; 77% in colon cancer and 81% in rectal cancer. The total RT dose ranged 8-60 Gy (median: 36 Gy) with 1.8-8 Gy per fraction. When the α/β for the tumor was assumed to be 10 Gy for the biologically equivalent dose (BED), the median RT dose was 46.8 Gy 10 (14.4-78). Twenty one patients (26%) were treated with CCRT. Symptom palliation was assessed one month after the completion of RT. Symptom palliation was achieved in 80% of the cases. During the median follow-up period of five months (1-44 months), 45% of the cases experienced reappearance of symptoms; the median symptom control duration was five months. Median survival after RT was six months. On univariate analysis, the only significant prognostic factor for symptom control duration was BED ≥40 Gy 10 (p < 0.05), and CCRT was a marginally significant factor (p = 0.0644). On multivariate analysis, BED and CCRT were significant prognostic factors for symptom control duration (p < 0.05). RT was an effective palliation method in patients with a symptomatic pelvic mass of metastatic colorectal cancer. For improvement of symptom control rate and duration, a BED ≥ 40 Gy 10 is recommended when possible. Considering the low morbidity and improved symptom palliation, CCRT might be considered in patients with good performance status

Critical appraisal of the use of regorafenib in the management of colorectal cancer

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Festino L

2013-04-01

Full Text Available Lucia Festino*, Alessio Fabozzi*, Anna Manzo, Valentina Gambardella, Erika Martinelli, Teresa Troiani, Ferdinando De Vita, Michele Orditura, Fortunato Ciardiello, Floriana Morgillo Division of Medical Oncology, Department of clinical and experimental medicine and surgery "F. Magrassi e A. Lanzara", Second University of Naples, Napoli, Italy*These authors contributed equally to this work Abstract: The lack of valid clinical management options for patients affected by metastatic colorectal cancer, which has progressed after all approved standard treatments, has lead to research into new active molecules. Regorafenib is an oral small-molecule multi kinase inhibitor, binding to several intracellular kinases, with powerful inhibitory activity against vascular endothelial growth factor receptors (VEGFR-1,VEGFR-2, and VEGFR-3, platelet-derived growth factor receptor, fibroblast growth factor receptor 1, Raf, TIE-2, and the kinases KIT, RET, and BRAF. The antitumor activity of regorafenib has been tested in vitro and in vivo, and inhibition of tumor growth has been observed in several cancer models, particularly colorectal cancer and gastrointestinal stromal tumors. The most frequent adverse events of grade 3 or higher related to regorafenib were hand-foot skin reaction, fatigue, diarrhea, hypertension, and rash or desquamation. Only a few Phase I–II trials, and most recently a Phase III trial in pretreated colorectal cancer, have been carried out to date. Several ongoing trials are testing the efficacy of regorafenib in combination with chemotherapy. At this point in time, regorafenib is the first small-molecule tyrosine kinase inhibitor to gain approval by the US Food and Drug Administration for pretreated metastatic colorectal cancer patients. Keywords: colorectal cancer, angiogenesis, regorafenib

ESMO consensus guidelines for the management of patients with metastatic colorectal cancer

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Van Cutsem, E; Cervantes, A; Adam, R

2016-01-01

for and undergoing surgical resection of their localised metastatic disease but also to a more strategic approach to the delivery of systemic therapy and an expansion in the use of ablative techniques. This reflects the increase in the number of patients that are being managed within a multidisciplinary team...... based on the current available evidence to provide a series of evidence-based recommendations to assist in the treatment and management of patients with mCRC in this rapidly evolving treatment setting.......Colorectal cancer (CRC) is one of the most common malignancies in Western countries. Over the last 20 years, and the last decade in particular, the clinical outcome for patients with metastatic CRC (mCRC) has improved greatly due not only to an increase in the number of patients being referred...

Fournier gangrene as a manifestation of undiagnosed metastatic perforated colorectal cancer.

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Chan, Cyrus C; Williams, Mallory

2013-01-01

Abstract Fournier gangrene is a necrotizing soft tissue infection involving the perineum. We present a case of Fournier gangrene as the clinical presentation of perforated metastatic rectal cancer. The patient is a 78-year-old man in a nursing home who presented to our institution with necrosis and ischemia of the scrotum. After wide debridement of necrotic tissue and bilateral orchiectomy, computed tomography was carried out to investigate abnormal findings seen on his chest X-ray, which revealed multiple pulmonary metastases as well as a mass highly suspicious for a perforated rectal mass. Once stable, a diverting colostomy and biopsies of the rectal mass were performed, confirming the presence of a metastatic, poorly differentiated rectal adenocarcinoma. Albeit an unusual etiology of Fournier gangrene, this case highlights the rare but important causes of this deadly condition and teaches us to be cognizant of the variations in the presentation of colorectal cancer.

Peripheral White Blood Cell Subsets in Metastatic Colorectal Cancer Patients Treated with Cetuximab: The Potential Clinical Relevance

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Ivana Z. Matić

2018-01-01

Full Text Available It was demonstrated that cetuximab-induced tumor regression is based on the effects exerted by immune cells included mainly in the innate immune response. Therefore, the focus of this study was to explore the alterations in the percentages of CD16+, and/or CD56+ lymphocytes, which are comprised of NK cells, and minority of CD56+CD3+ cells, in patients with metastatic colorectal cancer before or 2 months after the treatment with cetuximab-based regimens associated with the response to therapy. The changes in the percentages of lymphocytes and granulocytes in these patients were evaluated as well. We enrolled 50 patients with wild-type KRAS metastatic colorectal cancer. Disease progression was observed in 11/50 patients (non-responders, while other patients achieved partial response or stable disease (responders. Control groups included up to 72 healthy individuals. A significant decrease in the percentages of CD56+ and CD16+CD56+ lymphocytes together with a significant decrease in the percentage of lymphocytes and an increase in the ratio of granulocyte to lymphocyte percentages were observed in patients with metastatic colorectal cancer before therapy, compared with those in the healthy individuals. In contrast to those in the responders, the percentage of CD16+ lymphocytes in the overall white blood cell pool was shown to be significantly decreased in the non-responders, together with a significantly decreased percentage of lymphocytes, a significantly increased percentage of granulocytes, and an increased ratio of granulocyte to lymphocyte percentages before treatment compared with those in the healthy controls. Two months after the initiation of the treatment, significantly decreased percentages of CD16+, CD56+, and CD16+CD56+ lymphocytes were observed in patients, compared with those determined in the healthy controls. The same changes in the amounts of circulating immune cells were also observed in the responder subgroup, but the

[Depression screening test for patients with metastatic gastric and colorectal cancer].

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Ina, Kenji; Sugiyama, Akemi; Yuasa, Shu; Koga, Chiaki; Yamazaki, Emiko; Katayama, Yoshiko; Nagaoka, Masatoshi; Nagao, Seiji

2010-06-01

The prevalence of depression has been reported to be higher in cancer patients, especially those of advanced stage, compared to normal controls. However, depression is often under-recognized in clinical oncology settings. And this psychological problem is not routinely assessed even in patients with inoperable metastatic cancer who often have psychological disorders. Psychological distress including depression, is affected by physical, psychosocial, and clinical factors. In order to detect psychiatric problems at the early stage, we assessed the mental conditions of 47 inpatients with metastatic gastric and colorectal cancerusing the Japanese version of Zung's Self Rating Depression Scale(SDS)and analyzed the relationships between these factors and SDS scores. While SDS scores of our patients did not differ according to their gender, age, performance status (PS), ortypes of patients' character, they were significantly higher in Group B(cancer patients with palliative care alone), compared to Group A(those receiving chemotherapy)(pterminal stage, their scores were significantly increased, respectively(pterminally ill patients without any indication of chemotherapy.

Loss of Muscle Mass During Chemotherapy Is Predictive for Poor Survival of Patients With Metastatic Colorectal Cancer

NARCIS (Netherlands)

Blauwhoff-Buskermolen, Susanne; Versteeg, Kathelijn S.; de van der Schueren, Marian A. E.; den Braver, Nicole R.; Berkhof, Johannes; Langius, Jacqueline A. E.; Verheul, Henk M. W.

2016-01-01

Low muscle mass is present in approximately 40% of patients with metastatic colorectal cancer (mCRC) and may be associated with poor outcome. We studied change in skeletal muscle during palliative chemotherapy in patients with mCRC and its association with treatment modifications and overall

Oral etoposide in heavily pre-treated metastatic breast cancer: A retrospective series.

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Giannone, G; Milani, A; Ghisoni, E; Genta, S; Mittica, G; Montemurro, F; Valabrega, G

2018-04-01

Patients with metastatic breast cancer (MBC) can derive clinical benefit from several subsequent lines of chemotherapy. However, in heavily pre-treated patients, agents with clinical activity, a favourable side effects profile and a convenient administration modality are preferred. We retrospectively analyzed 110 patients with previously treated MBC, who received oral etoposide at the dose of 50 mg/day for 20 days in 28 days cycles, between 2003 and 2017. Because this was not a prospectively planned study, to describe the clinical performance of oral etoposide we adopted the approach suggested by Dzimitrowicz and colleagues (J Clin Oncol. 2016; 34:3511-17); Tumour Response (TR) was defined as the proportion of physician-reported clinical or imaging response; Prolonged Duration on Therapy (PDT) as the proportion of non-progressing patients whose treatment lasted more than 6 months. Furthermore, we evaluated median duration on therapy (TD) and median Overall Survival (OS) by the Kaplan Meier method. The median number of previous chemotherapy lines was 5 (range 2-8). TR, PDT, median TD and median OS were 6.4%, 18.2% 4 (range 3.5-4.5) and 10.6 (range 8.4-12.8) months respectively. Interestingly, etoposide activity was unrelated to the number of previous lines and type of metastatic involvement. Oral etoposide was well tolerated with only two patients discontinuing therapy due to toxicity. In this large, single Institution, real practice analysis oral etoposide is a valuable and safe option for pre-treated metastatic breast cancer patients and might be considered in patients failing other approaches, but still suitable for chemotherapy. Copyright © 2018 Elsevier Ltd. All rights reserved.

Suppressor of cytokine signaling 1 modulates invasion and metastatic potential of colorectal cancer cells.

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David, Muriel; Naudin, Cécile; Letourneur, Martine; Polrot, Mélanie; Renoir, Jack-Michel; Lazar, Vladimir; Dessen, Philippe; Roche, Serge; Bertoglio, Jacques; Pierre, Josiane

2014-07-01

Suppressor of cytokine signaling (SOCS) 1 is an inducible negative regulator of cytokine signaling but its role in human cancer is not completely established. Here we report that, while SOCS1 is expressed in normal colonic epithelium and colon adenocarcinomas, its level decreases during progression of colon adenocarcinomas, the lowest level being found in the most aggressive stage and least differentiated carcinomas. Forced expression of SOCS1 in metastatic colorectal SW620 cells reverses many characteristics of Epithelial-Mesenchymal Transition (EMT), as highlighted by the disappearance of the transcription factor ZEB1 and the mesenchymal form of p120ctn and the re-expression of E-cadherin. Furthermore, miRNA profiling indicated that SOCS1 also up-regulates the expression of the mir-200 family of miRNAs, which can promote the mesenchymal-epithelial transition and reduce tumor cell migration. Accordingly, overexpression of SOCS1 induced cell morphology changes and dramatically reduced tumor cell invasion in vitro. When injected in nude mice, SOCS1-expressing SW620 cells induced metastases in a smaller number of animals than parental SW620 cells, and did not generate any adrenal gland or bone metastasis. Overall, our results suggest that SOCS1 controls metastatic progression of colorectal tumors by preventing the mesenchymal-epithelial transition (MET), including E-cadherin expression. This pathway may be associated with survival to colorectal cancer by reducing the capacity of generating metastases. Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Right- vs. Left-Sided Metastatic Colorectal Cancer: Differences in Tumor Biology and Bevacizumab Efficacy

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Paola Ulivi

2017-06-01

Full Text Available There is evidence of a different response to treatment with regard to the primary tumor localization (right-sided or left-sided in patients with metastatic colorectal cancer (mCRC. We analyzed the different outcomes and biomolecular characteristics in relation to tumor localization in 122 of the 370 patients with metastatic colorectal cancer enrolled onto the phase III prospective multicenter “Italian Trial in Advanced Colorectal Cancer (ITACa”, randomized to receive first-line chemotherapy (CT or CT plus bevacizumab (CT + B. RAS and BRAF mutations; baseline expression levels of circulating vascular endothelial growth factor (VEGF, endothelial nitric oxide synthase (eNOS, cyclooxygenase-2 (COX2, ephrin type-B receptor 4 (EPHB4, hypoxia-inducible factor 1-alpha (HIF-1α, lactate dehydrogenase (LDH, and high-sensitivity C reactive protein (hs-CRP; and inflammatory indexes such as the neutrophil-to-lymphocyte ratio, platelet-lymphocyte rate and systemic immune-inflammation index were evaluated. Patients with right-sided tumors showed a longer median progression-free survival in the CT + B arm than in the CT group (12.6 vs. 9.0 months, respectively, p = 0.017. Baseline inflammatory indexes were significantly higher in left-sided tumors, whereas eNOS and EPHB4 expression was significantly higher and BRAF mutation more frequent in right-sided tumors. Our data suggest a greater efficacy of the CT + B combination in right-sided mCRC, which might be attributable to the lower inflammatory status and higher expression of pro-angiogenic factors that appear to characterize these tumors.

Patient characteristics and stratification in medical treatment studies for metastatic colorectal cancer: a proposal for standardization of patient characteristic reporting and stratification.

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Sorbye, H; Köhne, C-H; Sargent, D J; Glimelius, B

2007-10-01

Prognostic factors have the potential to determine the survival of patients to a greater extent than current antineoplastic agents. Despite this knowledge, there is no consensus on, first, what patient characteristics to report and, second, what stratification factors to use in metastatic colorectal cancer trials. Seven leading oncology and medical journals were reviewed for phase II and III publications reporting on medical treatment of metastatic colorectal cancer patients during 2001-2005. One hundred and forty-three studies with 21 214 patients were identified. The reporting of patient characteristics and use of stratification was noted. Age, gender, performance status, metastases location, sites and adjuvant chemotherapy were often reported (99-63%). Laboratory values as alkaline phosphatase, lactate dehydrogenase and white blood cell count, repeatedly found to be of prognostic relevance, were rarely reported (5-9%). Stratification was used in all phase III trials; however, only study centre was used with any consistency. There is considerable inconsistency in the reporting of patient characteristics and use of stratification factors in metastatic colorectal cancer trials. We propose a standardization of patient characteristics reporting and stratification factors. A common set of characteristics and strata will aid in trial reporting, interpretation and future meta-analyses.

Current status of treatment of metastatic colorectal cancer with special reference to cetuximab and elderly patients

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Per Pfeiffer

2008-12-01

Full Text Available Per Pfeiffer, Camilla Qvortrup, Jon K BjerregaardDepartment of Oncology, Odense University Hospital. Institute of Clinical Research, University of Southern Denmark. Odense C, DenmarkPurpose: Elderly cancer patients often have co-morbidities and other characteristics that make the selection of optimal treatment more complex. The introduction of targeted therapies in colorectal cancer has further complicated this problem. This review will focus on the role of the EGFR antibody cetuximab in elderly patients.Methods: We have reviewed the available evidence in the literature to evaluate the results of therapy with cetuximab, alone or in combination with chemotherapy, with a focus on elderly patients with metastatic colorectal cancer (mCRC.Results: In patients with mCRC, combination chemotherapy prolongs median survival to more than 18 months and even around 24 months in combination with cetuximab in selected patients. No prospective studies have evaluated cetuximab in elderly patients. However, subgroup analyses from randomized trials and retrospective analysis suggest that the efficacy of chemotherapy and cetuximab is maintained in fit elderly patients, but with slightly increased but acceptable toxicity.Conclusion: No prospective cetuximab studies have been conducted solely in a population of elderly patients. However, available data suggest that outcomes in the fit elderly mirror results observed in younger patients.Keywords: metastatic colorectal cancer, cetuximab, elderly patients

Clinical Usefulness of Tools to Support Decision-making for Palliative Treatment of Metastatic Colorectal Cancer: A Systematic Review

NARCIS (Netherlands)

Engelhardt, Ellen G.; Révész, Dóra; Tamminga, Hans J.; Punt, Cornelis J. A.; Koopman, Mirjam; Onwuteaka-Philipsen, Bregje D.; Steyerberg, Ewout W.; Jansma, Ilse P.; de Vet, Henrica C. W.; Coupé, Veerle M. H.

2018-01-01

Decision-making regarding palliative treatment for patients with metastatic colorectal cancer (mCRC) is complex and comprises numerous decisions. Decision-making should be guided by the premise of maintaining and/or improving patients' quality of life, by patient preference, and by the trade-off

Bevacizumab treatment in the elderly patient with metastatic colorectal cancer

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Di Bartolomeo M

2015-01-01

Full Text Available Maria Di Bartolomeo,1 Claudia Maggi,1 Francesca Ricchini,1 Filippo Pietrantonio,1 Roberto Iacovelli,1 Filippo de Braud,1 Alessandro Inno2 1Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, 2Department of Medical Oncology, Sacro Cuore-Don Calabria Hospital, Negrar, Italy Abstract: Metastatic colorectal cancer (mCRC, like many cancers, is primarily a disease of elderly people. Despite this prevalence, such patients are often excluded from randomized trials or represent a minority of enrolled patients. Moreover, the criteria for establishing benefit or side effects of treatment strategies in this population are uncertain and not well recognized. Bevacizumab improves the outcome of mCRC when used in combination with standard first-line and second-line chemotherapy and beyond the first disease progression when given with a chemotherapy backbone different from that used in the precedent line. The particular toxicity profile of this antiangiogenesis agent (in particular hypertension, thromboembolic events, hemorrhage, and renal failure may discourage its use in elderly patients with comorbidities. Data from subgroup analyses of randomized trials and the results of recent cohort studies suggest a significant benefit from the addition of bevacizumab to standard chemotherapy for elderly patients comparable with that observed in younger patients, except for the increased risk for thromboembolic events. Age alone should not be a barrier to use of bevacizumab, and further research with a more complete geriatric assessment should investigate the role of bevacizumab in elderly patients with mCRC to avoid undertreatment of this patient population due to a ­historical conservative approach. Keywords: bevacizumab, elderly, metastatic colorectal cancer, antivascular treatment, review

Oxaliplatin in patients with metastatic colorectal cancer: efficacy and pharmacokinetics parameters.

Science.gov (United States)

Burz, C; Berindan-Neagoe, I; Balacescu, O; Todor, N; Pelau, D; Floares, C; Kacso, G; Tanaselia, C; Ursu, M; Vlase, L; Leucuta, S E; Cristea, V; Irimie, A

2010-01-01

The aim of this study was to investigate the efficiency of the FOLFOX-4 regimen and to evaluate the pharmacokinetics of oxaliplatin in untreated patients with metastatic colorectal cancer. 43 patients were enrolled in the study. Patients received oxaliplatin 85 mg/m(2) as 2-h i.v. infusion, on day 1, and bolus 5-fluorouracil (5FU) 400 mg/m(2) plus leucovorin (LV) 200 mg/m(2) followed by 5FU 600 mg/m(2) as 22-h infusion on day 1 and 2, every 2 weeks. The pharmacokinetics of oxaliplatin evaluated in 4 patients was performed in blood, plasma and ultrafiltered plasma (UFT) by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). The overall response rate and the median time to progression (TTP) were 53.49% and 7.1 months, respectively. Grade 3-4 toxic effects were observed in 11 (25.5%) patients. Grade 3 neuropathy was observed in 13.95% of the cases. In univariate analysis only Eastern Cooperative Oncology Group (ECOG) performance status (PS) was correlated with response. No correlation was found between grade 3-4 adverse events and the patient characteristics. The area under the time-concentration curve (AUC) in UFT was 4.8 + or - 0.72 standard deviation (SD) microg h/ml and the total clearance 30.17 + or - 7.75 l/min. The values for volume of distribution and the maximum concentration were 567 + or - 20 liters and 0.38 + or - 0.17 ug/ml, respectively. FOLFOX-4 was an effective regimen with good tolerability in previously untreated metastatic colorectal cancer patients. The pharmacokinetics of oxaliplatin was triphasic with a short initial distribution phase and a long terminal elimination phase.

Efficacy and safety of regorafenib in the treatment of metastatic colorectal cancer: A systematic review.

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Røed Skårderud, Maria; Polk, Anne; Kjeldgaard Vistisen, Kirsten; Larsen, Finn Ole; Nielsen, Dorte Lisbet

2018-01-01

Despite advances in the treatment of colorectal cancer, third-line treatment options are still limited. Regorafenib was approved in 2012 for the treatment of patients with metastatic colorectal cancer previously treated with approved standard therapy. The purpose of this review is to present existing clinical data on regorafenib. We systematically searched the PubMed and Embase databases, as well as ASCO and ESMO conference abstracts, for studies in English including ≥30 patients, evaluating the efficacy and safety of regorafenib in patients with metastatic colorectal cancer. A meta-analysis was conducted on the published, randomized phase III trials. 24 eligible studies were included. In two phase III trials, regorafenib significantly increased overall survival (OS), progression free survival (PFS), and disease control rate when compared to placebo. Survival benefits of 1.4 and 2.5 months were presented. The meta-analysis indicated a significant greater treatment effect on OS (hazard ratio 0.67) and PFS (hazard ratio 0.40), compared to placebo. The non-randomized studies mostly supported these results. The most frequently reported adverse events were hand-foot-skin reaction (25%-86%), hypertension (11%-47%) and fatigue (2%-73%). Large phase III randomized trials indicate that regorafenib provides a benefit in OS and PFS when compared to placebo. Adverse events were common, but manageable and typical of multi-target tyrosine kinase inhibitors. Further research is needed to investigate alternative approaches to the dosing of regorafenib and to explore clinical and molecular biomarkers that can guide patient selection. Copyright © 2017 Elsevier Ltd. All rights reserved.

Identification of 42 Genes Linked to Stage II Colorectal Cancer Metastatic Relapse

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Rabeah A. Al-Temaimi

2016-04-01

Full Text Available Colorectal cancer (CRC is one of the leading causes of cancer mortality. Metastasis remains the primary cause of CRC death. Predicting the possibility of metastatic relapse in early-stage CRC is of paramount importance to target therapy for patients who really need it and spare those with low-potential of metastasis. Ninety-six stage II CRC cases were stratified using high-resolution array comparative genomic hybridization (aCGH data based on a predictive survival algorithm and supervised clustering. All genes included within the resultant copy number aberrations were each interrogated independently at mRNA level using CRC expression datasets available from public repositories, which included 1820 colon cancers, and 167 normal colon tissues. Reduced mRNA expression driven by copy number losses and increased expression driven by copy number gains revealed 42 altered transcripts (29 reduced and 13 increased transcripts associated with metastatic relapse, short disease-free or overall survival, and/or epithelial to mesenchymal transition (EMT. Resultant genes were classified based on gene ontology (GO, which identified four functional enrichment groups involved in growth regulation, genomic integrity, metabolism, and signal transduction pathways. The identified 42 genes may be useful for predicting metastatic relapse in stage II CRC. Further studies are necessary to validate these findings.

Proactive strategies for regorafenib in metastatic colorectal cancer: implications for optimal patient management

International Nuclear Information System (INIS)

Khan, Gazala; Moss, Rebecca A; Braiteh, Fadi; Saltzman, Marc

2014-01-01

Regorafenib is a broad-spectrum oral multikinase inhibitor that targets several angiogenic, oncogenic, and stromal receptor tyrosine kinases that support the tumor microenvironment. Results from the pivotal Phase III Patients with Metastatic Colorectal Cancer Treated with Regorafenib or Placebo After Failure of Standard Therapy (CORRECT) trial showed that the addition of regorafenib to best supportive care resulted in a significant improvement in median overall survival and progression-free survival compared with placebo plus best supportive care in patients with metastatic colorectal cancer (mCRC) following all available approved therapies. Thus, regorafenib is the first oral multikinase inhibitor indicated for mCRC; it currently has approval in the USA, EU, Japan, Canada, and Singapore for the treatment of mCRC patients who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-vascular endothelial growth factor therapy, and, if the tumor is KRAS wild-type, an anti-epidermal growth factor receptor therapy. In this review, we highlight regorafenib’s mechanism of action, present key efficacy data from the CORRECT trial, and discuss how to proactively manage common adverse events (eg, hand-foot skin reaction, hypertension, oral mucositis, diarrhea, and fatigue) experienced by patients receiving regorafenib. Increased awareness of potential adverse events associated with regorafenib and the implementation of proactive strategies to prevent, monitor, and manage these events early in the course of treatment will be instrumental in ensuring optimal patient management and continuation of regorafenib therapy

Comparison of the Mismatch Repair System between Primary and Metastatic Colorectal Cancers Using Immunohistochemistry

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Jiyoon Jung

2017-03-01

Full Text Available Background Colorectal cancer (CRC is one of the most common malignancies worldwide. Approximately 10%–15% of the CRC cases have defective DNA mismatch repair (MMR genes. Although the high level of microsatellite instability status is a predictor of favorable outcome in primary CRC, little is known about its frequency and importance in secondary CRC. Immunohistochemical staining (IHC for MMR proteins (e.g., MLH1, MSH2, MSH6, and PMS2 has emerged as a useful technique to complement polymerase chain reaction (PCR analyses. Methods In this study, comparison between the MMR system of primary CRCs and paired liver and lung metastatic lesions was done using IHC and the correlation with clinical outcomes was also examined. Results Based on IHC, 7/61 primary tumors (11.4% showed deficient MMR systems, while 13/61 secondary tumors (21.3% showed deficiencies. In total, 44 cases showed proficient expression in both the primary and metastatic lesions. Three cases showed deficiencies in both the primary and paired metastatic lesions. In 10 cases, proficient expression was found only in the primary lesions, and not in the corresponding metastatic lesions. In four cases, proficient expression was detected in the secondary tumor, but not in the primary tumor. Conclusions Although each IHC result and the likely defective genes were not exactly matched between the primary and the metastatic tumors, identical results for primary and metastatic lesions were obtained in 77% of the cases (47/61. These data are in agreement with the previous microsatellite detection studies that used PCR and IHC.

Investigation of the roles of exosomes in colorectal cancer liver metastasis.

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Wang, Xia; Ding, Xiaoling; Nan, Lijuan; Wang, Yiting; Wang, Jing; Yan, Zhiqiang; Zhang, Wei; Sun, Jihong; Zhu, Wei; Ni, Bing; Dong, Suzhen; Yu, Lei

2015-05-01

The leading cause of death among cancer patients is tumor metastasis. Tumor-derived exosomes are emerging as mediators of metastasis. In the present study, we demonstrated that exosomes play a pivotal role in the metastatic progression of colorectal cancer. First, a nude mouse model of colorectal cancer liver metastasis was established and characterized. Then, we demonstrated that exosomes from a highly liver metastatic colorectal cancer cell line (HT-29) could significantly increase the metastatic tumor burden and distribution in the mouse liver of Caco-2 colorectal cancer cells, which ordinarily exhibit poor liver metastatic potential. We further investigated the mechanisms by which HT-29-derived-exosomes influence the liver metastasis of colorectal cancer and found that mice treated with HT-29-derived exosomes had a relatively higher level of CXCR4 in the metastatic microenvironment, indicating that exosomes may promote colorectal cancer metastasis by recruiting CXCR4-expressing stromal cells to develop a permissive metastatic microenvironment. Finally, the migration of Caco-2 cells was significantly increased following treatment with HT-29-derived exosomes in vitro, further supporting a role for exosomes in modulating colorectal tumor-derived liver metastasis. The data from the present study may facilitate further translational medicine research into the prevention and treatment of colorectal cancer liver metastasis.

The development of a value based pricing index for new drugs in metastatic colorectal cancer

OpenAIRE

Lubbe, Martha Susanna; Dranitsaris, George; Truter, Ilse

2011-01-01

Background Worldwide, prices for cancer drugs have been under downward pressure where several governments have mandated price cuts of branded products. A better alternative to government mandated price cuts would be to estimate a final price based on drug performance, cost effectiveness and a country’s ability to pay. We developed a global pricing index for new cancer drugs in patients with metastatic colorectal cancer (mCRC) that encompasses all of these attributes. Methods ...

Profile of trifluridine/tipiracil hydrochloride in the treatment of metastatic colorectal cancer: efficacy, safety, and place in therapy

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Sunakawa Y

2017-09-01

Full Text Available Yu Sunakawa, Naoki Izawa, Takuro Mizukami, Yoshiki Horie, Mami Hirakawa, Hiroyuki Arai, Takashi Ogura, Takashi Tsuda, Takako Eguchi Nakajima Department of Clinical Oncology, St Marianna University School of Medicine, Kawasaki, Japan Abstract: TAS-102, with its robust survival efficacy and feasible toxicity, is one of the standard salvage-line treatments for patients with metastatic colorectal cancer (mCRC. No definitive data are available to determine which drug should be administered first during salvage-line treatment. Therefore, it is imperative that we establish the sequence of administration by considering drug toxicity profiles based on patient characteristics, such as age, performance status, comorbidities, tolerability to previous treatments, and patient preferences. The identification of predictive biomarkers in response to TAS-102 or its toxicity is urgently needed for better patient selection. Moreover, to strengthen efficacy or relieve toxicity, combinations with other agents, which could potentially emerge as standard treatment regimens, have been investigated and compared to existing active regimens for mCRC. Keywords: TAS-102, metastatic colorectal cancer, regorafenib, biomarker

The Effect of Overweight Status on Total and Metastatic Number of Harvested Lymph Nodes During Colorectal Surgery

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Sezgin Zeren

2016-03-01

Full Text Available Objective: The aim of this study is to evaluate the rela­tionship between higher body mass index (BMI and har­vested total or metastatic lymph node numbers in patients who underwent surgery for colorectal cancers. Methods: Between March 2014 and January 2016, totally 71patients who underwent laparoscopic or conventional surgery for colorectal cancer were evaluated retrospec­tively. The data of age, gender, BMI, surgical procedure, tumor localization , postoperative mortality status, total number of harvested and metastatic lymph node were collected. The patients having 24.9 (kg/m2 or lower BMI values were classified as normal (Group 1 and patients having BMI values of 25 or over were overweight (Group 2. Afterwards, the parameters between groups and the effect of higher BMI were analyzed. Results: The mean age of the patients was 64.5 ± 14 years. The average BMI value in group 1 was 22.3 (kg/m2 and 27.0 (kg/m2 in group 2. According to localisation of tumor, transverse colon was the rare region for both groups. The common regions for tumor localisation in group 1 were right colon, sigmoid colon and rectum. In group 2 the common localisation for tumors were rectum, right colon and sigmoid colon. There was no difference between groups about postoperative mortality rates (p > 0.05. The mean of the total number of harvested lymph nodes were 14 in group 1 and 12 in group 2. There were no relationship between BMI and tumor diameter, total or metastatic number of harvested lymph nodes. Conclusion: Higher BMI values does not effect the num­ber of excised total or metastatic lymph nodes and tumor diameters. Therefore, the surgeons should not hesitate in overweight patients cancer surgery for dissecting ad­equate number of lymph nodes.

Imaging of primary and metastatic colorectal carcinoma with monoclonal antibody 791T/36 and the therapeutic potential of antibody-drug conjugates

International Nuclear Information System (INIS)

Pimm, M.V.; Armitage, N.C.; Ballantyne, K.; Baldwin, R.W.; Perkins, A.C.; Durrant, L.G.; Garnett, M.C.; Hardcastle, J.D.

1987-01-01

Monoclonal antibody 791T/36, prepared against a tumor-associated 72,000 dalton glycoprotein, reacted with cells from primary and metastatic colorectal carcinomas. I-131 or In-111-labelled antibody localized in xenografts of colorectal carcinomas established from in vitro clonogenic populations. Clinically, with I-131-labelled antibody, 8/11 colonic tumors imaged positively. Imaging was negative in four patients with benign colon disease. 5/11 rectal tumors were positively imaged, but excreted I-131 in the bladder obscured tumors in several studies. In-111-labelled antibody gave superior images and positively imaged primary and metastatic sites in 13/14 patients. Prospectively in the detection of recurrent disease, I-131 or In-111-antibody detected 29/33 separate sites in 24 patients. Seven negative patients remain disease free. There were 3 false positives; overall sensitivity was 88%, with 70% specificity. Specific localization of radiolabel was confirmed immunochemically and by counting radioactivity in resected specimens. Antibody conjugates with methotrexate, vindesine and daunomycin retained drug activity and antibody function, including xenograft localization and conjugates were therapeutically effective against xenografts. 791T/36 antibody has potential for immunodetection of primary and recurrent colorectal carcinoma and for targeting of therapeutic agents

Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer

NARCIS (Netherlands)

Cohen, Steven J.; Punt, Cornelis J. A.; Iannotti, Nicholas; Saidman, Bruce H.; Sabbath, Kert D.; Gabrail, Nashat Y.; Picus, Joel; Morse, Michael; Mitchell, Edith; Miller, M. Craig; Doyle, Gerald V.; Tissing, Henk; Terstappen, Leon W. M. M.; Meropol, Neal J.

2008-01-01

As treatment options expand for metastatic colorectal cancer (mCRC), a blood marker with a prognostic and predictive role could guide treatment. We tested the hypothesis that circulating tumor cells (CTCs) could predict clinical outcome in patients with mCRC. In a prospective multicenter study, CTCs

Phase II Trial of Biweekly Cetuximab and Irinotecan as Third-Line Therapy for Pretreated KRAS Exon 2 Wild-Type Colorectal Cancer.

Science.gov (United States)

Osumi, Hiroki; Shinozaki, Eiji; Mashima, Tetsuo; Wakatsuki, Takeru; Suenaga, Mitsukuni; Ichimura, Takashi; Ogura, Mariko; Ota, Yumiko; Nakayama, Izuma; Takahari, Daisuke; Chin, Keisho; Miki, Yoshio; Yamaguchi, Kensei

2018-06-16

Efficacy and safety of biweekly cetuximab plus irinotecan were evaluated to provide guidance for its use in Japan as third-line treatment for pretreated metastatic colorectal cancer patients harboring wild-type KRAS Exon 2. Objective response rate was used as primary endpoint based on an expected proportion of 0.23 with confidence width of 0.298 (95% confidence interval, 0.105-0.403), which showed 35 to be the minimal participant number. Forty patients, refractory to first- and second-line chemotherapy containing irinotecan, oxaliplatin, and fluoropyrimidine were enrolled. Objective response and disease control rates were 25.0% (95% CI:11.5%-38.4%) and 72.5% (95% CI:56.8%-86.4%), respectively. Median progression-free survival, overall survival, and number of courses were 5.70 months (95% CI;2.7-7.9), 15.1 months (95% CI;11.8-19.0), and 10.5 (range:3.0-31.0), respectively. Grade 3 adverse events were skin toxicity (12.5%), diarrhea (10.0%), neutropenia (5.0%), febrile neutropenia (5.0%), nausea (5.0%), anorexia (5.0%), and fatigue (2.5%). Cetuximab C max mean was 723.2 μg/mL after first dose. High AUC last variance was associated with t 1/2 range of 131.2-1209.6 h (median, 174.4 h). Early tumor shrinkage and median depth of response were 25.0% and 13.0%, respectively. Mutation frequencies in KRAS exon 3 or 4, NRAS, BRAF, and PIK3CA were 5.5%, 2.7%, 8.3%, and 5.5%, respectively. Multivariate Cox regression analysis assessed whether any gene mutations and early tumor shrinkage are predictors for progression-free survival, and whether performance status, synchronous metastasis, and early tumor shrinkage are predictors for overall survival. Importantly, the data provide guidance for a biweekly cetuximab plus irinotecan regimen in metastatic colorectal cancer patients. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Correlation of FCGR3A and EGFR germline polymorphisms with the efficacy of cetuximab in KRAS wild-type metastatic colorectal cancer

NARCIS (Netherlands)

Pander, Jan; Gelderblom, Hans; Antonini, Ninja F.; Tol, Jolien; van Krieken, Johan H. J. M.; van der Straaten, Tahar; Punt, Cornelis J. A.; Guchelaar, Henk-Jan

2010-01-01

Next to KRAS mutation status, additional predictive markers are needed for the response to cetuximab in patients with metastatic colorectal cancer (mCRC). Previous studies indicated that germline polymorphisms in specific genes may predict efficacy and toxicity of cetuximab in mCRC patients.

Clinical trial enrollment, patient characteristics, and survival differences in prospectively registered metastatic colorectal cancer patients

DEFF Research Database (Denmark)

Sorbye, Halfdan; Pfeiffer, Per; Cavalli-Björkman, Nina

2009-01-01

BACKGROUND: Trial accrual patterns were examined to determine whether metastatic colorectal cancer (mCRC) patients enrolled in trials are representative of a general cancer population concerning patient characteristics and survival. METHODS: A total of 760 mCRC patients referred for their first...... oncological consideration at 3 hospitals in Scandinavia covering defined populations were registered consecutively during 2003 to 2006. Clinical trial enrollment, patient characteristics, and treatment were recorded prospectively, and the follow-up was complete. RESULTS: Palliative chemotherapy was initiated...

Vertebral compression fractures after spine irradiation using conventional fractionation in patients with metastatic colorectal cancer

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Ree, Woo Joong; Kim, Kyung Hwan; Chang, Jee Suk; Kim, Hyun Ju; Choi, Seo Hee; Koom, Woong Sub [Dept.of Radiation Oncology, Yonsei Cancer Center, Yonsei University Health System, Seoul (Korea, Republic of)

2014-12-15

To evaluate the risk of vertebral compression fracture (VCF) after conventional radiotherapy (RT) for colorectal cancer (CRC) with spine metastasis and to identify risk factors for VCF in metastatic and non-metastatic irradiated spines. We retrospectively reviewed 68 spinal segments in 16 patients who received conventional RT between 2009 and 2012. Fracture was defined as a newly developed VCF or progression of an existing fracture. The target volume included all metastatic spinal segments and one additional non-metastatic vertebra adjacent to the tumor-involved spines. The median follow-up was 7.8 months. Among all 68 spinal segments, there were six fracture events (8.8%) including three new VCFs and three fracture progressions. Observed VCF rates in vertebral segments with prior irradiation or pre-existing compression fracture were 30.0% and 75.0% respectively, compared with 5.2% and 4.7% for segments without prior irradiation or pre-existing compression fracture, respectively (both p < 0.05). The 1-year fracture-free probability was 87.8% (95% CI, 78.2-97.4). On multivariate analysis, prior irradiation (HR, 7.30; 95% CI, 1.31-40.86) and pre-existing compression fracture (HR, 18.45; 95% CI, 3.42-99.52) were independent risk factors for VCF. The incidence of VCF following conventional RT to the spine is not particularly high, regardless of metastatic tumor involvement. Spines that received irradiation and/or have pre-existing compression fracture before RT have an increased risk of VCF and require close observation.

The impact of bone marrow micrometastases on metastatic disease-free survival in patients with colorectal carcinoma.

LENUS (Irish Health Repository)

O'Connor, O J

2012-02-03

AIMS: The biological relevance of bone marrow micrometastases (BMM) in colorectal cancer remains unknown. Here, we investigate their nature by examining the impact of the presence of BMM on metastatic disease-free survival in a cohort of patients with this disease. METHODS: Sixty-three consecutive patients undergoing surgery for colorectal cancer of any stage were studied after approval of the study protocol by the local ethics committee and with full individual informed consent. All had bilateral iliac crest bone marrow aspirates prior to operation. Aspirates were then examined for the presence of aberrant cytokeratin-18-positive cells by a blinded observer using both flow cytometric and APAAP immunohistochemical techniques. RESULTS: Mean follow-up after surgery was 4.6 years (range 1.9-6.9) for those without hepatic metastases at diagnosis. Seven of 34 patients with Dukes\\' stage A or B developed metastatic disease after a mean interval of 4.7 years (range 3.8-6.8). However, only 2 of these patients demonstrated BMM at the time of surgery. Nine of 15 patients with Dukes\\' C carcinoma at the time of surgery subsequently developed metastases after a mean interval of 4.4 years (range 1.9-6.9). Again, only two of these patients had BMM detectable initially. In only three of the 14 patients known to have metastases at the time of operation (i.e. Dukes\\'\\'D\\' disease) were BMM found. CONCLUSION: The presence of BMM as detected by this methodology was not predictive of tumour recurrence or metastasis. This study does not support the consideration of adjuvant therapy based on the presence of BMM at a single pre-operative time point in patients with colorectal cancer.

Immunotherapy of metastatic colorectal cancer with vitamin D-binding protein-derived macrophage-activating factor, GcMAF.

Science.gov (United States)

Yamamoto, Nobuto; Suyama, Hirofumi; Nakazato, Hiroaki; Yamamoto, Nobuyuki; Koga, Yoshihiko

2008-07-01

Serum vitamin D binding protein (Gc protein) is the precursor for the principal macrophage-activating factor (MAF). The MAF precursor activity of serum Gc protein of colorectal cancer patients was lost or reduced because Gc protein is deglycosylated by serum alpha-N-acetylgalactosaminidase (Nagalase) secreted from cancerous cells. Deglycosylated Gc protein cannot be converted to MAF, leading to immunosuppression. Stepwise treatment of purified Gc protein with immobilized beta-galactosidase and sialidase generated the most potent macrophage-activating factor (GcMAF) ever discovered, but it produces no side effect in humans. Macrophages treated with GcMAF (100 microg/ml) develop an enormous variation of receptors and are highly tumoricidal to a variety of cancers indiscriminately. Administration of 100 nanogram (ng)/ human maximally activates systemic macrophages that can kill cancerous cells. Since the half-life of the activated macrophages is approximately 6 days, 100 ng GcMAF was administered weekly to eight nonanemic colorectal cancer patients who had previously received tumor-resection but still carried significant amounts of metastatic tumor cells. As GcMAF therapy progressed, the MAF precursor activities of all patients increased and conversely their serum Nagalase activities decreased. Since serum Nagalase is proportional to tumor burden, serum Nagalase activity was used as a prognostic index for time course analysis of GcMAF therapy. After 32-50 weekly administrations of 100 ng GcMAF, all colorectal cancer patients exhibited healthy control levels of the serum Nagalase activity, indicating eradication of metastatic tumor cells. During 7 years after the completion of GcMAF therapy, their serum Nagalase activity did not increase, indicating no recurrence of cancer, which was also supported by the annual CT scans of these patients.

Economic Analysis of First-Line Treatment with Cetuximab or Panitumumab for RAS Wild-Type Metastatic Colorectal Cancer in England.

Science.gov (United States)

Tikhonova, Irina A; Huxley, Nicola; Snowsill, Tristan; Crathorne, Louise; Varley-Campbell, Jo; Napier, Mark; Hoyle, Martin

2018-03-01

Combination therapies with cetuximab (Erbitux ® ; Merck Serono UK Ltd) and panitumumab (Vectibix ® ; Amgen UK Ltd) are shown to be less effective in adults with metastatic colorectal cancer who have mutations in exons 2, 3 and 4 of KRAS and NRAS oncogenes from the rat sarcoma (RAS) family. The objective of the study was to estimate the cost effectiveness of these drugs in patients with previously untreated RAS wild-type (i.e. non-mutated) metastatic colorectal cancer, not eligible for liver resection at baseline, from the UK National Health Service and Personal Social Services perspective. We constructed a partitioned survival model to evaluate the long-term costs and benefits of cetuximab and panitumumab combined with either FOLFOX (folinic acid, fluorouracil and oxaliplatin) or FOLFIRI (folinic acid, fluorouracil and irinotecan) vs. FOLFOX or FOLFIRI alone. The economic analysis was based on three randomised controlled trials. Costs and quality-adjusted life-years were discounted at 3.5% per annum. Based on the evidence available, both drugs fulfil the National Institute for Health and Care Excellence's end-of-life criteria. In the analysis, assuming discount prices for the drugs from patient access schemes agreed by the drug manufacturers with the Department of Health, predicted mean incremental cost-effectiveness ratios for cetuximab + FOLFOX, panitumumab + FOLFOX and cetuximab + FOLFIRI compared with chemotherapy alone appeared cost-effective at the National Institute for Health and Care Excellence's threshold of £50,000 per quality-adjusted life-year gained, applicable to end-of-life treatments. Cetuximab and panitumumab were recommended by the National Institute for Health and Care Excellence for patients with previously untreated RAS wild-type metastatic colorectal cancer, not eligible for liver resection at baseline, for use within the National Health Service in England. Both treatments are available via the UK Cancer Drugs Fund.

Phase II DeCOG-study of ipilimumab in pretreated and treatment-naïve patients with metastatic uveal melanoma.

Directory of Open Access Journals (Sweden)

Lisa Zimmer

Full Text Available Up to 50% of patients with uveal melanoma (UM develop metastatic disease with limited treatment options. The immunomodulating agent ipilimumab has shown an overall survival (OS benefit in patients with cutaneous metastatic melanoma in two phase III trials. As patients with UM were excluded in these studies, the Dermatologic Cooperative Oncology Group (DeCOG conducted a phase II to assess the efficacy and safety of ipilimumab in patients with metastatic UM.We undertook a multicenter phase II study in patients with different subtypes of metastatic melanoma. Here we present data on patients with metastatic UM (pretreated and treatment-naïve who received up to four cycles of ipilimumab administered at a dose of 3 mg/kg in 3 week intervals. Tumor assessments were conducted at baseline, weeks 12, 24, 36 and 48 according to RECIST 1.1 criteria. Adverse events (AEs, including immune-related AEs were graded according to National Cancer Institute Common Toxicity Criteria (CTC v.4.0. Primary endpoint was the OS rate at 12 months.Forty five pretreated (85% and eight treatment-naïve (15% patients received at least one dose of ipilimumab. 1-year and 2-year OS rates were 22% and 7%, respectively. Median OS was 6.8 months (95% CI 3.7-8.1, median progression-free survival 2.8 months (95% CI 2.5-2.9. The disease control rate at weeks 12 and 24 was 47% and 21%, respectively. Sixteen patients had stable disease (47%, none experienced partial or complete response. Treatment-related AEs were observed in 35 patients (66%, including 19 grade 3-4 events (36%. One drug-related death due to pancytopenia was observed.Ipilimumab has very limited clinical activity in patients with metastatic UM. Toxicity was manageable when treated as per protocol-specific guidelines.ClinicalTrials.gov NCT01355120.

Changes in circulating microRNA-126 during treatment with chemotherapy and bevacizumab predicts treatment response in patients with metastatic colorectal cancer

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Hansen, T F; Carlsen, A L; Heegaard, N H H

2015-01-01

BACKGROUND: This study investigated the predictive value of circulating microRNA-126 (cir-miRNA-126) in patients with metastatic colorectal cancer (mCRC) treated with first-line chemotherapy combined with bevacizumab.METHODS: The study included 68 patients. Blood samples (plasma) were collected b...

Bevacizumab plus chemotherapy in elderly patients with previously untreated metastatic colorectal cancer: single center experience

International Nuclear Information System (INIS)

Ocvirk, Janja; Moltara, Maja Ebert; Mesti, Tanja; Boc, Marko; Rebersek, Martina; Volk, Neva; Benedik, Jernej; Hlebanja, Zvezdana

2016-01-01

Metastatic colorectal cancer (mCRC) is mainly a disease of elderly, however, geriatric population is underrepresented in clinical trials. Patient registries represent a tool to assess and follow treatment outcomes in this patient population. The aim of the study was with the help of the patients’ register to determine the safety and efficacy of bevacizumab plus chemotherapy in elderly patients who had previously untreated metastatic colorectal cancer. The registry of patients with mCRC was designed to prospectively evaluate the safety and efficacy of bevacizumab-containing chemotherapy as well as selection of patients in routine clinical practice. Patient baseline clinical characteristics, pre-specified bevacizumab-related adverse events, and efficacy data were collected, evaluated and compared according to the age categories. Between January 2008 and December 2010, 210 patients with mCRC (median age 63, male 61.4%) started bevacizumab-containing therapy in the 1 st line setting. Majority of the 210 patients received irinotecan-based chemotherapy (68%) as 1 st line treatment and 105 patients (50%) received bevacizumab maintenance therapy. Elderly (≥ 70 years) patients presented 22.9% of all patients and they had worse performance status (PS 1/2, 62.4%) than patients in < 70 years group (PS 1/2, 35.8%). Difference in disease control rate was mainly due to inability to assess response in elderly group (64.6% in elderly and 77.8% in < 70 years group, p = 0.066). The median progression free survival was 10.2 (95% CI, 6.7–16.2) and 11.3 (95% CI, 10.2–12.6) months in elderly and < 70 years group, respectively (p = 0.58). The median overall survival was 18.5 (95% CI, 12.4–28.9) and 27.4 (95% CI, 22.7–31.9) months for elderly and < 70 years group, respectively (p = 0.03). Three-year survival rate was 26% and 37.6% in elderly vs. < 70 years group (p = 0.03). Overall rates of bevacizumab-related adverse events were similar in both groups: proteinuria 21

Consistent expression of guanylyl cyclase-C in primary and metastatic gastrointestinal cancers.

Directory of Open Access Journals (Sweden)

Hadi Danaee

Full Text Available The transmembrane receptor guanylate cyclase-C (GCC has been found to be expressed in colorectal cancers. However, limited data are available on GCC protein expression in non-colorectal gastrointestinal tumors and few studies have reported whether GCC protein expression was consistently preserved in synchronous primary and metastatic cancer tissues.GCC protein status was assessed by immunohistochemistry in tumor specimens from individuals (n = 627 with gastrointestinal tumors, including esophageal (n = 130, gastric (n = 276, pancreatic (n = 136, and colorectal (n = 85 primary and metastatic tumors. Tissue specimens consisted of tissue microarrays containing esophageal, gastric, pancreatic tumors, and whole-slide tissue sections from colorectal cancer patients with matching primary and metastatic tumors.Among the evaluated esophageal, gastric, and pancreatic tumors, the frequency of GCC positivity at the protein level ranged from 59% to 68%. GCC was consistently expressed in primary and matched/synchronous metastatic lesions of colorectal cancer tissues derived from the same patients.This observational study demonstrated the protein expression of GCC across various gastrointestinal malignancies. In all cancer histotypes, GCC protein localization was observed predominantly in the cytoplasm compared to the membrane region of tumor cells. Consistent immunohistochemistry detection of GCC protein expression in primary colorectal cancers and in their matched liver metastases suggests that the expression of GCC is maintained throughout the process of tumor progression and formation of metastatic disease.

Patterns of somatic alterations between matched primary and metastatic colorectal tumors characterized by whole-genome sequencing.

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Xie, Tao; Cho, Yong Beom; Wang, Kai; Huang, Donghui; Hong, Hye Kyung; Choi, Yoon-La; Ko, Young Hyeh; Nam, Do-Hyun; Jin, Juyoun; Yang, Heekyoung; Fernandez, Julio; Deng, Shibing; Rejto, Paul A; Lee, Woo Yong; Mao, Mao

2014-10-01

Colorectal cancer (CRC) patients have poor prognosis after formation of distant metastasis. Understanding the molecular mechanisms by which genetic changes facilitate metastasis is critical for the development of targeted therapeutic strategies aimed at controlling disease progression while minimizing toxic side effects. A comprehensive portrait of somatic alterations in CRC and the changes between primary and metastatic tumors has yet to be developed. We performed whole genome sequencing of two primary CRC tumors and their matched liver metastases. By comparing to matched germline DNA, we catalogued somatic alterations at multiple scales, including single nucleotide variations, small insertions and deletions, copy number aberrations and structural variations in both the primary and matched metastasis. We found that the majority of these somatic alterations are present in both sites. Despite the overall similarity, several de novo alterations in the metastases were predicted to be deleterious, in genes including FBXW7, DCLK1 and FAT2, which might contribute to the initiation and progression of distant metastasis. Through careful examination of the mutation prevalence among tumor cells at each site, we also proposed distinct clonal evolution patterns between primary and metastatic tumors in the two cases. These results suggest that somatic alterations may play an important role in driving the development of colorectal cancer metastasis and present challenges and opportunities when considering the choice of treatment. Copyright © 2014 Elsevier Inc. All rights reserved.

A systematic review of salvage therapy to patients with metastatic colorectal cancer previously treated with fluorouracil, oxaliplatin and irinotecan +/- targeted therapy

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Nielsen, Dorte Lisbet; Palshof, Jesper Andreas; Larsen, Finn Ole

2014-01-01

in the third-line setting. We therefore performed a systematic review of the current literature on third or later lines of treatment to patients with metastatic colorectal cancer after the use of approved drugs or combinations. METHODS: A computer-based literature search was carried out using Pubmed and data...

Multicenter, randomized, double-blind phase 2 trial of FOLFIRI with regorafenib or placebo as second-line therapy for metastatic colorectal cancer.

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Sanoff, Hanna K; Goldberg, Richard M; Ivanova, Anastasia; O'Reilly, Seamus; Kasbari, Samer S; Kim, Richard D; McDermott, Ray; Moore, Dominic T; Zamboni, William; Grogan, William; Cohn, Allen Lee; Bekaii-Saab, Tanios S; Leonard, Gregory; Ryan, Theresa; Olowokure, Olugbenga O; Fernando, Nishan H; McCaffrey, John; El-Rayes, Bassel F; Horgan, Anne M; Sherrill, Gary Bradley; Yacoub, George Hosni; O'Neil, Bert H

2018-06-15

Regorafenib, a multikinase inhibitor that inhibits angiogenesis, growth, and proliferation, prolongs survival as monotherapy in patients with refractory colorectal cancer. This international, double-blind, placebo-controlled, multicenter trial assessed the efficacy of regorafenib with folinic acid, fluorouracil, and irinotecan (FOLFIRI) as a second-line treatment for metastatic colorectal cancer. Patients with metastatic colorectal cancer who progressed on first-line oxaliplatin and fluoropyrimidine enrolled at 45 sites in the United States and Ireland. Patients, stratified by prior bevacizumab use, were randomized 2:1 to regorafenib or placebo. The treatment consisted of FOLFIRI on days 1 and 2 and days 15 and 16 with 160 mg of regorafenib or placebo on days 4 to 10 and days 18 to 24 of every 28-day cycle. Crossover was not allowed. The primary endpoint was progression-free survival (PFS). Under the assumption of a 75% event rate, 180 patients were required for 135 events to achieve 90% power to detect a hazard ratio (HR) of 0.65 with a 1-sided α value of .1. One hundred eighty-one patients were randomized (120 to regorafenib-FOLFIRI and 61 to placebo-FOLFIRI) with a median age of 62 years. Among these, 117 (65%) received prior bevacizumab or aflibercept. PFS was longer with regorafenib-FOLFIRI than placebo-FOLFIRI (median, 6.1 vs 5.3 months; HR, 0.73; 95% confidence interval [CI], 0.53-1.01; log-rank P = .056). The median overall survival was not longer (HR, 1.01; 95% CI, 0.71-1.44). The response rate was higher with regorafenib-FOLFIRI (34%; 95% CI, 25%-44%) than placebo-FOLFIRI (21%; 95% CI, 11%-33%; P = .07). Grade 3/4 adverse events with a >5% absolute increase from regorafenib included diarrhea, neutropenia, febrile neutropenia, hypophosphatemia, and hypertension. The addition of regorafenib to FOLFIRI as second-line therapy for metastatic colorectal cancer only modestly prolonged PFS over FOLFIRI alone. Cancer 2018. © 2018 American Cancer

Mutational analysis and clinical correlation of metastatic colorectal cancer.

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Russo, Andrea L; Borger, Darrell R; Szymonifka, Jackie; Ryan, David P; Wo, Jennifer Y; Blaszkowsky, Lawrence S; Kwak, Eunice L; Allen, Jill N; Wadlow, Raymond C; Zhu, Andrew X; Murphy, Janet E; Faris, Jason E; Dias-Santagata, Dora; Haigis, Kevin M; Ellisen, Leif W; Iafrate, Anthony J; Hong, Theodore S

2014-05-15

Early identification of mutations may guide patients with metastatic colorectal cancer toward targeted therapies that may be life prolonging. The authors assessed tumor genotype correlations with clinical characteristics to determine whether mutational profiling can account for clinical similarities, differences, and outcomes. Under Institutional Review Board approval, 222 patients with metastatic colon adenocarcinoma (n = 158) and rectal adenocarcinoma (n = 64) who underwent clinical tumor genotyping were reviewed. Multiplexed tumor genotyping screened for >150 mutations across 15 commonly mutated cancer genes. The chi-square test was used to assess genotype frequency by tumor site and additional clinical characteristics. Cox multivariate analysis was used to assess the impact of genotype on overall survival. Broad-based tumor genotyping revealed clinical and anatomic differences that could be linked to gene mutations. NRAS mutations were associated with rectal cancer versus colon cancer (12.5% vs 0.6%; P colon cancer (13% vs 3%; P = .024) and older age (15.8% vs 4.6%; P = .006). TP53 mutations were associated with rectal cancer (30% vs 18%; P = .048), younger age (14% vs 28.7%; P = .007), and men (26.4% vs 14%; P = .03). Lung metastases were associated with PIK3CA mutations (23% vs 8.7%; P = .004). Only mutations in BRAF were independently associated with decreased overall survival (hazard ratio, 2.4; 95% confidence interval, 1.09-5.27; P = .029). The current study suggests that underlying molecular profiles can differ between colon and rectal cancers. Further investigation is warranted to assess whether the differences identified are important in determining the optimal treatment course for these patients. © 2014 American Cancer Society.

Quantitative cell-free DNA, KRAS, and BRAF mutations in plasma from patients with metastatic colorectal cancer during treatment with cetuximab and irinotecan

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Spindler, Karen-Lise Garm; Pallisgaard, Niels; Vogelius, Ivan Storgaard

2012-01-01

The present study investigated the levels of circulating cell-free DNA (cfDNA) in plasma from patients with metastatic colorectal cancer (mCRC) in relation to third-line treatment with cetuximab and irinotecan and the quantitative relationship of cfDNA with tumor-specific mutations in plasma....

Phase II DeCOG-Study of Ipilimumab in Pretreated and Treatment-Naïve Patients with Metastatic Uveal Melanoma

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Zimmer, Lisa; Vaubel, Julia; Mohr, Peter; Hauschild, Axel; Utikal, Jochen; Simon, Jan; Garbe, Claus; Herbst, Rudolf; Enk, Alexander; Kämpgen, Eckhart; Livingstone, Elisabeth; Bluhm, Leonie; Rompel, Rainer; Griewank, Klaus G.; Fluck, Michael; Schilling, Bastian; Schadendorf, Dirk

2015-01-01

Purpose Up to 50% of patients with uveal melanoma (UM) develop metastatic disease with limited treatment options. The immunomodulating agent ipilimumab has shown an overall survival (OS) benefit in patients with cutaneous metastatic melanoma in two phase III trials. As patients with UM were excluded in these studies, the Dermatologic Cooperative Oncology Group (DeCOG) conducted a phase II to assess the efficacy and safety of ipilimumab in patients with metastatic UM. Patients and Methods We undertook a multicenter phase II study in patients with different subtypes of metastatic melanoma. Here we present data on patients with metastatic UM (pretreated and treatment-naïve) who received up to four cycles of ipilimumab administered at a dose of 3 mg/kg in 3 week intervals. Tumor assessments were conducted at baseline, weeks 12, 24, 36 and 48 according to RECIST 1.1 criteria. Adverse events (AEs), including immune-related AEs were graded according to National Cancer Institute Common Toxicity Criteria (CTC) v.4.0. Primary endpoint was the OS rate at 12 months. Results Forty five pretreated (85%) and eight treatment-naïve (15%) patients received at least one dose of ipilimumab. 1-year and 2-year OS rates were 22% and 7%, respectively. Median OS was 6.8 months (95% CI 3.7–8.1), median progression-free survival 2.8 months (95% CI 2.5–2.9). The disease control rate at weeks 12 and 24 was 47% and 21%, respectively. Sixteen patients had stable disease (47%), none experienced partial or complete response. Treatment-related AEs were observed in 35 patients (66%), including 19 grade 3–4 events (36%). One drug-related death due to pancytopenia was observed. Conclusions Ipilimumab has very limited clinical activity in patients with metastatic UM. Toxicity was manageable when treated as per protocol-specific guidelines. Trial Registration ClinicalTrials.gov NCT01355120 PMID:25761109

Comparison of EORTC criteria and PERCIST for PET/CT response evaluation of patients with metastatic colorectal cancer treated with irinotecan and cetuximab

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Skougaard, Kristin; Nielsen, Dorte; Jensen, Benny Vittrup

2013-01-01

The study aim was to compare European Organization for Research and Treatment of Cancer (EORTC) criteria with PET Response Criteria in Solid Tumors (PERCIST) for response evaluation of patients with metastatic colorectal cancer treated with a combination of the chemotherapeutic drug irinotecan an...... and the monoclonal antibody cetuximab....

Effectiveness of bevacizumab and cetuximab in metastatic colorectal cancer across selected public hospitals in Queensland.

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Chapman, Suzannah J; McKavanagh, Daniel; Burge, Matthew E; McPherson, Ian; Walpole, Euan; Hollingworth, Samantha A

2017-10-01

Metastatic colorectal cancer has a large burden of disease in Australia. Medical therapy is fundamental to extending survival and improving quality of life. The benefits of two costly medicines, bevacizumab and cetuximab, used in Australia remain unclear. The aim of this study was to retrospectively examine the use of these two medicines in metastatic colorectal cancer across five public hospitals in south east Queensland and to compare clinical outcomes to those of published clinical trials. We extracted data from the chemotherapy prescribing database for patients planned for bevacizumab or cetuximab therapy between 2009 and 2013. Median overall survival was estimated using Kaplan-Meier methods. There were 490 bevacizumab-containing protocols planned and 292 patients received at least one dose of bevacizumab. Median overall survival was 17.2 months (95% confidence interval [CI], 15.4-19.3). Of 208 planned cetuximab-containing protocols, 134 patients received at least one dose of cetuximab. Median overall survival was 9.1 months (95% CI, 7.6-12.0). Thirty-day mortality rates from date of first dose were 0.7% for bevacizumab and 7.5% for cetuximab. Overall survival of patients receiving bevacizumab and cetuximab was consistent with clinical trials, providing some assurance that benefits seen in trials are observed in usual practice. This study provides a methodology of using routinely collected health data for clinical monitoring and research. Because of the high cost of these medicines and the lack of toxicity data in this study, further analysis in the postmarketing setting should be explored. © 2016 John Wiley & Sons Australia, Ltd.

Metabolomic NMR fingerprinting to identify and predict survival of patients with metastatic colorectal cancer

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Bertini, Ivano; Cacciatore, Stefano; Jensen, Benny V

2012-01-01

Earlier detection of patients with metastatic colorectal cancer (mCRC) might improve their treatment and survival outcomes. In this study, we used proton nuclear magnetic resonance ((1)H-NMR) to profile the serum metabolome in patients with mCRC and determine whether a disease signature may exist...... survival (HR, 3.4; 95% confidence interval, 2.06-5.50; P = 1.33 × 10(-6)). A number of metabolites concurred with the (1)H-NMR fingerprint of mCRC, offering insights into mCRC metabolic pathways. Our findings establish that (1)H-NMR profiling of patient serum can provide a strong metabolomic signature of m...

Prophylactic Use of Oral Dexamethasone to Alleviate Fatigue During Regorafenib Treatment for Patients With Metastatic Colorectal Cancer.

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Fukuoka, Shota; Shitara, Kohei; Noguchi, Masaaki; Kawazoe, Akihito; Kuboki, Yasutoshi; Bando, Hedeaki; Okamoto, Wataru; Kojima, Takashi; Doi, Toshihiko; Ohtsu, Atsushi; Yoshino, Takayuki

2017-06-01

Fatigue is the most common toxicity of all grade toxicities with regorafenib, was the second most common toxicity in the CORRECT (regorafenib monotherapy for previously treated metastatic colorectal cancer) study, and is a major reason for early dose modification. The results from a recent randomized study suggested that dexamethasone (DEX) can improve cancer-related fatigue. We retrospectively analyzed the effect of prophylactic use of an oral DEX on fatigue during regorafenib treatment in patients with metastatic colorectal cancer (mCRC). A total of 105 patients who had received regorafenib at our institution from May 2013 to August 2014 were divided into 2 groups according to oral DEX use (2 mg/day; at the physician's discretion). Of the 105 patients, 31 received prophylactic DEX and 74 received regorafenib alone. The time to dose modification was significantly longer in the DEX group than in the no DEX group (15 days vs. 9 days; P = .009). The incidence of fatigue (grade ≥ 1) was significantly lower with DEX than without DEX (25.8% vs. 50.0%; P = .022). Fewer patients experienced a decreased appetite (grade ≥ 1; 3.2% vs. 35.1%; P regorafenib treatment, resulting in prolonging the time to dose modification for regorafenib. The decreased incidence of appetite loss and HFSR also suggest that concurrent DEX administration with regorafenib warrants further investigation. Copyright © 2016 Elsevier Inc. All rights reserved.

[Treatment Strategy for Liver Metastasis of Colorectal Cancer - Including Treatment for Oligometastasis].

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Sato, Takeo; Nakamura, Takatoshi; Yamanashi, Takahiro; Miura, Hirohisa; Tsutsui, Atsuko; Shimazu, Masashi; Watanabe, Masahiko

2017-10-01

The mainstay of treatment for metastatic colorectal cancer is surgery. Therefore, colorectal cancer metastasis is distinctive, compared to other cancer types in which chemotherapy is the main treatment. Initially, Japan experienced medical druglag compared with western countries. However, the use of oxaliplatin for unresectable recurrent metastatic colorectal cancer became available in Japan, as well as in western countries, in 2005. We have since shifted chemotherapeutic regimens from monotherapy to combination therapy with molecular targeted agents. The combination therapy has rapidly become a standard therapy for unresectable metastatic colorectal cancer, and prognosis has dramatically increased for patients with this condition. Herein, we describe the treatment of liver metastasis of colorectal cancer, and surgery and adjuvant or neoadjuvant therapy options for resectable cancer. Furthermore, we focus on conversion therapy for unresectable cancer.

Efficacy of A Fluoropyrimidine plus Mitomycin C in Pretreated Patients with Metastatic Colorectal Cancer Eligible for Regorafenib: A Retrospective Study

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Federica Martorana

2017-11-01

Full Text Available Objective: In the placebo-controlled CORRECT study, individuals with metastatic colorectal cancer (mCRC receiving Regorafenib (RGR achieved significant benefits in both median overall survival (OS: 6.4 months and progression-free survival (PFS 1.9 months. Patients included in the study had previously failed all standard therapies, which must have included Fluoropyrimidines (FPDs, Oxaliplatin, Irinotecan, Bevacizumab, and Cetuximab or Panitumumab for K-RAS wild-type subjects. FPDs plus Mitomycin C (MMC represent one of the few treatment options for mCRC patients currently eligible for RGR. We wanted to investigate the therapeutic benefit of this pharmacological association in the same clinical setting defined for RGR. Methods: We retrospectively evaluated the records of mCRC patients followed in our Institutions that would have fulfilled inclusion/exclusion criteria for the CORRECT trial and received instead the combination of FPDs and MMC. We therefore collected data from 87 patients: 61 fulfilled the criteria required for this analysis. Results: Median OS was 9.3 months (95% CI 9.0–15.4, with a median PFS of 3.3 months (95% CI 2.9–3.8. One third of the patients (29.5% achieved disease control. No significant differences in OS and PFS were found between K-RAS WT and K-RAS mutant individuals. Likewise, Performance Status (PS and the primary site of disease were not associated with differences in response rates. Conclusions: These results suggest the need for a prospective study assessing RGR cost-effectiveness compared to FPDs plus MMC for mCRC patients that progress after standard treatments.

Negative hyper-selection of metastatic colorectal cancer patients for anti-EGFR monoclonal antibodies: the PRESSING case-control study.

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Cremolini, C; Morano, F; Moretto, R; Berenato, R; Tamborini, E; Perrone, F; Rossini, D; Gloghini, A; Busico, A; Zucchelli, G; Baratelli, C; Tamburini, E; Tampellini, M; Sensi, E; Fucà, G; Volpi, C; Milione, M; Di Maio, M; Fontanini, G; De Braud, F; Falcone, A; Pietrantonio, F

2017-12-01

Refining the selection of metastatic colorectal cancer patients candidates for anti-epidermal growth factor receptor (EGFR) monoclonal antibodies beyond RAS and BRAF testing is a challenge of precision oncology. Several uncommon genomic mechanisms of primary resistance, leading to activation of tyrosine kinase receptors other than EGFR or downstream signalling pathways, have been suggested by preclinical and retrospective studies. We conducted this multicentre, prospective, case-control study to demonstrate the negative predictive impact of a panel of rare genomic alterations [PRESSING (PRimary rESiStance IN RAS and BRAF wild-type metastatic colorectal cancer patients treated with anti-eGfr monoclonal antibodies) panel], including HER2/MET amplifications, ALK/ROS1/NTRK1-3/RET fusions and PIK3CA mutations. Hypothesizing a prevalence of candidate alterations of 15% and 0% in resistant and sensitive RAS and BRAF wild-type patients, respectively, with two-sided α and β errors of 0.05 and 0.20, 47 patients per group were needed. Forty-seven patients per group were included. PRESSING panel alterations were significantly more frequent in resistant (24 out of 47, 51.1%) than in sensitive (1 out of 47, 2.1%) patients (P < 0.001) and in right- (12 out of 29, 41.4%) than left-sided (13 out of 65, 20.0%) tumours (P = 0.03). The predictive accuracy of PRESSING panel and sidedness was 75.3% and 70.2%, respectively. Among hyper-selected patients, right-sidedness was still associated with resistance (P = 0.002). The predictive accuracy of the combined evaluation of PRESSING panel and sidedness was 80.4%. As a secondary analysis, 8 (17.0%) resistant and 0 sensitive patients showed microsatellite instability (P < 0.001). The investigated panel of genomic alterations allows refining the selection of RAS and BRAF wild-type metastatic colorectal cancer patients candidates for anti-EGFRs, partially explaining and further corroborating the predictive ability of primary

Prognostic value of primary tumour resection in synchronous metastatic colorectal cancer: Individual patient data analysis of first-line randomised trials from the ARCAD database

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van Rooijen, K. L.; Shi, Q.; Goey, K. K. H.; Meyers, J.; Heinemann, V.; Diaz-Rubio, E.; Aranda, E.; Falcone, A.; Green, E.; de Gramont, A.; Sargent, D. J.; Punt, C. J. A.; Koopman, M.

2018-01-01

Indication for primary tumour resection (PTR) in asymptomatic metastatic colorectal cancer (mCRC) patients is unclear. Previous retrospective analyses suggest a survival benefit for patients who underwent PTR. The aim was to evaluate the prognostic value of PTR in patients with synchronous mCRC by

Combination chemotherapy with Regorafenib in metastatic colorectal cancer treatment: A single center, retrospective study.

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Chun-Yu Lin

Full Text Available Regorafenib has been demonstrated as effective in refractory metastatic colorectal cancer. Combination use with chemotherapy has not been reported. We examined the efficacy and safety of adding chemotherapy to Regorafenib for the treatment of metastatic colorectal cancer(mCRC patients.We recruited mCRC patients at our institute who received either regorafenib monotherapy or regorafenib in combination with other chemotherapies. All patients had received chemo and target therapies and presented with disease progression before regorafenib treatment. The primary end point was overall survival.Between September1, 2015 and May 31, 2017, 100 mCRC patients at our institute received regorafenib treatment. 39 patients were excluded due to poor performance, lack of timely treatment, or inadequate clinical data. A total of 34 patients received regorafenib combined with other chemotherapies, and 27 patients received regorafenib alone. Median follow up time was 10.4 and 6.1 months, respectively. The primary end point of median OS was higher in the combination group than in the single use group (20.9m vs 10.3m, p = 0.015. The most frequent adverse events were hand-foot skin reactions(16[47.1%]vs 12[44.4%], fatigue(6[17.6%] vs 7[25.9%], gastrointestinal discomfort (7[20.6%] vs 6[22.2%], neutropenia (4[11.8%] vs 1[3.7%], diarrhea(4[11.8%] vs 1[3.7%], and mucositis(5[14.7%] vs 1[3.7%].The present study showed the efficacy and side effects of regorafenib combination treatment. Superiority in median OS and median PFS was noted in the combination group. The sampling difference between the study and observation groups effects justifies the comparison. Further clinical evidence of combination therapy efficacy is pending future studies.

Combination chemotherapy with Regorafenib in metastatic colorectal cancer treatment: A single center, retrospective study.

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Lin, Chun-Yu; Lin, Tseng-Hsi; Chen, Chou-Chen; Chen, Ming-Cheng; Chen, Chou-Pin

2018-01-01

Regorafenib has been demonstrated as effective in refractory metastatic colorectal cancer. Combination use with chemotherapy has not been reported. We examined the efficacy and safety of adding chemotherapy to Regorafenib for the treatment of metastatic colorectal cancer(mCRC) patients. We recruited mCRC patients at our institute who received either regorafenib monotherapy or regorafenib in combination with other chemotherapies. All patients had received chemo and target therapies and presented with disease progression before regorafenib treatment. The primary end point was overall survival. Between September1, 2015 and May 31, 2017, 100 mCRC patients at our institute received regorafenib treatment. 39 patients were excluded due to poor performance, lack of timely treatment, or inadequate clinical data. A total of 34 patients received regorafenib combined with other chemotherapies, and 27 patients received regorafenib alone. Median follow up time was 10.4 and 6.1 months, respectively. The primary end point of median OS was higher in the combination group than in the single use group (20.9m vs 10.3m, p = 0.015). The most frequent adverse events were hand-foot skin reactions(16[47.1%]vs 12[44.4%]), fatigue(6[17.6%] vs 7[25.9%]), gastrointestinal discomfort (7[20.6%] vs 6[22.2%]), neutropenia (4[11.8%] vs 1[3.7%]), diarrhea(4[11.8%] vs 1[3.7%]), and mucositis(5[14.7%] vs 1[3.7%]). The present study showed the efficacy and side effects of regorafenib combination treatment. Superiority in median OS and median PFS was noted in the combination group. The sampling difference between the study and observation groups effects justifies the comparison. Further clinical evidence of combination therapy efficacy is pending future studies.

Combination chemotherapy with Regorafenib in metastatic colorectal cancer treatment: A single center, retrospective study

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Lin, Chun-Yu; Lin, Tseng-Hsi; Chen, Chou-Chen; Chen, Ming-Cheng

2018-01-01

Background Regorafenib has been demonstrated as effective in refractory metastatic colorectal cancer. Combination use with chemotherapy has not been reported. We examined the efficacy and safety of adding chemotherapy to Regorafenib for the treatment of metastatic colorectal cancer(mCRC) patients. Methods We recruited mCRC patients at our institute who received either regorafenib monotherapy or regorafenib in combination with other chemotherapies. All patients had received chemo and target therapies and presented with disease progression before regorafenib treatment. The primary end point was overall survival. Findings Between September1, 2015 and May 31, 2017, 100 mCRC patients at our institute received regorafenib treatment. 39 patients were excluded due to poor performance, lack of timely treatment, or inadequate clinical data. A total of 34 patients received regorafenib combined with other chemotherapies, and 27 patients received regorafenib alone. Median follow up time was 10.4 and 6.1 months, respectively. The primary end point of median OS was higher in the combination group than in the single use group (20.9m vs 10.3m, p = 0.015). The most frequent adverse events were hand-foot skin reactions(16[47.1%]vs 12[44.4%]), fatigue(6[17.6%] vs 7[25.9%]), gastrointestinal discomfort (7[20.6%] vs 6[22.2%]), neutropenia (4[11.8%] vs 1[3.7%]), diarrhea(4[11.8%] vs 1[3.7%]), and mucositis(5[14.7%] vs 1[3.7%]). Conclusion The present study showed the efficacy and side effects of regorafenib combination treatment. Superiority in median OS and median PFS was noted in the combination group. The sampling difference between the study and observation groups effects justifies the comparison. Further clinical evidence of combination therapy efficacy is pending future studies. PMID:29304109

Clinical Implication of Anti-Angiogenic Effect of Regorafenib in Metastatic Colorectal Cancer.

Directory of Open Access Journals (Sweden)

Yoojoo Lim

Full Text Available Regorafenib induces distinct radiological changes that represent its anti-angiogenic effect. However, clinical implication of the changes is unclear.Tumor attenuation as measured by Hounsfield units (HU in contrast-enhanced computed tomography (CT and cavitary changes of lung metastases were analyzed in association with treatment outcome of metastatic colorectal cancer patients (N = 80 treated with regorafenib in a prospective study.141 lesions in 72 patients were analyzed with HU. After 2 cycles of regorafenib, 87.5% of patients showed decrease of HU (Median change -23.9%, range -61.5%-20.7%. Lesional attenuation change was modestly associated with metabolic changes of 18-fluoro-deoxyglucose positron emission tomography-CT (Pearson's r = 0.37, p = 0.002. Among 53 patients with lung metastases, 17 (32.1% developed cavitary changes. There were no differences in disease control rate, progression-free survival, or overall survival according to the radiological changes. At the time of progressive disease (PD according to RECIST 1.1, HU was lower than baseline in 86.0% (43/50 and cavitary change of lung metastasis persisted without refilling in 84.6% (11/13.Regorafenib showed prominent anti-angiogenic effect in colorectal cancer, but the changes were not associated with treatment outcome. However, the anti-angiogenic effects persisted at the time of PD, which suggests that we may need to develop new treatment strategies.

Clinical Implication of Anti-Angiogenic Effect of Regorafenib in Metastatic Colorectal Cancer

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Yoon, Jeong Hee; Lee, Jeong Min; Lee, Jung Min; Paeng, Jin Chul; Won, Jae-Kyung; Kang, Gyeong Hoon; Jeong, Seung-Yong; Park, Kyu Joo; Lee, Kyung-Hun; Kim, Jee Hyun; Kim, Tae-You

2015-01-01

Background Regorafenib induces distinct radiological changes that represent its anti-angiogenic effect. However, clinical implication of the changes is unclear. Methods Tumor attenuation as measured by Hounsfield units (HU) in contrast-enhanced computed tomography (CT) and cavitary changes of lung metastases were analyzed in association with treatment outcome of metastatic colorectal cancer patients (N = 80) treated with regorafenib in a prospective study. Results 141 lesions in 72 patients were analyzed with HU. After 2 cycles of regorafenib, 87.5% of patients showed decrease of HU (Median change -23.9%, range -61.5%–20.7%). Lesional attenuation change was modestly associated with metabolic changes of 18-fluoro-deoxyglucose positron emission tomography-CT (Pearson’s r = 0.37, p = 0.002). Among 53 patients with lung metastases, 17 (32.1%) developed cavitary changes. There were no differences in disease control rate, progression-free survival, or overall survival according to the radiological changes. At the time of progressive disease (PD) according to RECIST 1.1, HU was lower than baseline in 86.0% (43/50) and cavitary change of lung metastasis persisted without refilling in 84.6% (11/13). Conclusion Regorafenib showed prominent anti-angiogenic effect in colorectal cancer, but the changes were not associated with treatment outcome. However, the anti-angiogenic effects persisted at the time of PD, which suggests that we may need to develop new treatment strategies. PMID:26671465

Targeting Angiogenesis and Tumor Microenvironment in Metastatic Colorectal Cancer: Role of Aflibercept

Directory of Open Access Journals (Sweden)

Guido Giordano

2014-01-01

Full Text Available In the last decades, we have progressively observed an improvement in therapeutic options for metastatic colorectal cancer (mCRC treatment with a progressive prolongation of survival. mCRC prognosis still remains poor with low percentage of 5-year survival. Targeted agents have improved results obtained with standard chemotherapy. Angiogenesis plays a crucial role in colorectal cancer growth, proliferation, and metastasization and it has been investigated as a potential target for mCRC treatment. Accordingly, novel antiangiogenic targeted agents bevacizumab, regorafenib, and aflibercept have been approved for mCRC treatment as the result of several phase III randomized trials. The development of a tumor permissive microenvironment via the aberrant expression by tumor cells of paracrine factors alters the tumor-stroma interactions inducing an expansion of proangiogenic signals. Recently, the VELOUR study showed that addition of aflibercept to FOLFIRI regimen as a second-line therapy for mCRC improved significantly OS, PFS, and RR. This molecule represents a valid second-line therapeutic option and its peculiar ability to interfere with placental growth factor (PlGF/vascular endothelial growth factor receptor 1 (VEGFR1 axis makes it effective in targeting angiogenesis, inflammatory cells and in overcoming resistances to anti-angiogenic first-line treatment. Here, we discuss about Aflibercept peculiar ability to interfere with tumor microenvironment and angiogenic pathway.

Clinical Value of a One-Stop-Shop Low-Dose Lung Screening Combined with (18)F-FDG PET/CT for the Detection of Metastatic Lung Nodules from Colorectal Cancer.

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Han, Yeon-Hee; Lim, Seok Tae; Jeong, Hwan-Jeong; Sohn, Myung-Hee

2016-06-01

The aim of this study was to evaluate the clinical usefulness of additional low-dose high-resolution lung computed tomography (LD-HRCT) combined with (18)F-fluoro-2-deoxyglucose positron emission tomography with CT ((18)F-FDG PET/CT) compared with conventional lung setting image of (18)F-FDG PET/CT for the detection of metastatic lung nodules from colorectal cancer. From January 2011 to September 2011, 649 patients with colorectal cancer underwent additional LD-HRCT at maximum inspiration combined with (18)F-FDG PET/CT. Forty-five patients were finally diagnosed to have lung metastasis based on histopathologic study or clinical follow-up. Twenty-five of the 45 patients had ≤5 metastatic lung nodules and the other 20 patients had >5 metastatic nodules. One hundred and twenty nodules in the 25 patients with ≤5 nodules were evaluated by conventional lung setting image of (18)F-FDG PET/CT and by additional LD-HRCT respectively. Sensitivities, specificities, diagnostic accuracies, positive predictive values (PPVs), and negative predictive values (NPVs) of conventional lung setting image of (18)F-FDG PET/CT and additional LD-HRCT were calculated using standard formulae. The McNemar test and receiver-operating characteristic (ROC) analysis were performed. Of the 120 nodules in the 25 patients with ≤5 metastatic lung nodules, 66 nodules were diagnosed as metastatic. Eleven of the 66 nodules were confirmed histopathologically and the others were diagnosed by clinical follow-up. Conventional lung setting image of (18)F-FDG PET/CT detected 40 of the 66 nodules and additional LD-HRCT detected 55 nodules. All 15 nodules missed by conventional lung setting imaging but detected by additional LD-HRCT were LD-HRCT. By ROC analysis, the area under the ROC curve (AUC) of conventional lung setting image and additional LD-HRCT were 0.712 and 0.827 respectively. Additional LD-HRCT with maximum inspiration was superior to conventional lung setting image of (18)F-FDG PET

Circulating Tumor Cell Count Correlates with Colorectal Neoplasm Progression and Is a Prognostic Marker for Distant Metastasis in Non-Metastatic Patients

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Tsai, Wen-Sy; Chen, Jinn-Shiun; Shao, Hung-Jen; Wu, Jen-Chia; Lai-Ming, Jr.; Lu, Si-Hong; Hung, Tsung-Fu; Chiu, Yen-Chi; You, Jeng-Fu; Hsieh, Pao-Shiu; Yeh, Chien-Yuh; Hung, Hsin-Yuan; Chiang, Sum-Fu; Lin, Geng-Ping; Tang, Reiping; Chang, Ying-Chih

2016-04-01

Enumeration of circulating tumor cells (CTCs) has been proven as a prognostic marker for metastatic colorectal cancer (m-CRC) patients. However, the currently available techniques for capturing and enumerating CTCs lack of required sensitivity to be applicable as a prognostic marker for non-metastatic patients as CTCs are even more rare. We have developed a microfluidic device utilizing antibody-conjugated non-fouling coating to eliminate nonspecific binding and to promote the multivalent binding of target cells. We then established the correlation of CTC counts and neoplasm progression through applying this platform to capture and enumerate CTCs in 2 mL of peripheral blood from healthy (n = 27), benign (n = 21), non-metastatic (n = 95), and m-CRC (n = 15) patients. The results showed that the CTC counts progressed from 0, 1, 5, to 36. Importantly, after 2-year follow-up on the non-metastatic CRC patients, we found that those who had ≥5 CTCs were 8 times more likely to develop distant metastasis within one year after curable surgery than those who had marker for the non-metastatic CRC patients who are at high risk of early recurrence.

Primary tumor location predicts poor clinical outcome with cetuximab in RAS wild-type metastatic colorectal cancer.

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Kim, Dalyong; Kim, Sun Young; Lee, Ji Sung; Hong, Yong Sang; Kim, Jeong Eun; Kim, Kyu-Pyo; Kim, Jihun; Jang, Se Jin; Yoon, Young-Kwang; Kim, Tae Won

2017-11-23

In metastatic colorectal cancer, the location of the primary tumor has been suggested to have biological significance. In this study, we investigated whether primary tumor location affects cetuximab efficacy in patients with RAS wild-type metastatic colorectal cancer. Genotyping by the SequenomMassARRAY technology platform (OncoMap) targeting KRAS, NRAS, PIK3CA, and BRAF was performed in tumors from 307 patients who had been given cetuximab as salvage treatment. Tumors with mutated RAS (KRAS or NRAS; n = 127) and those with multiple primary location (n = 10) were excluded. Right colon cancer was defined as a tumor located in the proximal part to splenic flexure. A total of 170 patients were included in the study (right versus left, 23 and 147, respectively). Patients with right colon cancer showed more mutated BRAF (39.1% vs. 5.4%), mutated PIK3CA (13% vs. 1.4%), poorly differentiated tumor (17.4% vs. 3.4%), and peritoneal involvement (26.1% vs. 8.8%) than those with left colon and rectal cancer. Right colon cancer showed poorer progression-free survival (2.0 vs.5.0 months, P = 0.002) and overall survival (4.1 months and 13.0 months, P < 0.001) than the left colon and rectal cancer. By multivariable analysis, BRAF mutation, right colon primary, poorly differentiated histology, and peritoneal involvement were associated with risk of death. In RAS wild-type colon cancer treated with cetuximab as salvage treatment, right colon primary was associated with poorer survival outcomes than left colon and rectal cancer.

Proactive strategies for regorafenib in metastatic colorectal cancer: implications for optimal patient management

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Khan G

2014-03-01

Full Text Available Gazala Khan,1 Rebecca A Moss,2 Fadi Braiteh,3,4 Marc Saltzman5 1Department of Hematology and Oncology, Henry Ford Hospital, Detroit, MI, USA; 2Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA; 3US Oncology Research, Las Vegas, NV, USA; 4Comprehensive Cancer Centers of Nevada, Las Vegas, NV, USA; 5Innovative Medical Research of South Florida, Inc, Aventura, FL, USA Abstract: Regorafenib is a broad-spectrum oral multikinase inhibitor that targets several angiogenic, oncogenic, and stromal receptor tyrosine kinases that support the tumor microenvironment. Results from the pivotal Phase III Patients with Metastatic Colorectal Cancer Treated with Regorafenib or Placebo After Failure of Standard Therapy (CORRECT trial showed that the addition of regorafenib to best supportive care resulted in a significant improvement in median overall survival and progression-free survival compared with placebo plus best supportive care in patients with metastatic colorectal cancer (mCRC following all available approved therapies. Thus, regorafenib is the first oral multikinase inhibitor indicated for mCRC; it currently has approval in the USA, EU, Japan, Canada, and Singapore for the treatment of mCRC patients who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-vascular endothelial growth factor therapy, and, if the tumor is KRAS wild-type, an anti-epidermal growth factor receptor therapy. In this review, we highlight regorafenib's mechanism of action, present key efficacy data from the CORRECT trial, and discuss how to proactively manage common adverse events (eg, hand-foot skin reaction, hypertension, oral mucositis, diarrhea, and fatigue experienced by patients receiving regorafenib. Increased awareness of potential adverse events associated with regorafenib and the implementation of proactive strategies to prevent, monitor, and manage these

Predictive biomarkers with potential of converting conventional chemotherapy to targeted therapy in patients with metastatic colorectal cancer

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Jensen, Niels Frank; Smith, David Hersi; Nygård, Sune Boris

2012-01-01

Abstract The availability of systemic chemotherapy regimens for the treatment of patients with metastatic colorectal cancer (mCRC) is based on the results from large prospective, randomized studies. The main chemotherapeutic drugs used in treatment of mCRC are the fluoropyrimidines (5-fluorouracil......, a number of preclinical and clinical studies have indicated lack of full cross resistance between oxaliplatin based and irinotecan based treatment. Therefore, it is possible that certain mCRC patient subpopulations would benefit more from one drug combination rather than the other. To address this clinical...

Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer

NARCIS (Netherlands)

Peeters, Marc; Price, Timothy Jay; Cervantes, Andrés; Sobrero, Alberto F.; Ducreux, Michel; Hotko, Yevhen; André, Thierry; Chan, Emily; Lordick, Florian; Punt, Cornelis J. A.; Strickland, Andrew H.; Wilson, Gregory; Ciuleanu, Tudor-Eliade; Roman, Laslo; van Cutsem, Eric; Tzekova, Valentina; Collins, Simon; Oliner, Kelly S.; Rong, Alan; Gansert, Jennifer

2010-01-01

Panitumumab is a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody that improves progression-free survival (PFS) in chemotherapy-refractory metastatic colorectal cancer (mCRC). This trial evaluated the efficacy and safety of panitumumab plus fluorouracil, leucovorin, and

Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer

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Tveit, Kjell Magne; Guren, Tormod; Glimelius, Bengt

2012-01-01

The NORDIC-VII multicenter phase III trial investigated the efficacy of cetuximab when added to bolus fluorouracil/folinic acid and oxaliplatin (Nordic FLOX), administered continuously or intermittently, in previously untreated metastatic colorectal cancer (mCRC). The influence of KRAS mutation...

The effect of individualized nutritional counseling on muscle mass and treatment outcome in patients with metastatic colorectal cancer undergoing chemotherapy: a randomized controlled trial protocol

NARCIS (Netherlands)

van der Werf, Anne; Blauwhoff-Buskermolen, Susanne; Langius, Jacqueline A. E.; Berkhof, Johannes; Verheul, Henk M. W.; de van der Schueren, Marian A. E.

2015-01-01

A low muscle mass is prevalent in patients with metastatic colorectal cancer (mCRC) and has been associated with poor treatment outcome. Chemotherapeutic treatment has an additional unfavorable effect on muscle mass. Sufficient protein intake and physical activity are known to induce muscle protein

Differentiation of Metastatic and Non-Metastatic Mesenteric Lymph Nodes by Strain Elastography in Surgical Specimens

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Havre, R F; Leh, S M; Gilja, O H

2016-01-01

Purpose: To investigate if strain elastography could differentiate between metastatic and non-metastatic mesenteric lymph nodes ex-vivo. Materials and Methods: 90 mesenteric lymph nodes were examined shortly after resection from 25 patients including 17 patients with colorectal cancer and 8...... patients with Crohn's disease. Ultrasound-based strain elastography was performed with a linear probe. Tissue hardness in lymph nodes was assessed using visual scales and measuring the strain ratio. B-mode characteristics were also recorded. Pathological diagnosis with grading of fibrosis served...... non-metastatic nodes, but the difference was not significant (65.5 vs. 55.0, p = 0.055). There was no difference between lymph nodes in Crohn's and non-metastatic cancer specimens. The metastatic lymph nodes were significantly more fibrotic than the non-metastatic lymph nodes by the ordinal fibrosis...

Cytogenetic findings in metastases from colorectal cancer

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Bardi, G; Parada, L A; Bomme, L

1997-01-01

Eighteen tumor samples from 11 patients with metastatic colorectal cancer were cytogenetically analyzed after short-term culturing. Of the 13 metastases examined, 11 were from lymph nodes, 1 from the peritoneum and 1 from the lung. In 5 of the 11 patients, matched samples from the primary tumor...... colorectal carcinomas, and del(10)(q22) and add(16)(p13), which so far have not been associated with primary tumors and which may play a particular pathogenetic role in the metastatic process....

Personality variables as predictors of early non-metastatic colorectal cancer patients' psychological distress and health-related quality of life: a one-year prospective study.

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Hyphantis, Thomas; Paika, Vassiliki; Almyroudi, Augoustina; Kampletsas, Eleftherios O; Pavlidis, Nicholas

2011-05-01

We aimed to assess the course of early non-metastatic colorectal cancer patients' psychological distress and health-related quality of life (HRQOL) and to identify relevant clinical and psychological predictors during a one-year period. Of the 144 early non-metastatic colorectal cancer patients initially assessed for psychological distress symptoms (SCL-90-R), HRQOL (WHOQOL-BREF), sense of coherence (SOC), defense mechanisms (LSI) and hostility (HDHQ), 84 (58.3%) completed the one-year follow-up. Mean (SD) age was 65.1 (9.8) years and 67.4% were male. Mean (SD) disease duration was 1.7 (2.2) years, with 49.3% being diagnosed within the last six months. In 75.0% the site was at colon and in 25.0% at rectum; 2.1% had stage I, 59.0% stage II and 38.9% stage III disease. Paranoid ideation, psychoticism, interpersonal sensitivity, anxiety and depressive symptoms increased significantly over the one-year period of the study and most of the HRQOL components were significantly decreased over the same period. Men were at greater risk for further developing depressive symptomatology. Low SOC was independent predictor of depression, while hostility independently predicted anxiety, interpersonal sensitivity and psychoticism symptoms. General psychological distress and low SOC were independent predictors of HRQOL, while repression was also an independent predictor of Physical HRQOL. In early non-metastatic colorectal cancer patients, psychological distress symptoms are increased and HRQOL is decreased over one-year period. Symptoms of psychological distress are strong predictors of HRQOL, while personality variables can also predict psychological distress symptoms' increase and HRQOL decrease over time, and this could be relevant to psychological interventions. Copyright © 2010 Elsevier Inc. All rights reserved.

Lymph node status as a prognostic factor after palliative resection of primary tumor for patients with metastatic colorectal cancer.

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Li, Qingguo; Wang, Changjian; Li, Yaqi; Li, Xinxiang; Xu, Ye; Cai, Guoxiang; Lian, Peng; Cai, Sanjun

2017-07-18

Lymph node (LN) status is one of the most important predictors for M0 colorectal cancer patients. However, its clinical impact on stage IV colorectal cancer remains unclear. The study aimed to explore the prognostic value of LN status after palliative resection of primary tumor for patients with metastatic colorectal cancer (mCRC). We combined analyses of mCRC patients in Surveillance, Epidemiology and End Results (SEER) database and Fudan University Shanghai Cancer Center (FUSCC).A total of 17,553 patients with mCRC were identified in SEER database. X-tile program was adopted to identify 2 and 10 as optimal cutoff values for negative lymph node (NLN) count to divide patients into 3 subgroups of high, middle and low risk of cancer related death. N stage and NLN count were verified as independent prognostic factors in multivariate analyses of patients in whole cohort and in subgroup analyses of each N stage (Pcolorectal cancer. Advanced N stage and small number of NLN were correlated with high risk of cancer related death after palliative resection of primary tumor.

Ocoxin oral solution? as a complement to irinotecan chemotherapy in the metastatic progression of colorectal cancer to the liver

OpenAIRE

Hernandez-Unzueta, Iera; Benedicto, Aitor; Olaso, Elvira; Sanz, Eduardo; Viera, Cristina; Arteta, Beatriz; M?rquez, Joana

2017-01-01

Colorectal cancer (CRC) is an aggressive disease in which patients usually die due to its metastatic progression to the liver. Up to date, irinotecan is one of the most used chemotherapeutic agents to treat CRC metastasis with demonstrated efficacy. However, the severity of the side effects constitute the main limitation to its use in the treatment. Consequently, new complementary therapies are being developed to avoid these adverse effects while maintaining the efficacy of the antitumoral dr...

Statin use is not associated with improved progression free survival in cetuximab treated KRAS mutant metastatic colorectal cancer patients: results from the CAIRO2 study

NARCIS (Netherlands)

Krens, Lisanne L.; Simkens, Lieke H. J.; Baas, Jara M.; Koomen, Els R.; Gelderblom, Hans; Punt, Cornelis J. A.; Guchelaar, Henk-Jan

2014-01-01

Statins may inhibit the expression of the mutant KRAS phenotype by preventing the prenylation and thus the activation of the KRAS protein. This study was aimed at retrospectively evaluating the effect of statin use on outcome in KRAS mutant metastatic colorectal cancer patients (mCRC) treated with

Second-line systemic therapy for metastatic colorectal cancer.

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Mocellin, Simone; Baretta, Zora; Roqué I Figuls, Marta; Solà, Ivan; Martin-Richard, Marta; Hallum, Sara; Bonfill Cosp, Xavier

2017-01-27

The therapeutic management of people with metastatic colorectal cancer (CRC) who did not respond to first-line treatment represents a formidable challenge. To determine the efficacy and toxicity of second-line systemic therapy in people with metastatic CRC. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2016, Issue 4), Ovid MEDLINE (1950 to May 2016), Ovid MEDLINE In-process & Other Non-Indexed Citations (1946 to May 2016) and Ovid Embase (1974 to May 2016). There were no language or date of publication restrictions. Randomized controlled trials (RCTs) assessing the efficacy (survival, tumour response) and toxicity (incidence of severe adverse effects (SAEs)) of second-line systemic therapy (single or combined treatment with any anticancer drug, at any dose and number of cycles) in people with metastatic CRC that progressed, recurred or did not respond to first-line systemic therapy. Authors performed a descriptive analysis of each included RCT in terms of primary (survival) and secondary (tumour response, toxicity) endpoints. In the light of the variety of drug regimens tested in the included trials, we could carry out meta-analysis considering classes of (rather than single) anticancer regimens; to this aim, we applied the random-effects model to pool the data. We used hazard ratios (HRs) and risk ratios (RRs) to describe the strength of the association for survival (overall (OS) and progression-free survival (PFS)) and dichotomous (overall response rate (ORR) and SAE rate) data, respectively, with 95% confidence intervals (CI). Thirty-four RCTs (enrolling 13,787 participants) fulfilled the eligibility criteria. Available evidence enabled us to address multiple clinical issues regarding the survival effects of second-line systemic therapy of people with metastatic CRC.1. Chemotherapy (irinotecan) was more effective than best supportive care (HR for OS: 0.58, 95% CI 0.43 to 0.80; 1 RCT; moderate-quality evidence); 2

Intrabilary obstruction by colorectal metastases

OpenAIRE

Traeger, Luke; Kiroff, George

2018-01-01

Abstract Intrabiliary colorectal metastases are rare. We present a case of an 84-year-old man who developed obstructive jaundice secondary to intrabiliary growth of colorectal metastases. The patient presented with three weeks of jaundice and significant weight loss in the preceding months. The patient’s background included metastatic colorectal carcinoma, with a previous right hemicolectomy and left hepatectomy for liver metastases. A MRCP showed an obstruction of the biliary tract transitio...

Early dissemination of bevacizumab for advanced colorectal cancer: a prospective cohort study

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Fouad Mona N

2011-08-01

Full Text Available Abstract Background We describe early dissemination patterns for first-line bevacizumab given for metastatic colorectal cancer treatment. Methods We analyzed patient surveys and medical records for a population-based cohort with metastatic colorectal cancer treated in multiple regions and health systems in the United States (US. Eligible patients were diagnosed with metastatic colorectal cancer and initiated first-line chemotherapy after US Food & Drug Administration (FDA bevacizumab approval in February 2004. First-line bevacizumab therapy was defined as receiving bevacizumab within 8 weeks of starting chemotherapy for metastatic colorectal cancer. We evaluated factors associated with first-line bevacizumab treatment using logistic regression. Results Among 355 patients, 31% received first-line bevacizumab in the two years after FDA approval, including 26% of men, 41% of women, and 16% of those ≥ 75 years. Use rose sharply within 6 months after FDA approval, then plateaued. 20% of patients received bevacizumab in combination with irinotecan; 53% received it with oxaliplatin. Men were less likely than women to receive bevacizumab (adjusted OR 0.55; 95% CI 0.32-0.93; p = 0.026. Patients ≥ 75 years were less likely to receive bevacizumab than patients Conclusions One-third of eligible metastatic colorectal cancer patients received first-line bevacizumab shortly after FDA approval. Most patients did not receive bevacizumab as part of the regimen used in the pivotal study leading to FDA approval.

Regorafenib in combination with silybin as a novel potential strategy for the treatment of metastatic colorectal cancer.

Science.gov (United States)

Belli, Valentina; Sforza, Vincenzo; Cardone, Claudia; Martinelli, Erika; Barra, Giusi; Matrone, Nunzia; Napolitano, Stefania; Morgillo, Floriana; Tuccillo, Concetta; Federico, Alessandro; Dallio, Marcello; Loguercio, Carmelina; Gravina, Antonietta Gerarda; De Palma, Raffaele; Ciardiello, Fortunato; Troiani, Teresa

2017-09-15

Regorafenib, an oral multikinase inhibitor, has demonstrated survival benefit in metastatic colorectal cancer (mCRC) patients that have progressed after all standard therapies. However, novel strategies to improve tolerability and enhance anti-cancer efficacy are needed. We have evaluated in vitro the effects of regorafenib in combination with silybin, a biologically active component extracted from the seeds of Silybum marianum, in a panel of human colon cancer cells. Furthermore, we have prospectively treated a cohort of 22 refractory mCRC patients with regorafenib plus silybin. Treatment with regorafenib determined a dose-dependent growth inhibition whereas treatment with silybin had no anti-proliferative effects among all cancer cells tested. The combined treatment with regorafenib and silybin induced synergistic anti-proliferative and apoptotic effects by blocking PI3K/AKT/mTOR intracellular pathway. Moreover, combined treatment with regorafenib and silybin increased the production of reactive oxygen species levels within cells. In an exploratory proof of concept clinical study in a cohort of 22 mCRC patients after failure of all standard therapies, the clinical activity of regorafenib in combination with silybin was assessed. A median progression-free survival of 10.0 months and a median overall survival of 17.6 months were observed in these patients. These results suggest that the combined treatment potentially increases the clinical efficacy of regorafenib. Moreover, due to its anti-oxidative properties, silybin could protect patients from drug-induced liver damages, allowing to continue an effective anti-cancer therapy. The present study suggests that silybin in combination with regorafenib is a promising strategy for treatment of metastatic colorectal patients.

FOLFOXIRI Plus Bevacizumab as Conversion Therapy for Patients With Initially Unresectable Metastatic Colorectal Cancer: A Systematic Review and Pooled Analysis.

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Tomasello, Gianluca; Petrelli, Fausto; Ghidini, Michele; Russo, Alessandro; Passalacqua, Rodolfo; Barni, Sandro

2017-07-13

The combination of fluorouracil, oxaliplatin, and irinotecan plus bevacizumab (FOLFOXIRI-Bev) is an established and effective first-line chemotherapy regimen for metastatic colorectal cancer. However, resection rates of metastases and overall survival with this schedule have never been systematically evaluated in published studies including, but not limited to, the TRIBE (TRIplet plus BEvacizumab) trial. To assess the clinical efficacy of FOLFOXIRI-Bev, including outcomes and rates of surgical conversions. A systematic review was conducted in October 2016 in concordance with the PRISMA guidelines of PubMed, the Cochrane Central Register of Controlled Trials, SCOPUS, Web of Science, Google Scholar, CINAHL, Ovid, and EMBASE using the terms FOLFOXIRI and bevacizumab and (colorectal cancer). Clinical trials, retrospective case series, and prospective case series that used FOLFOXIRI-Bev for the treatment of initially unresectable metastatic colorectal cancer in humans were included. Individual case reports and retrospective case series with fewer than 10 patients were excluded. Data were extracted independently by 2 reviewers on a predesigned, standardized form. Ultimately, data were aggregated to obtain the pooled effect size of efficacy, according to the random-effects model and weighted for the number of patients included in each trial. Median overall survival and progression-free survival, overall response rates, and rates of R0 surgical conversions and overall surgical conversions. Eleven FOLFOXIRI-Bev studies published between 2010 and 2016 met the inclusion criteria and were pooled for analysis. The studies included 889 patients, with 877 patients clinically evaluable for overall response rates. The objective response rate to FOLFOXIRI-Bev was 69% (95% CI, 65%-72%; I2 = 25%). The rate of overall surgical conversions was 39.1% (95% CI, 26.9%-52.8%), and the rate of R0 surgical conversions was 28.1% (95% CI, 18.1%-40.8%). Median pooled overall survival was 30

An Evaluation of Algorithms for Identifying Metastatic Breast, Lung, or Colorectal Cancer in Administrative Claims Data.

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Whyte, Joanna L; Engel-Nitz, Nicole M; Teitelbaum, April; Gomez Rey, Gabriel; Kallich, Joel D

2015-07-01

Administrative health care claims data are used for epidemiologic, health services, and outcomes cancer research and thus play a significant role in policy. Cancer stage, which is often a major driver of cost and clinical outcomes, is not typically included in claims data. Evaluate algorithms used in a dataset of cancer patients to identify patients with metastatic breast (BC), lung (LC), or colorectal (CRC) cancer using claims data. Clinical data on BC, LC, or CRC patients (between January 1, 2007 and March 31, 2010) were linked to a health care claims database. Inclusion required health plan enrollment ≥3 months before initial cancer diagnosis date. Algorithms were used in the claims database to identify patients' disease status, which was compared with physician-reported metastases. Generic and tumor-specific algorithms were evaluated using ICD-9 codes, varying diagnosis time frames, and including/excluding other tumors. Positive and negative predictive values, sensitivity, and specificity were assessed. The linked databases included 14,480 patients; of whom, 32%, 17%, and 14.2% had metastatic BC, LC, and CRC, respectively, at diagnosis and met inclusion criteria. Nontumor-specific algorithms had lower specificity than tumor-specific algorithms. Tumor-specific algorithms' sensitivity and specificity were 53% and 99% for BC, 55% and 85% for LC, and 59% and 98% for CRC, respectively. Algorithms to distinguish metastatic BC, LC, and CRC from locally advanced disease should use tumor-specific primary cancer codes with 2 claims for the specific primary cancer >30-42 days apart to reduce misclassification. These performed best overall in specificity, positive predictive values, and overall accuracy to identify metastatic cancer in a health care claims database.

Potentially functional SNPs (pfSNPs as novel genomic predictors of 5-FU response in metastatic colorectal cancer patients.

Directory of Open Access Journals (Sweden)

Jingbo Wang

Full Text Available 5-Fluorouracil (5-FU and its pro-drug Capecitabine have been widely used in treating colorectal cancer. However, not all patients will respond to the drug, hence there is a need to develop reliable early predictive biomarkers for 5-FU response. Here, we report a novel potentially functional Single Nucleotide Polymorphism (pfSNP approach to identify SNPs that may serve as predictive biomarkers of response to 5-FU in Chinese metastatic colorectal cancer (CRC patients. 1547 pfSNPs and one variable number tandem repeat (VNTR in 139 genes in 5-FU drug (both PK and PD pathway and colorectal cancer disease pathways were examined in 2 groups of CRC patients. Shrinkage of liver metastasis measured by RECIST criteria was used as the clinical end point. Four non-responder-specific pfSNPs were found to account for 37.5% of all non-responders (P<0.0003. Five additional pfSNPs were identified from a multivariate model (AUC under ROC = 0.875 that was applied for all other pfSNPs, excluding the non-responder-specific pfSNPs. These pfSNPs, which can differentiate the other non-responders from responders, mainly reside in tumor suppressor genes or genes implicated in colorectal cancer risk. Hence, a total of 9 novel SNPs with potential functional significance may be able to distinguish non-responders from responders to 5-FU. These pfSNPs may be useful biomarkers for predicting response to 5-FU.

Curable Metastatic Colorectal Cancer

OpenAIRE

Hochster, Howard S.

2010-01-01

Colon cancer, though already metastatic, may still be curable through multi-modality approaches, which require combined planning between medical and surgical oncologists. Retrospective surgical series have historically shown 5-year survival or “cures” for 30% to 50% of patients with solitary or a few resectable liver metastases. The role of adjuvant chemotherapy in this setting has been poorly defined. A recent European Organization for Research and Treatment of Cancer (EORTC) study randomize...

Heparan sulfate proteoglycans undergo differential expression alterations in right sided colorectal cancer, depending on their metastatic character

International Nuclear Information System (INIS)

Fernández-Vega, Iván; García-Suárez, Olivia; García, Beatriz; Crespo, Ainara; Astudillo, Aurora; Quirós, Luis M.

2015-01-01

Heparan sulfate proteoglycans (HSPGs) are complex molecules involved in the growth, invasion and metastatic properties of cancerous cells. This study analyses the alterations in the expression patterns of these molecules in right sided colorectal cancer (CRC), both metastatic and non-metastatic. Twenty right sided CRCs were studied. A transcriptomic approach was used, employing qPCR to analyze both the expression of the enzymes involved in heparan sulfate (HS) chains biosynthesis, as well as the proteoglycan core proteins. Since some of these proteoglycans can also carry chondroitin sulfate (CS) chains, we include the study of the genes involved in the biosynthesis of these glycosaminoglycans. Immunohistochemical techniques were also used to analyze tissue expression of particular genes showing significant expression differences, of potential interest. Changes in proteoglycan core proteins differ depending on their location; those located intracellularly or in the extracellular matrix show very similar alteration patterns, while those located on the cell surface vary greatly depending on the nature of the tumor: glypicans 1, 3, 6 and betaglycan are affected in the non-metastatic tumors, whereas in the metastatic, only glypican-1 and syndecan-1 are modified, the latter showing opposing alterations in levels of RNA and of protein, suggesting post-transcriptional regulation in these tumors. Furthermore, in non-metastatic tumors, polymerization of glycosaminoglycan chains is modified, particularly affecting the synthesis of the tetrasaccharide linker and the initiation and elongation of CS chains, HS chains being less affected. Regarding the enzymes responsible for the modificaton of the HS chains, alterations were only found in non-metastatic tumors, affecting N-sulfation and the isoforms HS6ST1, HS3ST3B and HS3ST5. In contrast, synthesis of the CS chains suggests changes in epimerization and sulfation of the C4 and C2 in both types of tumor. Right sided CRCs show

Plasma YKL-40 in patients with metastatic colorectal cancer treated with first line oxaliplatin-based regimen with or without cetuximab: RESULTS from the NORDIC VII Study.

Directory of Open Access Journals (Sweden)

Line S Tarpgaard

Full Text Available We aim to test the hypothesis that high plasma YKL-40 is associated with short progression-free survival (PFS and overall survival (OS in patients with metastatic colorectal cancer (mCRC treated with first-line oxaliplatin and 5-flourouracil with or without cetuximab.A total of 566 patients in the NORDIC VII Study were randomized 1∶1∶1 to arm A (Nordic FLOX, arm B (Nordic FLOX + cetuximab, or arm C (Nordic FLOX + cetuximab for 16 weeks followed by cetuximab alone as maintenance therapy. Pretreatment plasma samples were available from 510 patients. Plasma YKL-40 was determined by ELISA and dichotomized according to the age-corrected 95% YKL-40 level in 3130 healthy subjects.Pretreatment plasma YKL-40 was elevated in 204 patients (40%, and median YKL-40 was higher in patients with mCRC than in healthy subjects (age adjusted, P<0.001. Patients with elevated YKL-40 had shorter PFS than patients with normal YKL-40 (7.5 vs. 8.2 months; hazard ratio (HR  = 1.27 95% confidence interval (CI 1.05-1.53 P = 0.013 and shorter OS (16.8 vs. 23.9 months; HR = 1.33, 1.04-1.69, P = 0.024. Multivariate Cox analysis demonstrated that elevated pretreatment YKL-40 was an independent biomarker of short OS (HR = 1.12, 1.01-1.25, P = 0.033. The ratio of the updated plasma YKL-40 (i.e. level after 1, 2, 8 weeks of treatment, and at end of treatment compared to the baseline level was associated with OS (HR = 1.27, 1.06-1.52, P = 0.011.Plasma YKL-40 is an independent prognostic biomarker in patients with mCRC treated with first-line oxaliplatin-based therapy alone or combined with cetuximab.

Trifluridine/Tipiracil (TAS-102) in Refractory Metastatic Colorectal Cancer: A Multicenter Register in the Frame of the Italian Compassionate Use Program.

Science.gov (United States)

Cremolini, Chiara; Rossini, Daniele; Martinelli, Erika; Pietrantonio, Filippo; Lonardi, Sara; Noventa, Silvia; Tamburini, Emiliano; Frassineti, Giovanni Luca; Mosconi, Stefania; Nichetti, Federico; Murgioni, Sabina; Troiani, Teresa; Borelli, Beatrice; Zucchelli, Gemma; Dal Maso, Alessandro; Sforza, Vincenzo; Masi, Gianluca; Antoniotti, Carlotta; Di Bartolomeo, Maria; Miceli, Rosalba; Ciardiello, Fortunato; Falcone, Alfredo

2018-05-08

TAS-102 is indicated for patients with metastatic colorectal cancer (mCRC) previously treated with, or not considered candidates for, available therapies. Given the complete inefficacy in half of patients, the lack of predictive factors, the palliative setting, and the financial and clinical toxicity, optimizing the cost-benefit ratio is crucial. The "ColonLife" nomogram allows an estimate of the 12-week life expectancy of patients with refractory mCRC. We collected data from patients treated at eight Italian centers in the compassionate use program. Baseline characteristics of patients who were or were not progression free at 6 months were compared. The discriminative ability of the ColonLife nomogram was assessed. Among patients who received both TAS-102 and regorafenib, clinical outcomes of the two sequences were compared. This study included 341 patients. Six (2%) and 93 (27%) patients achieved response and disease stabilization, respectively. The median progression-free survival (PFS) was 2.4 months with an estimated 6-month PFS rate of 19%; the median overall survival (OS) was 6.2 months. An Eastern Cooperative Oncology Group performance status (ECOG PS) of 0, normal lactate dehydrogenase (LDH), and a time from the diagnosis of metastatic disease of >18 months were independently associated with higher chances of a patient being progression free at 6 months. The discriminative ability of ColonLife was confirmed. Among 121 patients who received both regorafenib and TAS-102, no differences in first or second PFS or OS were reported between the two sequences. One out of five patients achieves clinical benefit with TAS-102. ECOG PS, LDH, and time from diagnosis of metastatic disease may help to identify these patients. Excluding patients with very short life expectancy appears a reasonable approach. Improving the cost-efficacy ratio of TAS-102 in metastatic colorectal cancer is needed to spare useless toxicities in a definitely palliative setting. Eastern

Consensus on management of metastatic colorectal cancer in Central America and the Caribbean: San José, Costa Rica, August 2016

Science.gov (United States)

López, Roberto Ivan; Castro, Jenny Lissette; Cedeño, Heidy; Cisneros, Dagoberto; Corrales, Luis; González-Herrera, Ileana; Lima-Pérez, Mayté; Prestol, Rogelio; Salinas, Roberto; Soriano-García, Jorge Luis; T Zavala, Alejandra; Zetina, Luis Miguel; Zúñiga-Orlich, Carlos Eduardo

2018-01-01

Colorectal cancer (CRC) is the third most common cancer in men and the second most common in women worldwide. In Latin America and the Caribbean, it has a mortality of 56%. The median overall survival for patients with metastatic colorectal cancer (mCRC) is currently estimated as ~30 months, which has substantially improved through strategic changes in treatment and in the management of patients. As opposed to other metastatic cancers where first-line regimens are often determined, mCRC requires special attention because there is controversy in the possible combinations of the available drugs and the different periods of duration for each patient. Each combination must seek to be effective and to generate the minimum adverse effects as possible. Instead of giving the first-line regimen until the tumour progresses, treatment is often individualised. Furthermore, up to 60% of colorectal tumours are considered non-mutated or wild-type CRC. Not harbouring mutations in the RAS family of genes or mutations in the signalling pathways of the epidermal growth factor receptor causes a null response to anti-epidermal growth factor receptor antibody therapy, which implies even more complex considerations regarding its management. The primary objective of this consensus is to address the main scenarios of mCRC in order to warrant the most appropriate therapeutic intervention for these patients in the Central American and the Caribbean (CAC) region. This can lead to better clinical outcomes as well as quality of life for palliative patients. This document includes the formal expert consensus recommendations for scenarios of mutated and non-mutated mCRC, including synchronous or metachronous disease, management of mCRC with liver and lung metastasis, resectable, potentially resectable or non-resectable tumours and local in the CAC context. PMID:29636987

Comparison of quantitative methods on FDG PET/CT for treatment response evaluation of metastatic colorectal cancer

Energy Technology Data Exchange (ETDEWEB)

Bang, Ji In; Paeng, Jin Chul; Park, So Hyun [Dept. of Nuclear Medicine, Seoul National University Hospital, Seoul (Korea, Republic of); and others

2017-06-15

FDG PET is effective in treatment response evaluation of cancer. However, there is no standard method for quantitative evaluation of FDG PET, particularly regarding cytostatic drugs. We compared various FDG PET quantitative methods in terms of response determination. A total of 39 refractory metastatic colorectal cancer patients who received a multikinase inhibitor treatment were included. Baseline and posttreatment FDG PET/CT scans were performed before and two cycles after treatment. Standardized uptake value (SUV) and total lesion glycolysis (TLG) values using various margin thresholds (30–70 % of maximum SUV with increment 10 %, twice mean SUV of blood pool, SUV 3.0, and SUV 4.0) were measured, with measurement target of the hottest lesion or a maximum of five hottest lesions. Treatment response by the PERCIST criteria was also determined. Predictive values of the PET indexes were evaluated in terms of the treatment response determined by the RECIST 1.1 criteria. The agreement rate was 38 % between response determined by the PERCIST and the RECIST criteria (κ = 0.381). When patients were classified into disease control group (PR, SD) and non-control group (PD) by the RECIST criteria, percent changes of TLG with various margin thresholds (particularly, 30–50 % of maximum SUV) exhibited significant differences between the two groups, and high diagnostic power for the response by the RECIST criteria. TLG-based criteria, which used a margin threshold of 50 % of maximum SUV, exhibited a high agreement with the RECIST criteria compared with the PERCIST criteria (κ = 0.606). In metastatic colorectal cancer, FDG PET/CT could be effective for treatment response evaluation by using TLG measured by margin thresholds of 30–50 % of maximum SUV. Further studies are warranted regarding the optimal cutoff values for this method.

AGXT and ERCC2 polymorphisms are associated with clinical outcome in metastatic colorectal cancer patients treated with 5-FU/oxaliplatin

DEFF Research Database (Denmark)

Kjersem, J B; Thomsen, M.; Guren, T

2016-01-01

The objective of the study was to investigate whether specific single nucleotide polymorphisms (SNPs) with influence on drug transport, biotransformation and repair mechanisms are associated with treatment outcome and toxicity in metastatic colorectal cancer (mCRC). We genotyped blood samples fro...... as markers of clinical outcome in oxaliplatin-treated mCRC patients. If validated in other studies, they could improve the selection of therapy in mCRC.The Pharmacogenomics Journal advance online publication, 11 August 2015; doi:10.1038/tpj.2015.54....

Metastatic paediatric colorectal carcinoma.

LENUS (Irish Health Repository)

Woods, R

2012-03-01

A 16-year-old girl presented to our unit with crampy abdominal pain, change in bowel habit, a subjective impression of weight loss and a single episode of haematochezia. She was found to have a rectosigmoid adenocarcinoma and proceeded to laparoscopic anterior resection, whereupon peritoneal metastases were discovered. She received chemotherapy and is alive and well ten month later with no radiological evidence of disease. Colorectal carcinoma is rare in the paediatric population but is increasing in incidence. Early diagnosis is critical to enable optimal outcomes.

Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis

DEFF Research Database (Denmark)

De Roock, Wendy; Claes, Bart; Bernasconi, David

2010-01-01

with KRAS wild-type tumours still do not respond. We studied the effect of other downstream mutations on the efficacy of cetuximab in, to our knowledge, the largest cohort to date of patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab plus chemotherapy in the pre...

Anti-VEGF agents in metastatic colorectal cancer (mCRC: are they all alike?

Directory of Open Access Journals (Sweden)

Saif MW

2013-06-01

Full Text Available Muhammad Wasif Saif GI Oncology Program, Tufts University School of Medicine, Boston, MA, USA Abstract: Bevacizumab is a monoclonal antibody that binds and neutralizes vascular endothelial growth factor (VEGF-A, a key player in the angiogenesis pathway. Despite benefits of bevacizumab in cancer therapy, it is clear that the VEGF pathway is complex, involving multiple isoforms, receptors, and alternative ligands such as VEGF-B, and placental growth factor, which could enable escape from VEGF-A-targeted angiogenesis inhibition. Recently developed therapies have targeted other ligands in the VEGF pathway (eg, aflibercept, known as ziv-aflibercept in the United States, VEGF receptors (eg, ramucirumab, and their tyrosine kinase signaling (ie, tyrosine kinase inhibitors. The goal of the current review was to identify comparative preclinical data for the currently available VEGF-targeted therapies. Sources were compiled using PubMed searches (2007 to 2012, using search terms including, but not limited to: “bevacizumab,” “aflibercept,” “ramucirumab,” and “IMC-18F1.” Two preclinical studies were identified that compared bevacizumab and the newer agent, aflibercept. These studies identified some important differences in binding and pharmacodynamic activity, although the potential clinical relevance of these findings is not known. Newer antiangiogenesis therapies should help further expand treatment options for colorectal and other cancers. Comparative preclinical data on these agents is currently lacking. Keywords: aflibercept, antiangiogenesis, metastatic colorectal cancer (mCRC, tyrosine kinase inhibitor (TKI, vascular endothelial growth factor (VEGF

Hypoxia-inducible factor 1 alpha expression increases during colorectal carcinogenesis and tumor progression

International Nuclear Information System (INIS)

Simiantonaki, Nektaria; Taxeidis, Marios; Jayasinghe, Caren; Kurzik-Dumke, Ursula; Kirkpatrick, Charles James

2008-01-01

Hypoxia-inducible factor 1 alpha (HIF-1α) is involved in processes promoting carcinogenesis of many tumors. However, its role in the development of colorectal cancer is unknown. To investigate the significance of HIF-1α during colorectal carcinogenesis and progression we examined its expression in precursor lesions constituting the conventional and serrated pathways, as well as in non-metastatic and metastatic adenocarcinomas. Immunohistochemistry and Western blot is used to analyse HIF-1α expression in normal colonic mucosa, hyperplastic polyps (HPP), sessile serrated adenomas (SSA), low-grade (TA-LGD) and high-grade (TA-HGD) traditional adenomas as well as in non-metastatic and metastatic colorectal adenocarcinomas. Eight colorectal carcinoma cell lines are tested for their HIF-1α inducibility after lipopolysaccharide (LPS) stimulation using western blot and immunocytochemistry. In normal mucosa, HPP and TA-LGD HIF-1α was not expressed. In contast, perinuclear protein accumulation and nuclear expression of HIF-1α were shown in half of the examined SSA and TA-HGD. In all investigated colorectal carcinomas a significant nuclear HIF-1α overexpression compared to the premalignant lesions was observed but a significant correlation with the metastatic status was not found. Nuclear HIF-1α expression was strongly accumulated in perinecrotic regions. In these cases HIF-1α activation was seen in viable cohesive tumor epithelia surrounding necrosis and in dissociated tumor cells, which subsequently die. Enhanced distribution of HIF-1α was also seen in periiflammatory regions. In additional in vitro studies, treatment of diverse colorectal carcinoma cell lines with the potent pro-inflammatory factor lipopolysaccharide (LPS) led to HIF-1α expression and nuclear translocation. We conclude that HIF-1α expression occurs in early stages of colorectal carcinogenesis and achieves a maximum in the invasive stage independent of the metastatic status. Perinecrotic

Bevacizumab plus chemotherapy as third- or later-line therapy in patients with heavily treated metastatic colorectal cancer

Directory of Open Access Journals (Sweden)

Yang Q

2015-09-01

, patients with a primary colon tumor might have had a longer overall survival than patients with a primary rectal tumor (18.8 months vs 11.1 months, respectively; P=0.037. Common chemotherapy-related toxicities were nausea/vomiting (48.6%, fatigue (34.3%, leucopenia (40%, neutropenia (42.9%, and anemia (42.9%, with one patient with grade 3 neutropenia, and two patients with grade 3 thrombocytopenia. The common bevacizumab-associated toxicity was hypertension (31.4%. None of the patients discontinued therapy or died because of bevacizumab-associated toxicities.Conclusion: Our data showed that adding bevacizumab to third- or later-line therapy might lead to tumor control and improved survival in heavily pretreated mCRC patients. In addition, preliminary data suggested that primary colon cancer was more likely to benefit from bevacizumab-containing regimens. Toxicities were acceptable, and no new toxicity was identified. Further studies are needed to validate these findings.Keywords: bevacizumab, chemotherapy, metastatic colorectal cancer

Brain metastases from colorectal cancer

DEFF Research Database (Denmark)

Vagn-Hansen, Chris Aksel; Rafaelsen, Søren Rafael

2001-01-01

Brain metastases from colorectal cancer are rare. The prognosis for patients with even a single resectable brain metastasis is poor. A case of surgically treated cerebral metastasis from a rectal carcinoma is reported. The brain tumour was radically resected. However, cerebral, as well...... as extracerebral, disease recurred 12 months after diagnosis. Surgical removal of colorectal metastatic brain lesions in selected cases results in a longer survival time....

Clinical Usefulness of Serum CYFRA 21-1 in Patients with Colorectal Cancer

International Nuclear Information System (INIS)

Lee, Jai Hyuen

2013-01-01

Among diverse tumor markers, pretreatment evaluation and follow-up detection of recurrence in colorectal cancer are generally evaluated by serum carcinoembryonic antigen (CEA) levels. However, there have been some reports about the low accuracy and high false-positive results of CEA in colorectal cancer. We investigated the clinical utilities of CYFRA 21-1 by comparing CEA and cancer antigen 19-9 (CA 19-9) in pretreatment and recurrent colorectal cancer. Using a solid-phase immunoradiometric assay, serum levels of CYFRA 21-1, CEA and CA 19-9 were analyzed in 132 patients with primary colorectal cancer, 124 healthy controls, 104 patients with benign colorectal disease and 19 patients with recurrent colorectal cancer. We determined three different cutoff values to evaluate the sensitivity of diagnostic performance in pretreatment and recurrent colorectal cancer. CYFRA 21-1 (≥ 1.13 ng/ml) had a sensitivity of 47 %, compared with 37 % for CEA (≥ 3.05 ng/ml) and 32.6 % for CA 19-9 (≥ 23.1 ng/ml) in the initial staging of primary colorectal cancer. Using different cutoff values, CYFRA 21-1 showed higher sensitivity for pretreatment colorectal cancer than CEA and CA 19-9 in adenocarcinoma and adenosquamous carcinoma of this study. A mildly significant correlative relationship was noted between Dukes' stages and three tumor markers (p<0.01). The areas under the receiver operating characteristic curves of CYFRA 21-1, CEA and CA 19-9 were 0.81±0.03, 0.74±0.03 and 0.62±0.04, respectively, for discriminating colorectal cancer patients from patients with benign colorectal disease. In addition, CYFRA 21-1 was determined as the most sensitive tumor marker for evaluating recurrent colorectal cancer for all cutoff values. This study showed that CYFRA 21-1 could be a useful and dependable tumor marker for pretreatment and recurrent colorectal cancer. Further prospective studies on its usefulness with respect to the prognosis and utility of combined tumor markers are needed

Clinical Usefulness of Serum CYFRA 21-1 in Patients with Colorectal Cancer

Energy Technology Data Exchange (ETDEWEB)

Lee, Jai Hyuen [Dankook Univ. Medical College, Yongin (Korea, Republic of)

2013-09-15

Among diverse tumor markers, pretreatment evaluation and follow-up detection of recurrence in colorectal cancer are generally evaluated by serum carcinoembryonic antigen (CEA) levels. However, there have been some reports about the low accuracy and high false-positive results of CEA in colorectal cancer. We investigated the clinical utilities of CYFRA 21-1 by comparing CEA and cancer antigen 19-9 (CA 19-9) in pretreatment and recurrent colorectal cancer. Using a solid-phase immunoradiometric assay, serum levels of CYFRA 21-1, CEA and CA 19-9 were analyzed in 132 patients with primary colorectal cancer, 124 healthy controls, 104 patients with benign colorectal disease and 19 patients with recurrent colorectal cancer. We determined three different cutoff values to evaluate the sensitivity of diagnostic performance in pretreatment and recurrent colorectal cancer. CYFRA 21-1 (≥ 1.13 ng/ml) had a sensitivity of 47 %, compared with 37 % for CEA (≥ 3.05 ng/ml) and 32.6 % for CA 19-9 (≥ 23.1 ng/ml) in the initial staging of primary colorectal cancer. Using different cutoff values, CYFRA 21-1 showed higher sensitivity for pretreatment colorectal cancer than CEA and CA 19-9 in adenocarcinoma and adenosquamous carcinoma of this study. A mildly significant correlative relationship was noted between Dukes' stages and three tumor markers (p<0.01). The areas under the receiver operating characteristic curves of CYFRA 21-1, CEA and CA 19-9 were 0.81±0.03, 0.74±0.03 and 0.62±0.04, respectively, for discriminating colorectal cancer patients from patients with benign colorectal disease. In addition, CYFRA 21-1 was determined as the most sensitive tumor marker for evaluating recurrent colorectal cancer for all cutoff values. This study showed that CYFRA 21-1 could be a useful and dependable tumor marker for pretreatment and recurrent colorectal cancer. Further prospective studies on its usefulness with respect to the prognosis and utility of combined tumor markers are

Clinical value of a one-stop-shop low-dose lung screening combined with 18F-FDG PET/CT for the detection of metastatic lung nodules from colorectal cancer

International Nuclear Information System (INIS)

Han, Yeon Hee; Lim, Seok Tae; Jeong, Hwan Jeong; Sohn, Myung Hee

2016-01-01

The aim of this study was to evaluate the clinical usefulness of additional low-dose high-resolution lung computed tomography (LD-HRCT) combined with 18F-fluoro-2-deoxyglucose positron emission tomography with CT (18F-FDG PET/CT) compared with conventional lung setting image of 18F-FDG PET/CT for the detection of metastatic lung nodules from colorectal cancer. From January 2011 to September 2011, 649 patients with colorectal cancer underwent additional LD-HRCT at maximum inspiration combined with 18F-FDG PET/CT. Forty-five patients were finally diagnosed to have lung metastasis based on histopathologic study or clinical follow-up. Twenty-five of the 45 patients had ≤5 metastatic lung nodules and the other 20 patients had  >5 metastatic nodules. One hundred and twenty nodules in the 25 patients with ≤5 nodules were evaluated by conventional lung setting image of 18F-FDG PET/CT and by additional LD-HRCT respectively. Sensitivities, specificities, diagnostic accuracies, positive predictive values (PPVs), and negative predictive values (NPVs) of conventional lung setting image of 18F-FDG PET/CT and additional LD-HRCT were calculated using standard formulae. The McNemar test and receiver-operating characteristic (ROC) analysis were performed. Of the 120 nodules in the 25 patients with ≤5 metastatic lung nodules, 66 nodules were diagnosed as metastatic. Eleven of the 66 nodules were confirmed histopathologically and the others were diagnosed by clinical follow-up. Conventional lung setting image of 18F-FDG PET/CT detected 40 of the 66 nodules and additional LD-HRCT detected 55 nodules. All 15 nodules missed by conventional lung setting imaging but detected by additional LD-HRCT were <1 cm in size. The sensitivity, specificity, and diagnostic accuracy of the modalities were 60.6 %, 85.2 %, and 71.1 % for conventional lung setting image and 83.3 %, 88.9 %, and 85.8 % for additional LD-HRCT. By ROC analysis, the area under the ROC curve (AUC) of conventional

Bevacizumab for Metastatic Colorectal Cancer: A Global Cost-Effectiveness Analysis.

Science.gov (United States)

Goldstein, Daniel A; Chen, Qiushi; Ayer, Turgay; Chan, Kelvin K W; Virik, Kiran; Hammerman, Ariel; Brenner, Baruch; Flowers, Christopher R; Hall, Peter S

2017-06-01

In the U.S., the addition of bevacizumab to first-line chemotherapy in metastatic colorectal cancer (mCRC) has been demonstrated to provide 0.10 quality-adjusted life years (QALYs) at an incremental cost-effectiveness ratio (ICER) of $571,000/QALY. Due to variability in pricing, value for money may be different in other countries. Our objective was to establish the cost-effectiveness of bevacizumab in mCRC in the U.S., U.K., Canada, Australia, and Israel. We performed the analysis using a previously established Markov model for mCRC. Input data for efficacy, adverse events, and quality of life were considered to be generalizable and therefore identical for all countries. We used country-specific prices for medications, administration, and other health service costs. All costs were converted from local currency to U.S. dollars at the exchange rates in March 2016. We conducted one-way and probabilistic sensitivity analyses (PSA) to assess the model robustness across parameter uncertainties. Base case results demonstrated that the highest ICER was in the U.S. ($571,000/QALY) and the lowest was in Australia ($277,000/QALY). In Canada, the U.K., and Israel, ICERs ranged between $351,000 and $358,000 per QALY. PSA demonstrated 0% likelihood of bevacizumab being cost-effective in any country at a willingness to pay threshold of $150,000 per QALY. The addition of bevacizumab to first-line chemotherapy for mCRC consistently fails to be cost-effective in all five countries. There are large differences in cost-effectiveness between countries. This study provides a framework for analyzing the value of a cancer drug from the perspectives of multiple international payers. The cost-effectiveness of bevacizumab varies significantly between multiple countries. By conventional thresholds, bevacizumab is not cost-effective in metastatic colon cancer in the U.S., the U.K., Australia, Canada, and Israel. © AlphaMed Press 2017.

Administration of cetuximab every 2 weeks in the treatment of metastatic colorectal cancer

DEFF Research Database (Denmark)

Tabernero, Josep; Pfeiffer, Per; Cervantes, Andrés

2008-01-01

The primary purpose of this paper is to present the available evidence for the administration of cetuximab on an every-2-weeks basis in combination with irinotecan in metastatic colorectal cancer (mCRC). Cetuximab is an epidermal growth factor receptor-targeted IgG(1) monoclonal antibody...... that is approved for use in combination with irinotecan or as monotherapy in the treatment of mCRC. The currently approved dosing regimen for cetuximab is a 400-mg/m(2) initial dose followed by 250 mg/m(2) weekly. Many commonly used chemotherapy agents for mCRC (including irinotecan alone or in combination with 5......-fluorouracil [5-FU]/folinic acid [FA] and oxaliplatin plus 5-FU/FA) are administered on an every-2-weeks basis. The ability to synchronize the administration of cetuximab and concomitant chemotherapy is desirable for both patients and health care workers. A cetuximab dose of 500 mg/m(2) every 2 weeks exhibited...

ICECREAM: randomised phase II study of cetuximab alone or in combination with irinotecan in patients with metastatic colorectal cancer with either KRAS, NRAS, BRAF and PI3KCA wild type, or G13D mutated tumours

International Nuclear Information System (INIS)

Segelov, Eva; Waring, Paul; Desai, Jayesh; Wilson, Kate; Gebski, Val

2016-01-01

Patients with metastatic colorectal cancer whose disease has progressed on oxaliplatin- and irinotecan-containing regimens may benefit from EGFR-inhibiting monoclonal antibodies if they do not contain mutations in the KRAS gene (are “wild type”). It is unknown whether these antibodies, such as cetuximab, are more efficacious in refractory metastatic colorectal cancer as monotherapy, or in combination with irinotecan. Lack of mutation in KRAS, BRAF and PIK3CA predicts response to EFGR-inhibitors. The ICECREAM trial examines the question of monotherapy versus combination with chemotherapy in two groups of patients: those with a “quadruple wild type” tumour genotype (no mutations in KRAS, NRAS, PI3KCA or BRAF genes) and those with the specific KRAS mutation in codon G13D, for whom possibly EGFR-inhibitor efficacy may be equivalent. ICECREAM is a randomised, phase II, open-label, controlled trial comparing the efficacy of cetuximab alone or with irinotecan in patients with “quadruple wild type” or G13D-mutated metastatic colorectal cancer, whose disease has progressed on, or who are intolerant of oxaliplatin- and fluoropyrimidine-based chemotherapy. The primary endpoint is the 6-month progression-free survival benefit of the treatment regimen. Secondary endpoints are response rate, overall survival, and quality of life. The tertiary endpoint is prediction of outcome with further biological markers. International collaboration has facilitated recruitment in this prospective trial of treatment in these infrequently found molecular subsets of colorectal cancer. This unique trial will yield prospective information on the efficacy of cetuximab and whether this is further enhanced with chemotherapy in two distinct populations of patients with metastatic colorectal cancer: the “quadruple wild type”, which may ‘superselect’ for tumours sensitive to EGFR-inhibition, and the rare KRAS G13D mutated tumours, which are also postulated to be sensitive to the drug

Prognostic impact of the pretreatment aspartate transaminase/alanine transaminase ratio in patients treated with first-line systemic tyrosine kinase inhibitor therapy for metastatic renal cell carcinoma.

Science.gov (United States)

Kang, Minyong; Yu, Jiwoong; Sung, Hyun Hwan; Jeon, Hwang Gyun; Jeong, Byong Chang; Park, Se Hoon; Jeon, Seong Soo; Lee, Hyun Moo; Choi, Han Yong; Seo, Seong Il

2018-05-13

To examine the prognostic role of the pretreatment aspartate transaminase/alanine transaminase or De Ritis ratio in patients with metastatic renal cell carcinoma receiving first-line systemic tyrosine kinase inhibitor therapy. We retrospectively searched the medical records of 579 patients with metastatic renal cell carcinoma who visited Samsung Medical Center, Seoul, Korea, from January 2001 through August 2016. After excluding 210 patients, we analyzed 360 patients who received first-line tyrosine kinase inhibitor therapy. Cancer-specific survival and overall survival were defined as the primary and secondary end-points, respectively. A multivariate Cox proportional hazards regression model was used to identify independent prognosticators of survival outcomes. The overall population was divided into two groups according to the pretreatment De Ritis ratio as an optimal cut-off value of 1.2, which was determined by a time-dependent receiver operating characteristic curve analysis. Patients with a higher pretreatment De Ritis ratio (≥1.2) had worse cancer-specific survival and overall survival outcomes, compared with those with a lower De Ritis ratio (<1.2). Notably, a higher De Ritis ratio (≥1.2) was found to be an independent predictor of both cancer-specific survival (hazard ratio 1.61, 95% confidence interval 1.13-2.30) and overall survival outcomes (hazard ratio 1.69, 95% confidence interval 1.19-2.39), along with male sex, multiple metastasis (≥2), non-clear cell histology, advanced pT stage (≥3), previous metastasectomy and the Memorial Sloan Kettering Cancer Center risk classification. Our findings show that the pretreatment De Ritis ratio can provide valuable information about the survival outcomes of metastatic renal cell carcinoma patients receiving first-line tyrosine kinase inhibitor therapy. © 2018 The Japanese Urological Association.

Regorafenib-induced retinal and gastrointestinal hemorrhage in a metastatic colorectal cancer patient with liver dysfunction

Science.gov (United States)

Tsuchihashi, Kenji; Shimokawa, Hozumi; Takayoshi, Kotoe; Nio, Kenta; Aikawa, Tomomi; Matsushita, Yuzo; Wada, Iori; Arita, Shuji; Ariyama, Hiroshi; Kusaba, Hitoshi; Sonoda, Koh-Hei; Akashi, Koichi; Baba, Eishi

2017-01-01

Abstract Rationale: Regorafenib is effective for metastatic colorectal cancer but its toxicity such as hemorrhage should be considered. The safety of regorafenib for the patient with the liver disease is not known. Patient concerns: Seventy-one-year old man of colon cancer had myodesopsia and blood stool after 14 days from the initiation of regorafenib administration with 50% dose reduction due to liver dysfunction. Diagnoses: Fundus examination revealed hemorrhage of the retinal vein. Interventions: Regorafenib treatment was discontinued and observational therapy was pursued. Outcomes: Retinal and gastrointestinal hemorrhage resolved in 1 week. Lessons: Retinal hemorrhage should be considered as the differential diagnosis of myodesopsia in the patient treated by regorafenib. Safety and pharmacokinetic of continuous regorafenib administration for patients with liver dysfunction remains to be clarified. PMID:29049226

Emerging combination therapies for metastatic colorectal cancer – impact of trifluridine/tipiracil

Science.gov (United States)

Puthiamadathil, Jeevan M; Weinberg, Benjamin A

2017-01-01

Patients with metastatic colorectal cancer (mCRC) are surviving longer now than ever before, but mortality rates are still high and more effective therapies are clearly needed. For patients with disease that is refractory to fluoropyrimidines, oxaliplatin, irinotecan, and biologic agents targeting the vascular endothelial growth factor and epidermal growth factor receptor pathways, novel treatment options trifluridine/tipiracil (TAS-102) and regorafenib can be effective disease stabilizers. However, objective clinical responses are rare and toxicities are manageable but common. In order to tackle poor clinical responses to TAS-102, there is an ongoing effort to effectively combine this drug with other agents, particularly those targeting angiogenesis. Certain subpopulations appear to benefit more than others from TAS-102; those that benefit often have underlying genetic defects in DNA repair pathways and/or develop neutropenia. In this review, we focus on the role of TAS-102 in the treatment of mCRC, including its use in combination with other agents, potential predictive biomarkers of response to TAS-102, and possible future directions. PMID:29056855

European Medicines Agency approval summary: Zaltrap for the treatment of patients with oxaliplatin-resistant metastatic colorectal cancer.

Science.gov (United States)

Stanel, Stefan Cristian; Sjöberg, Jan; Salmonson, Tomas; Foggi, Paolo; Caleno, Mariapaola; Melchiorri, Daniela; Gravanis, Iordanis; Tzogani, Kyriaki; Pignatti, Francesco

2017-01-01

On 1 February 2013, a marketing authorisation valid throughout the European Union was issued for aflibercept (Zaltrap) in combination with irinotecan/5-fluorouracil/folinic acid chemotherapy for the treatment of adults with metastatic colorectal cancer resistant to or progressive after an oxaliplatin-containing regimen. Aflibercept is a recombinant fusion protein which blocks the activation of vascular endothelial growth factor (VEGF) receptors and the proliferation of endothelial cells, acting as a soluble decoy receptor that binds to VEGF-A with higher affinity than its native receptors, as well as placental growth factor and VEGF-B. The use of aflibercept was studied in a randomised, double-blind, placebo-controlled phase III study, in patients with metastatic colorectal cancer (mCRC) who had previously been treated with an oxaliplatin-based treatment with or without prior bevacizumab. Aflibercept (n=612) was compared with placebo (n=614), both in combination with FOLFIRI (infusional fluorouracil, leucovorin and irinotecan). The primary endpoint of the study was overall survival (OS). The median OS in the intent-to-treat population was 13.5 months in subjects treated with aflibercept compared with 12.1 months for subjects in the control arm (stratified HR=0.817, 95% CI 0.714 to 0.935, stratified pvalue=0.0032). The frequency of adverse events was higher in the aflibercept arm compared with the placebo arm, reflecting the toxicity profile of anti-VEGF agents in combination with chemotherapy. This paper is based on the scientific review of the application leading to approval of aflibercept in the EU. The detailed scientific assessment report and product information for this product are available on the European Medicines Agency website (http://www.ema.europa.eu). Trial registration number NCT00561470, Results.

The PANDA study: a randomized phase II study of first-line FOLFOX plus panitumumab versus 5FU plus panitumumab in RAS and BRAF wild-type elderly metastatic colorectal cancer patients.

Science.gov (United States)

Battaglin, Francesca; Schirripa, Marta; Buggin, Federica; Pietrantonio, Filippo; Morano, Federica; Boscolo, Giorgia; Tonini, Giuseppe; Lutrino, Eufemia Stefania; Lucchetti, Jessica; Salvatore, Lisa; Passardi, Alessandro; Cremolini, Chiara; Arnoldi, Ermenegildo; Scartozzi, Mario; Pella, Nicoletta; Boni, Luca; Bergamo, Francesca; Zagonel, Vittorina; Loupakis, Fotios; Lonardi, Sara

2018-01-25

Few data are available regarding the treatment of metastatic colorectal cancer elderly patients with anti-EGFR agents in combination with chemotherapy. FOLFOX plus panitumumab is a standard first-line option for RAS wild-type metastatic colorectal cancer. Slight adjustments in chemo-dosage are commonly applied in clinical practice to elderly patients, but those modified schedules have never been prospectively tested. Clinical definition of elderly (≥70 years old) patients that may deserve a more or less intensive combination therapy is still debated. Several geriatric screening tools have been developed to predict survival and risk of toxicity from treatment. Among those, the G8 screening tool has been tested in cancer patients showing the strongest prognostic value for overall survival, while the CRASH score can stratify patients according to an estimated risk of treatment-related toxicities. The PANDA study is a prospective, open-label, multicenter, randomized phase II trial of first-line therapy with panitumumab in combination with dose-adjusted FOLFOX or with 5-fluorouracil monotherapy, in previously untreated elderly patients (≥70 years) with RAS and BRAF wild-type unresectable metastatic colorectal cancer. RAS and BRAF analyses are centralized. Geriatric assessment by means of G8 and CRASH score is planned at baseline and G8 will be re-evaluated at disease progression. The primary endpoint is duration of progression-free survival in both arms. Secondary endpoints include prospective evaluation of the prognostic role of G8 score and the correlation of CRASH risk categories with toxicity. The PANDA study aims at exploring safety and efficacy of panitumumab in combination with FOLFOX or with 5FU/LV in elderly patients affected by RAS and BRAF wild-type metastatic colorectal cancer, to identify the most promising treatment strategy in this setting. Additionally, this is the first trial in which the prognostic role of the G8 score will be prospectively

Regorafenib plus modified FOLFOX6 as first-line treatment of metastatic colorectal cancer: A phase II trial.

Science.gov (United States)

Argilés, Guillem; Saunders, Mark P; Rivera, Fernando; Sobrero, Alberto; Benson, Al; Guillén Ponce, Carmen; Cascinu, Stefano; Van Cutsem, Eric; Macpherson, Iain R; Strumberg, Dirk; Köhne, Claus-Henning; Zalcberg, John; Wagner, Andrea; Luigi Garosi, Vittorio; Grunert, Julia; Tabernero, Josep; Ciardiello, Fortunato

2015-05-01

The oral multikinase inhibitor regorafenib improves overall survival (OS) in patients with metastatic colorectal cancer (CRC) for which all standard treatments have failed. This study investigated regorafenib plus modified FOLFOX (mFOLFOX6) as first-line treatment of metastatic CRC. In this single-arm, open-label, multicentre, phase II study, patients received mFOLFOX6 on days 1 and 15, and regorafenib 160 mg orally once daily on days 4-10 and 18-24 of each 28-day cycle. The primary end-point was centrally assessed objective response rate (ORR). Secondary end-points included disease control rate (DCR), OS, progression-free survival (PFS) and safety. Median overall treatment duration with any study drug was 9.9 months (range 0.6-19.6); median treatment duration with regorafenib was 7.7 months (range 0.1-19.5); six patients remained on regorafenib for more than 1 year. Fifty-three patients received at least one dose of regorafenib. ORR was 43.9% (all partial responses); DCR was 85.4%; median OS was not reached; median PFS was 8.5months. Treatment-emergent adverse events were experienced by all patients but were manageable with dose modifications. Regorafenib+mFOLFOX6 as first-line treatment in patients with metastatic CRC did not improve ORR over historical controls. Regorafenib plus mFOLFOX6 did not appear to be associated with a markedly worse tolerability profile versus mFOLFOX6 alone. Copyright © 2015. Published by Elsevier Ltd.

Biological Therapy in Treating Patients With Metastatic Cancer

Science.gov (United States)

2013-02-21

Breast Cancer; Colorectal Cancer; Extrahepatic Bile Duct Cancer; Gallbladder Cancer; Gastric Cancer; Head and Neck Cancer; Liver Cancer; Lung Cancer; Metastatic Cancer; Ovarian Cancer; Pancreatic Cancer; Testicular Germ Cell Tumor

Clinical value of a one-stop-shop low-dose lung screening combined with {sup 18}F-FDG PET/CT for the detection of metastatic lung nodules from colorectal cancer

Energy Technology Data Exchange (ETDEWEB)

Han, Yeon Hee; Lim, Seok Tae; Jeong, Hwan Jeong; Sohn, Myung Hee [Dept. of Nuclear Medicine, Research Institute of Clinical Medicine, Chonbuk National University-Biomedical Research Institute, Chonbuk National University Hospital, Cyclotron Research Center, Molecular Imaging and Therapeutic Medicine Research Center, Chonbuk National University Medical School and Hospital, Jeonju (Korea, Republic of)

2016-06-15

The aim of this study was to evaluate the clinical usefulness of additional low-dose high-resolution lung computed tomography (LD-HRCT) combined with 18F-fluoro-2-deoxyglucose positron emission tomography with CT (18F-FDG PET/CT) compared with conventional lung setting image of 18F-FDG PET/CT for the detection of metastatic lung nodules from colorectal cancer. From January 2011 to September 2011, 649 patients with colorectal cancer underwent additional LD-HRCT at maximum inspiration combined with 18F-FDG PET/CT. Forty-five patients were finally diagnosed to have lung metastasis based on histopathologic study or clinical follow-up. Twenty-five of the 45 patients had ≤5 metastatic lung nodules and the other 20 patients had  >5 metastatic nodules. One hundred and twenty nodules in the 25 patients with ≤5 nodules were evaluated by conventional lung setting image of 18F-FDG PET/CT and by additional LD-HRCT respectively. Sensitivities, specificities, diagnostic accuracies, positive predictive values (PPVs), and negative predictive values (NPVs) of conventional lung setting image of 18F-FDG PET/CT and additional LD-HRCT were calculated using standard formulae. The McNemar test and receiver-operating characteristic (ROC) analysis were performed. Of the 120 nodules in the 25 patients with ≤5 metastatic lung nodules, 66 nodules were diagnosed as metastatic. Eleven of the 66 nodules were confirmed histopathologically and the others were diagnosed by clinical follow-up. Conventional lung setting image of 18F-FDG PET/CT detected 40 of the 66 nodules and additional LD-HRCT detected 55 nodules. All 15 nodules missed by conventional lung setting imaging but detected by additional LD-HRCT were <1 cm in size. The sensitivity, specificity, and diagnostic accuracy of the modalities were 60.6 %, 85.2 %, and 71.1 % for conventional lung setting image and 83.3 %, 88.9 %, and 85.8 % for additional LD-HRCT. By ROC analysis, the area under the ROC curve (AUC) of conventional

Neurological Toxicity in Metastatic Colorectal Cancer Patients Treated with Modified FOLFOX6 plus Bevacizumab

Directory of Open Access Journals (Sweden)

Satoshi Otsu

2014-01-01

Full Text Available This study was conducted to investigate the toxicity and efficacy of modified FOLFOX6 plus bevacizumab in patients with metastatic colorectal cancer with particular regard to oxaliplatin-induced neuropathy. Toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE (version 3.0. The evaluation was especially focused on grade 2 oxaliplatin-induced neuropathy. The estimated median treatment time to occurrence of grade 2 sensory neuropathy was 7.3 months. The estimated median cumulative dose to occurrence of grade 2 sensory neuropathy was 931 mg/m 2 . This study clarified the treatment time from first dose as well as the cumulative dose of oxaliplatin leading to grade 2 neuropathy. It may be important to institute some clinical countermeasures when grade 2 neuropathy occurs so as to reduce the chance of progression to irreversible grade 3 neuropathy.

Current status of research on microRNA associated with colorectal cancer liver metastasis

Directory of Open Access Journals (Sweden)

WANG Dongxu

2016-12-01

Full Text Available Tumor metastasis is a complicated process with multiple steps, and liver metastasis is the most common metastatic mode of colorectal cancer. Deep understanding and study of metastatic mechanism helps to find solutions for colorectal cancer liver metastasis. Recent studies have shown that microRNA are involved in tumor metastasis and recurrence, and studies on microRNA associated with colorectal cancer liver metastasis can provide new thoughts for the development and progression, diagnosis and treatment, and prognosis of the disease. This article summarizes the research advances in microRNA associated with colorectal cancer liver metastasis and reviews the biological function and molecular mechanism of microRNA, which suggests that microRNA have a vital significance in the field of tumor metastasis, especially colorectal cancer liver metastasis.

Early outcomes of radiofrequency ablation in unresectable metastatic colorectal cancer from a tertiary cancer hospital in India

Directory of Open Access Journals (Sweden)

Suyash Kulkarni

2017-01-01

Full Text Available Aims: The study was carried out to evaluate the early outcomes using Radiofrequency Ablation (RFA for unresectable liver metastases in the management of metastatic colorectal cancer (mCRC from an area of low endemicity. Material and Methods: 60 Patients with unresectable colorectal liver metastases had undergone 88 sessions of RFA from January 2007 till December 2013. The results were retrospectively analysed to evaluate the outcomes in terms of efficacy and survival rates. Results: The median follow up of patients in our series was 24.8months. 35/52 (67.3% patients had complete response at 3 months while 8 patients were lost to follow up. Of the 17 patients who had recurrence, 4 (23.5% were at the ablated site while 13 patients (76.4% progressed elsewhere. Abdominal pain was commonest post procedural symptom (20%. There was no procedure related mortality or any major complications. Mean disease free interval and Progression free survival was 6.7 and 13.1 months. Estimated median survival in patients with liver limited disease and those with small lesion (3 cm was associated with decreased survival.

Immunotherapy for metastatic colorectal cancer

DEFF Research Database (Denmark)

Ellebaek, Eva; Andersen, Mads Hald; Svane, Inge Marie

2012-01-01

Although no immunotherapeutic treatment is approved for colorectal cancer (CRC) patients, promising results from clinical trials suggest that several immunotherapeutic strategies may prove efficacious and applicable to this group of patients. This review describes the immunogenicity of CRC...... and presents the most interesting strategies investigated so far: cancer vaccination including antigen-defined vaccination and dendritic cell vaccination, chemo-immunotherapy, and adoptive cell transfer. Future treatment options as well as the possibility of combining existing therapies will be discussed along...

Impact of third-line treatment with irinotecan plus cetuximab on non-tumor standardized uptake values in patients with metastatic colorectal cancer

DEFF Research Database (Denmark)

Andersen, Kim Francis; Skougaard, Kristin; Nielsen, Anne Lerberg

2012-01-01

The correct interpretation of metabolic response in cancer cells to therapy requires knowledge of how tumor-free tissue responds to the same treatment. The aim of this study was to evaluate standardized uptake values (SUVs) in tumor-free regions of patients with metastatic colorectal cancer prior...... body mass were registered. The procedure was repeated for a follow-up scan two weeks following a single administration of the third-line treatment with irinotecan plus cetuximab. The mean differences in SUV prior to and following therapy were non-significant (P>0.05) in all the registered tumor...

Experience with S-1 in older Caucasian patients with metastatic colorectal cancer (mCRC)

DEFF Research Database (Denmark)

Winther, Stine Braendegaard; Zubcevic, Kanita; Qvortrup, Camilla

2016-01-01

BACKGROUND: An aging population will increase the number of older patients with metastatic colorectal cancer (mCRC). However, there is limited knowledge about treatment in older patients as they are under-represented in clinical trials. The oral fluoropyrimidine S-1 is associated with a lower rate...... of adverse events than capecitabine and may therefore be a suitable drug for elderly. However, data on the use of S-1 in Caucasian mCRC patients are lacking/scarce. MATERIAL AND METHODS: In the present study we evaluated safety and the efficacy of S-1 alone or in combination with oxaliplatin (SOx......) or irinotecan (IRIS) in older mCRC patients. Patients who received at least one cycle of S-1 (first-line therapy), SOx (mainly first-line therapy) or IRIS (second-line therapy) were included. RESULTS: From June 2012 to December 2014, 71 older patients received ≥1 cycle of either S-1 (n = 9), SOx (n = 44...

Cetuximab Plus Various Chemotherapy Regimens for Patients with KRAS Wild-Type Metastatic Colorectal Cancer.

Science.gov (United States)

Azadeh, Payam; Mortazavi, Nafiseh; Tahmasebi, Arezoo; Hosseini Kamal, Farnaz; Novin, Kambiz

2016-01-01

The aim of this study was to compare the efficacy and hematologic toxicity of cetuximab combined with various types of chemotherapy regimens in patients with KRAS wild-type metastatic colorectal cancer (mCRC). The response rate, progression-free survival (PFS) and overall survival of the patients were analyzed. In total, 45 patients were included in the study. The overall response rate for the combination of cetuximab and FOLFOX, FOLFIRI and CAPOX was 20, 46 and 30%, respectively, but the differences were not statistically significant. The median PFS for the three groups were 8, 6 and 3.5 months, respectively, but again these differences were not significant. All-grade leukopenia and anemia for the cetuximab plus FOLFOX group were significantly higher than for the other chemotherapy regimens. Our findings suggest that the combination of cetuximab and the three standard chemotherapy regimens resulted in the same outcomes in our patient population of mCRC, with higher hematologic toxicities among the FOLFOX subgroup. © 2015 S. Karger AG, Basel.

Lower or Standard Dose Regorafenib in Treating Patients With Refractory Metastatic Colorectal Cancer

Science.gov (United States)

2018-03-22

Colon Adenocarcinoma; Rectal Adenocarcinoma; Stage III Colorectal Cancer AJCC v7; Stage IIIA Colorectal Cancer AJCC v7; Stage IIIB Colorectal Cancer AJCC v7; Stage IIIC Colorectal Cancer AJCC v7; Stage IV Colorectal Cancer AJCC v7; Stage IVA Colorectal Cancer AJCC v7; Stage IVB Colorectal Cancer AJCC v7

Determinants of survival after liver resection for metastatic colorectal carcinoma.

Science.gov (United States)

Parau, Angela; Todor, Nicolae; Vlad, Liviu

2015-01-01

Prognostic factors for survival after liver resection for metastatic colorectal cancer identified up to date are quite inconsistent with a great inter-study variability. In this study we aimed to identify predictors of outcome in our patient population. A series of 70 consecutive patients from the oncological hepatobiliary database, who had undergone curative hepatic surgical resection for hepatic metastases of colorectal origin, operated between 2006 and 2011, were identified. At 44.6 months (range 13.7-73), 30 of 70 patients (42.85%) were alive. Patient demographics, primary tumor and liver tumor factors, operative factors, pathologic findings, recurrence patterns, disease-free survival (DFS), overall survival (OS) and cancer-specific survival (CSS) were analyzed. Clinicopathologic variables were tested using univariate and multivariate analyses. The 3-year CSS after first hepatic resection was 54%. Median CSS survival after first hepatic resection was 40.2 months. Median CSS after second hepatic resection was 24.2 months. The 3-year DFS after first hepatic resection was 14%. Median disease free survival after first hepatic resection was 18 months. The 3-year DFS after second hepatic resection was 27% and median DFS after second hepatic resection 12 months. The 30-day mortality and morbidity rate after first hepatic resection was 5.71% and 12.78%, respectively. In univariate analysis CSS was significantly reduced for the following factors: age >53 years, advanced T stage of primary tumor, moderately- poorly differentiated tumor, positive and narrow resection margin, preoperative CEA level >30 ng/ml, DFS <18 months. Perioperative chemotherapy related to metastasectomy showed a trend in improving CSS (p=0.07). Perioperative chemotherapy improved DFS in a statistically significant way (p=0.03). Perioperative chemotherapy and achievement of resection margins beyond 1 mm were the major determinants of both CSS and DFS after first liver resection in multivariate

Sodium hyaluronate enhances colorectal tumour cell metastatic potential in vitro and in vivo.

LENUS (Irish Health Repository)

Tan, B

2012-02-03

BACKGROUND: Sodium hyaluronate has been used intraperitoneally to prevent postoperative adhesions. However, the effect of sodium hyaluronate on tumour growth and metastasis in vitro and in vivo is still unknown. METHODS: Human colorectal tumour cell lines SW480, SW620 and SW707 were treated with sodium hyaluronate (10-500 microg\\/ml) and carboxymethylcellulose (0.125-1 per cent), and tumour cell proliferation and motility were determined in vitro. For the in vivo experiments male BD IX rats were randomized to a sodium hyaluronate group (n = 11; intraperitoneal administration of 0.5 x 10(6) DHD\\/K12 tumour cells and 5 ml 0.4 per cent sodium hyaluronate) or a phosphate-buffered saline group (n = 11; 0.5 x 10(6) DHD\\/K12 tumour cells and 5 ml phosphate-buffered saline intraperitoneally). Four weeks later the intraperitoneal tumour load was visualized directly. RESULTS: In vitro sodium hyaluronate increased tumour cell proliferation and motility significantly. Sodium hyaluronate-induced tumour cell motility appeared to be CD44 receptor dependent, whereas sodium hyaluronate-induced tumour cell proliferation was CD44 receptor independent. In vivo there was a significantly higher total tumour nodule count in the peritoneal cavity of the sodium hyaluronate-treated group compared with the control (P = 0.016). CONCLUSION: Sodium hyaluronate enhances tumour metastatic potential in vitro and in vivo, which suggests that use of sodium hyaluronate to prevent adhesions in colorectal cancer surgery may also potentiate intraperitoneal tumour growth. Presented to the Patey Prize Session of the Surgical Research Society and the annual scientific meeting of the Association of Surgeons of Great Britain and Ireland, Brighton, UK, 4-7 May 1999

Regorafenib-induced retinal and gastrointestinal hemorrhage in a metastatic colorectal cancer patient with liver dysfunction: A case report.

Science.gov (United States)

Tsuchihashi, Kenji; Shimokawa, Hozumi; Takayoshi, Kotoe; Nio, Kenta; Aikawa, Tomomi; Matsushita, Yuzo; Wada, Iori; Arita, Shuji; Ariyama, Hiroshi; Kusaba, Hitoshi; Sonoda, Koh-Hei; Akashi, Koichi; Baba, Eishi

2017-10-01

Regorafenib is effective for metastatic colorectal cancer but its toxicity such as hemorrhage should be considered. The safety of regorafenib for the patient with the liver disease is not known. Seventy-one-year old man of colon cancer had myodesopsia and blood stool after 14 days from the initiation of regorafenib administration with 50% dose reduction due to liver dysfunction. Fundus examination revealed hemorrhage of the retinal vein. Regorafenib treatment was discontinued and observational therapy was pursued. Retinal and gastrointestinal hemorrhage resolved in 1 week. Retinal hemorrhage should be considered as the differential diagnosis of myodesopsia in the patient treated by regorafenib. Safety and pharmacokinetic of continuous regorafenib administration for patients with liver dysfunction remains to be clarified.

Radioimmunodetection of colorectal cancer

International Nuclear Information System (INIS)

Kim, E.E.; Deland, F.H.; Casper, S.; Corgan, R.L.; Primus, F.J.; Goldenberg, D.M.

1980-01-01

This study examines the accuracy of colorectal cancer radioimmunodetection. Twenty-seven patients with a history of histologically-confirmed colonic or rectal carcinoma received a high-titer, purified goat anti-CEA IgG labelled with 131 I at a total dose of at least 1.0 μCi. Various body views were scanned at 24 and 48 hours after administration of the radioantibody. Three additional cases were evaluated; one had a villous adenoma in the rectum and received the 131 I-labeled anti-CEA IgG, while two colonic carcinoma patients received normal goat IgG labelled with 131 I. All of the 7 cases with primary colorectal cancer showed true-positive tumor localization, while 20 of 25 sites of metastatic colorectal cancer detected by immune scintigraphy were corroborated by other detection measures. The sensitivity of the radioimmunodetection of colorectal cancers (primary and metastatic) was found to be 90% (true-positive rate), the putative specificity (true-negative rate) was 94%, and the apparent overall accuracy of the technique was 93%. Neither the case of a villous adenoma receiving the anti-CEA IgG nor the two cases of colonic cancer receiving normal goat IgG showed tumor radiolocalization. Very high circulating CEA titers did not appear to hinder successful tumor radiolocalization. These findings suggest that in colorectal cancers the method of CEA radioimmunodetection may be of value in preoperatively determining the location and extent of disease, in assessing possible recurrence or spread postoperatively, and in localizing the source of CEA production in patients with rising or elevated CEA titers. An ancilliary benefit could be a more tumor-specific detection test for confirming the findings of other, more conventional diagnostic measures

Importance of circulating tumor cells in newly diagnosed colorectal cancer

NARCIS (Netherlands)

van Dalum, Guus; Stam, Gerrit-Jan; Scholten, Loes F.A.; Mastboom, Walter J.B.; Vermes, I.; Tibbe, Arjan G.J.; De Groot, Marco R.; Terstappen, Leonardus Wendelinus Mathias Marie

2015-01-01

Presence of circulating tumor cells (CTC) is associated with poor prognosis in patients with metastatic colorectal cancer (CRC). The present study was conducted to determine if the presence of CTC prior to surgery and during follow‑up in patients with newly diagnosed non-metastatic CRC can identify

The CEA−/lo colorectal cancer cell population harbors cancer stem cells and metastatic cells

Science.gov (United States)

Zhang, Bo; Mu, Lei; Huang, Kaiyu; Zhao, Hui; Ma, Chensen; Li, Xiaolan; Tao, Deding; Gong, Jianping; Qin, Jichao

2016-01-01

Serum carcinoembryonic antigen (CEA) is the most commonly used tumor marker in a variety of cancers including colorectal cancer (CRC) for tumor diagnosis and monitoring. Recent studies have shown that colonic crypt cells expressing little or no CEA may enrich for stem cells. Numerous studies have clearly shown that there exist CRC patients with normal serum CEA levels during tumor progression or even tumor relapse, although CEA itself is considered to promote metastasis and block cell differentiation. These seemingly contradictory observations prompted us to investigate, herein, the biological properties as well as tumorigenic and metastatic capacity of CRC cells that express high (CEA+) versus low CEA (CEA−/lo) levels of CEA. Our findings show that the abundance of CEA−/lo cells correlate with poor differentiation and poor prognosis, and moreover, CEA−/lo cells form more spheres in vitro, generate more tumors and exhibit a higher potential in developing liver and lung metastases than corresponding CEA+ cells. Applying RNAi-mediated approach, we found that IGF1R mediated tumorigenic and capacity of CEA−/lo cells but did not mediate those of CEA+ cells. Notably, our data demonstrated that CEA molecule was capable of protecting CEA−/lo cells from anoikis, implying that CEA+ cells, although themselves possessing less tumorigenic and metastatic capacity, may promote metastasis of CEA−/lo cells via secreting CEA molecule. Our observations suggest that, besides targeting CEA molecule, CEA−/lo cells may represent a critical source of tumor progression and metastasis, and should therefore be the target of future therapies. PMID:27813496

Multicenter Phase II study of FOLFOX or biweekly XELOX and Erbitux (cetuximab) as first-line therapy in patients with wild-type KRAS/BRAF metastatic colorectal cancer: The FLEET study

International Nuclear Information System (INIS)

Soda, Hitoshi; Maeda, Hiromichi; Hasegawa, Junichi; Takahashi, Takao; Hazama, Shoichi; Fukunaga, Mutsumi; Kono, Emiko; Kotaka, Masahito; Sakamoto, Junichi; Nagata, Naoki; Oba, Koji; Mishima, Hideyuki

2015-01-01

The clinical benefit of cetuximab combined with oxaliplatin-based chemotherapy remains under debate. The aim of the present multicenter open-label Phase II study was to explore the efficacy and safety of biweekly administration of cetuximab and mFOLFOX-6 or XELOX as first-line chemotherapy in patients with metastatic colorectal cancer. Sixty-two patients with previously untreated KRAS/BRAF wild-type metastatic colorectal cancer were recruited to the study between April 2010 and May 2011. Patients received one of two treatment regimens, either cetuximab plus mFOLFOX-6 (FOLFOX + Cmab) or cetuximab plus biweekly XELOX (XELOX + Cmab), according to their own preference. Treatment was continued until disease progression or the appearance of intolerable toxicities. The primary endpoint was response rate; secondary endpoints were progression-free survival, overall survival, disease control rate, dose intensity, conversion rate to surgical resection, and safety. The response rates in the FOLFOX + Cmab (n = 37) and XELOX + Cmab (n = 25) groups were 64.9 % (24/37) and 72.0 % (18/25), respectively. The median PFS in the FOLFOX + Cmab and XELOX + Cmab groups was 13.1 months (95 % confidence interval [CI] 12.1–17.5) and 13.4 months (95 % CI 10.1–17.9), respectively. Neutropenia was the most frequent grade 3/4 adverse event in both groups (33.9 %), followed by anorexia, acneiform eruption, skin fissure and paronychia. A waterfall plot of tumor diameter showed prominent shrinkage of the tumors in 88.7 % of patients. The results of the present study indicate that biweekly cetuximab plus mFOLFOX-6/XELOX is an effective and tolerable treatment regimen. Biweekly administration of cetuximab requires only one hospital visit every 2 weeks, and may become a convenient treatment option for patients with KRAS/BRAF wild-type metastatic colorectal cancer

Extreme assay sensitivity in molecular diagnostics further unveils intratumour heterogeneity in metastatic colorectal cancer as well as artifactual low-frequency mutations in the KRAS gene.

Science.gov (United States)

Mariani, Sara; Bertero, Luca; Osella-Abate, Simona; Di Bello, Cristiana; Francia di Celle, Paola; Coppola, Vittoria; Sapino, Anna; Cassoni, Paola; Marchiò, Caterina

2017-07-25

Gene mutations in the RAS family rule out metastatic colorectal carcinomas (mCRCs) from anti-EGFR therapies. We report a retrospective analysis by Sequenom Massarray and fast COLD-PCR followed by Sanger sequencing on 240 mCRCs. By Sequenom, KRAS and NRAS exons 2-3-4 were mutated in 52.9% (127/240) of tumours, while BRAF codon 600 mutations reached 5% (12/240). Fast COLD-PCR found extra mutations at KRAS exon 2 in 15/166 (9%) of samples, previously diagnosed by Sequenom as wild-type or mutated at RAS (exons 3-4) or BRAF genes. After UDG digestion results were reproduced in 2/12 analysable subclonally mutated samples leading to a frequency of true subclonal KRAS mutations of 1.2% (2.1% of the previous Sequenom wild-type subgroup). In 10 out of 12 samples, the subclonal KRAS mutations disappeared (9 out of 12) or turned to a different sequence variant (1 out of 12). mCRC can harbour coexisting multiple gene mutations. High sensitivity assays allow the detection of a small subset of patients harbouring true subclonal KRAS mutations. However, DNA changes with mutant allele frequencies <3% detected in formalin-fixed paraffin-embedded samples may be artifactual in a non-negligible fraction of cases. UDG pre-treatment of DNA is mandatory to identify true DNA changes in archival samples and avoid misinterpretation due to artifacts.

Radioimmunoscintigraphy of recurrent, metastatic, or occult colorectal cancer with technetium 99m-labeled totally human monoclonal antibody 88BV59: results of pivotal, phase III multicenter studies.

Science.gov (United States)

Serafini, A N; Klein, J L; Wolff, B G; Baum, R; Chetanneau, A; Pecking, A; Fischman, A J; Hoover, H C; Wynant, G E; Subramanian, R; Goroff, D K; Hanna, M G

1998-05-01

To assess the performance and potential clinical impact of a totally human monoclonal antibody, 88BV59 (HumaSPECT) (INTRACEL, Corp, Rockville, MD), in 202 assessable presurgical patients with recurrent, metastatic, or occult colorectal cancer. 88BV59, labeled with technetium Tc 99m (99mTc) (HumaSPECT-Tc), was injected intravenously, and planar and single photon emission tomography (SPECT) images were obtained 14 to 20 hours postinjection. Surgical and pathologic verification of tumor were used as the standard against which the performance of HumaSPECT-Tc imaging and computed tomography (CT) analysis were evaluated. All patients entered onto the recurrent disease study had at least one tumor site defined on CT. The sensitivity of HumaSPECT-Tc in those CT-positive patients was 87%. The specificity of HumaSPECT-Tc was 57% compared with 17% for CT and the difference was statistically significant (P HAHA) response (90 ng/mL) at 9 weeks postinfusion was observed. HumaSPECT-Tc can provide important and accurate information about the presence and location of disease in patients with a high clinical suspicion of metastatic or recurrent colorectal cancer and either positive (known disease) or negative (occult disease) CT scans.

Efficacy, Safety and Cost of Regorafenib in Patients with Metastatic Colorectal Cancer in French Clinical Practice.

Science.gov (United States)

Calcagno, Fabien; Lenoble, Sabrina; Lakkis, Zaher; Nguyen, Thierry; Limat, Samuel; Borg, Christophe; Jary, Marine; Kim, Stefano; Nerich, Virginie

2016-01-01

Regorafenib is an orally administered multikinase inhibitor that has been approved for patients with chemotherapy-refractory metastatic colorectal cancer (mCRC). Even though regorafenib significantly improved survival in two international phase 3 trials (CORRECT and CONCUR), a high rate of treatment-related toxic effects and dose modifications were observed with a modest benefit. The aim of this study was to provide information concerning the efficacy, safety, and cost of regorafenib in patients with mCRC in clinical practice. We retrospectively reviewed patients treated with regorafenib monotherapy for unresectable mCRC in five Franche-Comté cancer hospitals (France). The primary end point was overall survival. Secondary end points were safety and descriptive cost analyses of patients treated with regorafenib in clinical practice. Another aim of this study was to assess the impact of regorafenib prescription on the risk of hospitalization in real-life practice. From January 2014 to August 2014, 29 consecutive patients were enrolled. Patients were heavily pretreated and were refractory to standard chemotherapies. The primary tumor sites were the colon and the rectum for 55% and 45% of patients, respectively. Fifteen patients (51%) harbored an RAS mutation. Eastern Cooperative Oncology Group - Performance Status (PS) was 0-1 for 86% of patients and 2 for 14% of patients. Nineteen patients (66%) initially received reduced doses of 120 or 80 mg/day. The median duration of treatment was 2.5 months (range, 0.13-11.4 months). Treatment-related adverse events occurred in 86% of patients. The most frequent adverse events of any grade were fatigue (35%), diarrhea (20%), and hand-foot skin reaction (20%). Grade 3 or 4 treatment-related adverse events occurred in 10 patients (35%). Three patients (10%) were admitted to hospital due to drug-related severe adverse events. The mean cost of patient management with regorafenib for the duration of treatment was 9908 ± 8191�

Dai-Kenchu-To, a Herbal Medicine, Attenuates Colorectal Distention-induced Visceromotor Responses in Rats

OpenAIRE

Nakaya, Kumi; Nagura, Yohko; Hasegawa, Ryoko; Ito, Hitomi; Fukudo, Shin

2016-01-01

Background/Aims Dai-kenchu-to (DKT), a traditional Japanese herbal medicine, is known to increase gastrointestinal motility and improve ileal function. We tested our hypotheses that (1) pretreatment with DKT would block the colorectal distention-induced visceromotor response in rats, and (2) pretreatment with DKT would attenuate colorectal distention-induced adrenocorticotropic hormone (ACTH) release and anxiety-related behavior. Methods Rats were pretreated with vehicle or DKT (300 mg/kg/5 m...

Characterization of global microRNA expression reveals oncogenic potential of miR-145 in metastatic colorectal cancer

International Nuclear Information System (INIS)

Arndt, Greg M; Retzlaff, Kathy; Bittner, Anton; Raponi, Mitch; Dossey, Lesley; Cullen, Lara M; Lai, Angela; Druker, Riki; Eisbacher, Michael; Zhang, Chunyan; Tran, Nham; Fan, Hongtao

2009-01-01

MicroRNAs (MiRNAs) are short non-coding RNAs that control protein expression through various mechanisms. Their altered expression has been shown to be associated with various cancers. The aim of this study was to profile miRNA expression in colorectal cancer (CRC) and to analyze the function of specific miRNAs in CRC cells. MirVana miRNA Bioarrays were used to determine the miRNA expression profile in eight CRC cell line models, 45 human CRC samples of different stages, and four matched normal colon tissue samples. SW620 CRC cells were stably transduced with miR-143 or miR-145 expression vectors and analyzed in vitro for cell proliferation, cell differentiation and anchorage-independent growth. Signalling pathways associated with differentially expressed miRNAs were identified using a gene set enrichment analysis. The expression analysis of clinical CRC samples identified 37 miRNAs that were differentially expressed between CRC and normal tissue. Furthermore, several of these miRNAs were associated with CRC tumor progression including loss of miR-133a and gain of miR-224. We identified 11 common miRNAs that were differentially expressed between normal colon and CRC in both the cell line models and clinical samples. In vitro functional studies indicated that miR-143 and miR-145 appear to function in opposing manners to either inhibit or augment cell proliferation in a metastatic CRC model. The pathways targeted by miR-143 and miR-145 showed no significant overlap. Furthermore, gene expression analysis of metastatic versus non-metastatic isogenic cell lines indicated that miR-145 targets involved in cell cycle and neuregulin pathways were significantly down-regulated in the metastatic context. MiRNAs showing altered expression at different stages of CRC could be targets for CRC therapies and be further developed as potential diagnostic and prognostic analytes. The identified biological processes and signalling pathways collectively targeted by co-expressed miRNAs in

Pretreatment Diffusion-Weighted MRI Can Predict the Response to Neoadjuvant Chemotherapy in Patients with Nasopharyngeal Carcinoma

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Guo-Yi Zhang

2015-01-01

Full Text Available Purpose. To explore the potential of diffusion-weighted (DW magnetic resonance imaging (MRI using apparent diffusion coefficient (ADC for predicting the response to neoadjuvant chemotherapy in nasopharyngeal carcinoma (NPC. Methods and Materials. Ninety-two consecutive patients with NPC who underwent three cycles of neoadjuvant chemotherapy were retrospectively analyzed. DW and anatomical MRI were performed before and after neoadjuvant chemotherapy prior to radiotherapy. Pretreatment ADCs and percentage increases in ADC after chemotherapy were calculated for the primary lesions and metastatic adenopathies. Receiver operating characteristic curve analysis was used to select optimal pretreatment ADCs. Results. Pretreatment mean ADCs were significantly lower for responders than for nonresponders (primary lesions, P=0.012; metastatic adenopathies, P=0.013. Mean percentage increases in ADC were higher for responders than for nonresponders (primary lesions, P=0.008; metastatic adenopathies, P<0.001. The optimal pretreatment primary lesion and metastatic adenopathy ADCs for differentiating responders from nonresponders were 0.897 × 10−3 mm2/sec and 1.031 × 10−3 mm2/sec, respectively. Conclusions. NPC patients with low pretreatment ADCs tend to respond better to neoadjuvant chemotherapy. Pretreatment ADCs could be used as a new pretreatment imaging biomarker of response to neoadjuvant chemotherapy.

Genome-Wide Screening of Genes Showing Altered Expression in Liver Metastases of Human Colorectal Cancers by cDNA Microarray

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Rempei Yanagawa

2001-01-01

Full Text Available In spite of intensive and increasingly successful attempts to determine the multiple steps involved in colorectal carcinogenesis, the mechanisms responsible for metastasis of colorectal tumors to the liver remain to be clarified. To identify genes that are candidates for involvement in the metastatic process, we analyzed genome-wide expression profiles of 10 primary colorectal cancers and their corresponding metastatic lesions by means of a cDNA microarray consisting of 9121 human genes. This analysis identified 40 genes whose expression was commonly upregulated in metastatic lesions, and 7 that were commonly downregulated. The upregulated genes encoded proteins involved in cell adhesion, or remodeling of the actin cytoskeleton. Investigation of the functions of more of the altered genes should improve our understanding of metastasis and may identify diagnostic markers and/or novel molecular targets for prevention or therapy of metastatic lesions.

Strategy for improving the detailed examination rate for colorectal cancer screening. New approach for detailed colorectal cancer examination. Study for optimal pre-treatment for CT colonography

International Nuclear Information System (INIS)

Mitsushima, Toru; Fujiwara, Masanori; Nagata, Koichi

2012-01-01

In order to drastically improve the detailed examination rate for strategic colorectal cancer examination in Japan, it is necessary to introduce CT colonography (CTC) as a detailed examination method for colorectal cancer examination, in addition to colonoscopy (CS) which is the conventional detailed examination method. In our study, a cleansing enema/contrast solution (3% Nif-C) was prepared by adding 60 ml of a water-soluble iodine-based contrast agent (Gastrografin) and water to an oral cleansing enema agent (Niflec) in solid (powder) form to a final amount of 2000 ml. The solution was compared with a Niflec solution. In terms of patient's acceptability, more than half of the examined patients answered ''easier to drink than the Niflec solution'' or ''as easy to drink as the Niflec solution. '' Also, the Nif-C solution was comparable or superior to the Niflec solution in terms of cleansing enema effects. Regarding imaging effects essential for CTC, the CT level was found to be 200 HU or greater for any large intestine region upon CTC using the Nif-C solution. Thus, practically sufficient imaging effects were achieved. In conclusion, CTC with pretreatment involving a cleansing enema with oral administration of 3% Nif-C is superior to CS in terms of patient's acceptability. In addition, at least in view of the overseas reports on CTC, there is no particular problem in terms of diagnostic accuracy. Thus, CTC is expected to resolve various problems related to colorectal cancer examination in Japan. (author)

Higher prevalence of KRAS mutations in colorectal cancer in Saudi ...

African Journals Online (AJOL)

We studied retrospectively tumor samples of 83 Saudi metastatic CRC patients for KRAS mutations in codon 12 and codon 13, to evaluate the relevance of KRAS mutation positive colorectal cancers with metastatic sites. KRAS mutation was observed in 42.2% (35/83) patients with CRC. The most common mutations were in ...

Sarcopenia is linked to treatment toxicity in patients with metastatic colorectal cancer.

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Barret, Maximilien; Antoun, Sami; Dalban, Cécile; Malka, David; Mansourbakht, Touraj; Zaanan, Aziz; Latko, Ewa; Taieb, Julien

2014-01-01

Chemotherapy toxicity could be linked to decreased skeletal muscle (sarcopenia). We evaluated the effect of sarcopenia on chemotherapy toxicity among metastatic colorectal cancer (mCRC) patients. All consecutive mCRC patients in 3 hospitals were enrolled in this prospective, cross-sectional, multicenter study. Several nutritional indexes and scores were generated. Computed tomography (CT) images were analyzed to evaluate cross-sectional areas of muscle tissue (MT), visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT). Toxicities were evaluated in the 2 mo following clinical evaluation. Fifty-one mCRC patients were included in the study. Sarcopenia was observed in 71% of patients (39% of women and 82% of men) whereas only 4% and 18% were considered as underweight using body mass index (BMI) or severely malnourished using the Nutritional Risk Index (NRI), respectively. Grade 3-4 toxicities were observed in 28% of patients. In multivariate analysis including age, sex, BMI, sarcopenia, SAT, and VAT, the only factor associated with Grade 3-4 toxicities was sarcopenia (odds ratio = 13.55; 95% confidence interval [1.08; 169.31], P = 0.043). In mCRC patients undergoing chemotherapy, sarcopenia was much more frequently observed than visible malnutrition. Despite the small number of patients included in our study, we found sarcopenia to be significantly associated with severe chemotherapy toxicity.

Reduced dose of salvage-line regorafenib monotherapy for metastatic colorectal cancer in Japan.

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Hirano, Gen; Makiyama, Akitaka; Makiyama, Chinatsu; Esaki, Taito; Oda, Hisanobu; Uchino, Keita; Komoda, Masato; Tanaka, Risa; Matsushita, Yuzo; Mitsugi, Kenji; Shibata, Yoshihiro; Kumagai, Hozumi; Arita, Shuji; Ariyama, Hiroshi; Kusaba, Hitoshi; Akashi, Koichi; Baba, Eishi

2015-01-01

Salvage-line regorafenib monotherapy exhibited a marked survival benefit for metastatic colorectal cancer (mCRC). However, the toxicity of this regimen has resulted in the clinical use of a reduced dose of regorafenib. Thirty-two Japanese mCRC patients (median age=61 years) who had been treated with regorafenib were retrospectively examined. Best objective response rate was 0% and stable disease (SD) was 31%. Median progression-free survival was 81 days and median overall survival was 233 days. Adverse events of any grade were observed in all patients: 17 (53%) patients suffered grade 3 or 4 adverse events including fatigue (13%), anorexia (13%), hand-foot skin reaction (22%) and elevations of alanine aminotransferase/aspartate aminotransferase (19%/16%). One patient with grade 5 liver dysfunction was identified (3%). Twenty-nine (91%) patients required treatment dose reduction or a delay in treatment. The relative dose intensity was 59%. Regorafenib treatments were terminated because of disease progression (59%) or adverse events (34%). Despite a decrease in the intensity of regorafenib treatment, because of severe adverse events, a fairly favorable efficacy was achieved in Japanese patients. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Prognostic value of {sup 18}F-FDG uptake by regional lymph nodes on pretreatment PET/CT in patients with resectable colorectal cancer

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Byun, Byung Hyun; Lim, Ilhan; Kim, Byung Il; Choi, Chang Woon; Lim, Sang Moo [Korea Institute of Radiological and Medical Sciences, Department of Nuclear Medicine, Korea Cancer Center Hospital, Seoul (Korea, Republic of); Moon, Sun Mi; Shin, Ui Sup [Korea Institute of Radiological and Medical Sciences (KIRAMS), Surgery, Korea Cancer Center Hospital, Seoul (Korea, Republic of)

2014-12-15

We evaluated the ability of pretreatment {sup 18}F-FDG uptake by regional lymph nodes to predict the survival of patients with resectable colorectal cancer. The records of 78 patients with AJCC stage III colorectal cancer (pathologically confirmed node-positive disease without evidence of distant metastasis) treated with surgery and adjuvant chemotherapy were retrospectively reviewed. The maximum standardized uptake values of the primary tumor (SUVp) and regional lymph nodes (SUVn) were measured by pretreatment {sup 18}F-FDG PET/CT. The ROC curve analyses and the Cox proportional hazard model were used to analyze whether SUVp, SUVn, and clinicopathologic parameters could predict disease-free survival. Although there were no significant differences between the median SUVp in the event group and that in the non-event group, the median SUVn was significantly higher in the event group (1.7) than in the non-event group (0.8, p = 0.023). Based on the ROC curve analysis, SUVn predicted the event for disease-free survival (AUC = 0.668, p = 0.02) with the optimal criterion, sensitivity, specificity, and accuracy of > 1.2, 71 %, 63 %, and 65 %, respectively. However, SUVp did not predict disease-free survival (AUC = 0.570, p = 0.349). Univariate analysis revealed that SUVn (p = 0.011) and venous invasion (p = 0.016) were associated with disease-free survival, but pathologic N stage was not (p = 0.09). By multivariate analysis, only SUVn > 1.2 independently shortened the disease-free survival (relative risk, 2.97; 95 % CI, 1.14-7.74, p = 0.026). SUVn before surgery may be a useful prognostic marker in patients with AJCC stage III colorectal cancer. (orig.)

Metastatic spread pattern after curative colorectal cancer surgery. A retrospective, longitudinal analysis.

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Augestad, K M; Bakaki, P M; Rose, J; Crawshaw, B P; Lindsetmo, R O; Dørum, L M; Koroukian, S M; Delaney, C P

2015-10-01

The most common sites of colorectal cancer (CRC) recurrence are the local tissues, liver or lungs. The objective was to identify risk factors associated with the primary CRC tumor and cancer recurrence in these anatomical sites. Retrospective, longitudinal analyses of data on CRC survivors. Multivariable Cox regression analysis was performed to examine the association between possible cofounders with recurrence to various anatomical sites. Data for 10,398CRC survivors (tumor location right colon=3870, left colon=2898, high rectum=2569, low rectum=1061) were analyzed; follow up time was up to five years. Mean age at curative surgery was 71.5 (SD 11.8) years, 20.2% received radio-chemotherapy, stage T3 (64.4%) and N0 (65.1%) were most common. Overall 1632 (15.7%) had cancer recurrence (Isolated liver n=412, 3,8%;  isolated lung n=252, 2,4%; isolated local n=223, 2.1%). Risk factors associated with recurrent CRC were identified, i.e. isolated liver metastases (male: Adjusted Hazard Ratio (AHR) 1,45; colon left: AHR 1,63; N2 disease: AHR 3,35; T2 disease: AHR 2,82), isolated lung metastases (colon left: AHR 1,53; rectum high: AHR 2,48; rectum low: AHR 2,65; N2 disease 3,76), and local recurrence (glands examined<12: AHR 1,51; CRM <3mm: AHR 1,60; rectum high: AHR 2,15; N2 disease: AHR 2,58) (all p values <0001). Our study finds that the site of the primary CRC tumor is associated with location of subsequent metastasis. Left sided colon cancers have increased risk of metastatic spread to the liver, whereas rectal cancers have increased risk of local recurrence and metastatic spread to the lungs. These results, in combination with other risk factors for CRC recurrence, should be taken into consideration when designing risk adapted post-treatment CRC surveillance programs. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

O-Linked β-N-Acetylglucosaminylation (O-GlcNAcylation) in Primary and Metastatic Colorectal Cancer Clones and Effect of N-Acetyl-β-d-glucosaminidase Silencing on Cell Phenotype and Transcriptome*

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Yehezkel, Galit; Cohen, Liz; Kliger, Adi; Manor, Esther; Khalaila, Isam

2012-01-01

O-Linked β-N-acetylglucosamine (O-GlcNAc) glycosylation is a regulatory post-translational modification occurring on the serine or threonine residues of nucleocytoplasmic proteins. O-GlcNAcylation is dynamically regulated by O-GlcNAc transferase and O-GlcNAcase (OGA), which are responsible for O-GlcNAc addition and removal, respectively. Although O-GlcNAcylation was found to play a significant role in several pathologies such as type II diabetes and neurodegenerative diseases, the role of O-GlcNAcylation in the etiology and progression of cancer remains vague. Here, we followed O-GlcNAcylation and its catalytic machinery in metastatic clones of human colorectal cancer and the effect of OGA knockdown on cellular phenotype and on the transcriptome. The colorectal cancer SW620 metastatic clone exhibited increased O-GlcNAcylation and decreased OGA expression compared with its primary clone, SW480. O-GlcNAcylation elevation in SW620 cells, through RNA interference of OGA, resulted in phenotypic alterations that included acquisition of a fibroblast-like morphology, which coincides with epithelial metastatic progression and growth retardation. Microarray analysis revealed that OGA silencing altered the expression of about 1300 genes, mostly involved in cell movement and growth, and specifically affected metabolic pathways of lipids and carbohydrates. These findings support the involvement of O-GlcNAcylation in various aspects of tumor cell physiology and suggest that this modification may serve as a link between metabolic changes and cancer. PMID:22730328

Anti-epidermal or anti-vascular endothelial growth factor as first-line metastatic colorectal cancer in modified Glasgow prognostic score 2' patients

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Dréanic, Johann; Dhooge, Marion; Barret, Maximilien; Brezault, Catherine; Mir, Olivier; Chaussade, Stanislas; Coriat, Romain

2015-01-01

Background In metastatic colorectal cancer, the modified Glasgow prognostic score (mGPS) has been approved as an independent prognostic indicator of survival. No data existed on poor prognosis patients treated with molecular-targeted agents. Methods From January 2007 to February 2012, patients with metastatic colorectal cancer and poor predictive survival score (mGPS = 2), treated with 5-fluorouracil-based chemotherapy in addition to an anti-epidermal growth factor receptor (EGFR) or anti-vascular epidermal growth factor (VEGF) therapy, were included to assess the interest of targeted therapy within mGPS = 2' patients. Results A total of 27 mGPS = 2' patients were included and received a 5-fluorouracil-based systemic chemotherapy in addition to an anti-EGFR treatment (cetuximab; n = 18) or an anti-VEGF treatment (bevacizumab; n = 9). Median follow-up was 12.1 months (interquartile range 4.9–22). Patients were Eastern Cooperative Oncology Group (ECOG) Performance Status 1, 2, and 3 in 66% (n = 18), 26% (n = 7), and 8% (n = 2), respectively. Comparing anti-EGFR and anti-VEGF groups, median progression-free survival was 3.9 and 15.4 months, respectively, and was significantly different (P = 0.046). Conversely, the median overall survival was not significantly different between the two groups (P = 0.15). Conclusion Our study confirmed the poor survival of patients with mGPS = 2 despite the use of targeted therapy and identified the superiority of an anti-VEGF treatment in progression-free survival, without a significant benefit in the overall survival compared with the anti-EGFR therapy. Our results deserved confirmation by a prospective clinical trial. PMID:26401469

Balancing risk and benefit for first-line treatment of metastatic colorectal cancer: a graphic communication tool for patients and physicians.

Science.gov (United States)

Sanatani, Michael S; Vincent, Mark D

2007-01-01

Advances in the treatment of metastatic colorectal cancer have improved overall survival (OS); however, this might come at the cost of increased toxicity. Health-related quality of life, a significant concern closely related to toxicity and important when discussing palliative therapy, is infrequently assessed and reported in older clinical trials. As the number of tested regimens increases, the question arises on how to best present palliative treatment options. We present a simple way to compare treatment options in terms of potential risks and benefits. The literature was surveyed for reports of first-line systemic chemotherapies for metastatic colorectal cancer. The largest recent reports with detailed toxicity data were selected as representative for a regimen. Toxicity sum of a regimen was calculated as percent occurrences in the study cohort of severe adverse effects: diarrhea, mucositis, neurocutaneous conditions (excluding alopecia), vomiting, and febrile neutropenia. Limitations of toxicity reporting precluded inclusion of other or milder adverse events. Benefits (OS and progression-free survival [PFS]) were plotted graphically as benefit versus toxicity sum. Thirty-four regimens were found. Overall survival, PFS, and toxicity sum ranged from 8.9-24.7 months, 4.9-9.2 months, and 12-70 months, respectively. Weaknesses of our study include omission of some specific toxicities and of symptom control benefit, as well as heterogeneity of trial design and study populations. Furthermore, more recent OS data might reflect the availability of more lines of therapy rather than the effect of the first-line regimen, as comparison with PFS outcomes show. Our comparative tool helps physicians discuss the large number of available options with a patient in order to arrive at the treatment plan most appropriate to the individual and improve informed consent and disclosure, while highlighting limitations in available evidence.

Location of Primary Tumor and Benefit From Anti-Epidermal Growth Factor Receptor Monoclonal Antibodies in Patients With RAS and BRAF Wild-Type Metastatic Colorectal Cancer

Science.gov (United States)

Moretto, Roberto; Cremolini, Chiara; Rossini, Daniele; Pietrantonio, Filippo; Battaglin, Francesca; Mennitto, Alessia; Bergamo, Francesca; Loupakis, Fotios; Marmorino, Federica; Berenato, Rosa; Marsico, Valentina Angela; Caporale, Marta; Antoniotti, Carlotta; Masi, Gianluca; Salvatore, Lisa; Borelli, Beatrice; Fontanini, Gabriella; Lonardi, Sara; De Braud, Filippo

2016-01-01

Introduction. Right- and left-sided colorectal cancers (CRCs) differ in clinical and molecular characteristics. Some retrospective analyses suggested that patients with right-sided tumors derive less benefit from anti-epidermal growth factor receptor (EGFR) antibodies; however, molecular selection in those studies was not extensive. Patients and Methods. Patients with RAS and BRAF wild-type metastatic CRC (mCRC) who were treated with single-agent anti-EGFRs or with cetuximab-irinotecan (if refractory to previous irinotecan) were included in the study. Differences in outcome between patients with right- and left-sided tumors were investigated. Results. Of 75 patients, 14 and 61 had right- and left-sided tumors, respectively. None of the right-sided tumors responded according to RECIST, compared with 24 left-sided tumors (overall response rate: 0% vs. 41%; p = .0032), and only 2 patients with right-sided tumors (15%) versus 47 patients with left-sided tumors (80%) achieved disease control (p < .0001). The median duration of progression-free survival was 2.3 and 6.6 months in patients with right-sided and left-sided tumors, respectively (hazard ratio: 3.97; 95% confidence interval: 2.09–7.53; p < .0001). Conclusion. Patients with right-sided RAS and BRAF wild-type mCRC seemed to derive no benefit from single-agent anti-EGFRs. Implications for Practice: Right- and left-sided colorectal tumors have peculiar epidemiological and clinicopathological characteristics, distinct gene expression profiles and genetic alterations, and different prognoses. This study assessed the potential predictive impact of primary tumor site with regard to anti-epidermal growth factor receptor (EGFR) monoclonal antibody treatment in patients with RAS and BRAF wild-type metastatic colorectal cancer. The results demonstrated the lack of activity of anti-EGFRs in RAS and BRAF wild-type, right-sided tumors, thus suggesting a potential role for primary tumor location in driving treatment choices

Expression of DIAPH1 is up-regulated in colorectal cancer and its down-regulation strongly reduces the metastatic capacity of colon carcinoma cells.

Science.gov (United States)

Lin, Yuan-Na; Izbicki, Jakob R; König, Alexandra; Habermann, Jens K; Blechner, Christine; Lange, Tobias; Schumacher, Udo; Windhorst, Sabine

2014-04-01

In most cases, metastatic colorectal cancer is not curable, thus new approaches are necessary to identify novel targets for colorectal cancer therapy. Actin-binding-proteins (ABPs) directly regulate motility of metastasising tumor cells, and for cortactin an association with colon cancer metastasis has been already shown. However, as its depletion only incompletely inhibits metastasis, additional, more suitable cellular targets have to be identified. Here we analyzed expression of the ABPs, DIAPH1, VASP, N-WASP, and fascin in comparison with cortactin and found that, besides cortactin, DIAPH1 was expressed with the highest frequency (63%) in colorectal cancer. As well as cortactin, DIAPH1 was not detectable in normal colon tissue and expression of both proteins was positively correlated with metastasis of colorectal cancer. To analyse the mechanistic role of DIAPH1 for metastasis of colon carcinoma cells in comparison with cortactin, expression of the proteins was stably down-regulated in the human colon carcinoma cell lines HT-29, HROC-24 and HCT-116. Analysis of metastasis of colon carcinoma cells in SCID mice revealed that depletion of DIAPH1 reduced metastasis 60-fold and depletion of cortactin 16-fold as compared with control cells. Most likely the stronger effect of DIAPH1 depletion on colon cancer metastasis is due to the fact that in vitro knock down of DIAPH1 impaired all steps of metastasis; adhesion, invasion and migration while down-regulation of cortactin only reduced adhesion and invasion. This very strong reducing effect of DIAPH1 depletion on colon carcinoma cell metastasis makes the protein a promising therapeutic target for individualized colorectal cancer therapy. © 2013 UICC.

Computed tomography in brain metastases of colorectal cancer

Energy Technology Data Exchange (ETDEWEB)

Kuratsu, Jun-ichi; Matsukado, Yasuhiko; Sueyoshi, Nobuyuki [Kumamoto Univ. (Japan). School of Medicine; Nonaka, Nobuhito; Sano, Yoshinori; Itoyama, Yoichi; Miura, Giichi

1984-10-01

Metastatic brain tumors from colorectal cancers are relatively rare. In previous reports, the incidence ranged from 3 to 5 percent of all metastatic brain tumors. We report 7 cases of metastatic brain tumors from colorectal cancers. The time interval from the diagnosis of the primary tumors to the brain metastasis was 3 years on the average. Metastasis to the lung and liver were also found in 6 cases at the time of the diagnosis of the brain metastasis. The CEA levels in the serum were highly elevated in all cases. Solitary metastasis was found in all cases; cancers tend to metastasize in the deep area of the cerebrum or cerebellum. On a plain CT scan, tumors were demonstrated as ring-type, with a high-density mass, and ring-like enhancement was seen in 6 cases. Prognosis was very poor in most cases. The median survival time from diagnosis of brain metastasis was 4.5 months in the 2 cases with surgery and 3.5 months in the 4 cases without surgery.

Predictive value of pretreatment lymphocyte count in stage II colorectal cancer and in high-risk patients treated with adjuvant chemotherapy.

Science.gov (United States)

Liang, Lei; Zhu, Ji; Jia, Huixun; Huang, Liyong; Li, Dawei; Li, Qingguo; Li, Xinxiang

2016-01-05

Pretreatment lymphocyte count (LC) has been associated with prognosis and chemotherapy response in several cancers. The predictive value of LC for stage II colorectal cancer (CRC) and for high-risk patients treated with adjuvant chemotherapy (AC) has not been determined. A retrospective review of prospectively collected data from 1332 consecutive stage II CRC patients who underwent curative tumor resection was conducted. A pretreatment LC value risk, 459 (62.2%) of whom received AC. Patients with low LCs had significantly worse 5-year OS (74.6% vs. 90.2%, p risk patients with low LCs had the poorest DFS (p value or combined with high-risk status were both independent prognostic factors(p risk, AC-treated patients with high LCs had significantly longer DFS than untreated patients (HR, 0.594; 95% CI, 0.364-0.970; p = 0.035). There was no difference or trend for DFS or OS in patients with low LCs, regardless of the use of AC (DFS, p = 0.692; OS, p = 0.522). Low LC was also independently associated with poorer DFS in high-risk, AC-treated patients (HR, 1.885; 95% CI, 1.112-3.196; p = 0.019). Pretreatment LC is an independent prognostic factor for survival in stage II CRC. Furthermore, pretreatment LC reliably predicts chemotherapeutic efficacy in high-risk patients with stage II CRC.

Identification and validation of cetuximab resistance associated long noncoding RNA biomarkers in metastatic colorectal cancer.

Science.gov (United States)

Peng, Ke; Liu, Ruiqi; Yu, Yiyi; Liang, Li; Yu, Shan; Xu, Xiaojing; Liu, Tianshu

2018-01-01

Cetuximab is one of the most widely used epidermal growth factor receptor (EGFR) inhibitors to treat patients with metastatic colorectal cancer (mCRC) harboring wild-type of RAS/RAF status. However, primary and acquired resistance to cetuximab is often found during target therapy. To gain insights into the functions of long non-coding RNA (lncRNA) in cetuximab resistance, we used a lncRNA-mining approach to distinguish lncRNA specific probes in Affymetrix HG-U133A 2.0 arrays. Then we performed lncRNA expression profiling in a cetuximab treated mCRC cohort from Gene Expression Ominus (GEO). The potential lncRNAs were further validated in acquired cetuximab resistant cell lines and clinical samples of our hospital. The functions and associated pathways of the prognostic lncRNA were predicted by GO and KEGG analyses. 249 lncRNA-specific probe sets (corresponding to 212 lncRNAs) were represented in Affymetrix HG-U133A 2.0 arrays. We found that 9 lncRNAs were differentially expressed between disease control group (DCG) and non-responders, and 5 of these 9 lncRNAs were significantly related with the progression-free survival (PFS) of the patients. Among those 5 lncRNAs, POU5F1P4 was also down-regulated in acquired cetuximab resistant cells, as well as in cetuximab resistant patients. Downregulation of POU5F1P4 decreased the sensitivity of colorectal cancer cells to cetuximab. Our findings indicate the potential roles of lncRNAs in cetuximab resistance, and may provide the useful information for discovery of new biomarkers and therapeutic targets. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Phase II open-label study to assess efficacy and safety of lenalidomide in combination with cetuximab in KRAS-mutant metastatic colorectal cancer.

Directory of Open Access Journals (Sweden)

Salvatore Siena

Full Text Available This study aimed to assess the efficacy and safety of combination treatment with lenalidomide and cetuximab in KRAS-mutant metastatic colorectal cancer patients. This was a phase II multicenter, open-label trial comprising a safety lead-in phase (phase IIa to determine the maximum tolerated dose, and a randomized proof of concept phase (phase IIb to determine the response rate of lenalidomide plus cetuximab combination therapy. Phase IIa treatment comprised oral lenalidomide (starting dose 25 mg/day and intravenous cetuximab (400 mg/m(2 followed by weekly 250 mg/m(2 in 28-day cycles. In phase IIb patients were randomized to either the phase IIa treatment schedule of lenalidomide plus cetuximab combination therapy or lenalidomide 25 mg/day monotherapy. Eight patients were enrolled into phase IIa. One patient developed a dose-limiting toxicity and the maximum tolerated dose of lenalidomide was determined at 25 mg/day. Forty-three patients were enrolled into phase IIb proof of concept. Best response was stable disease in 9 patients and study enrollment was terminated prematurely due to lack of efficacy in both treatment arms and failure to achieve the planned response objective. The majority of adverse events were grade 1 and 2. In both phases, the adverse events most commonly attributed to any study drugs were fatigue, rash and other skin disorders, diarrhea, nausea, and stomatitis. Thirty-nine deaths occurred; none was related to study drug. The combination of lenalidomide and cetuximab appeared to be well tolerated but did not have clinically meaningful activity in KRAS-mutant metastatic colorectal cancer patients.Clinicaltrials.gov NCT01032291.

Cost-effectiveness of cetuximab and panitumumab for chemotherapy-refractory metastatic colorectal cancer.

Science.gov (United States)

Carvalho, Adriana Camargo; Leal, Frederico; Sasse, Andre Deeke

2017-01-01

Cetuximab and panitumumab are monoclonal antibodies targeting the epidermal growth factor receptor. Both drugs are active against RAS wild type metastatic colorectal cancer after chemotherapy failure, with similar efficacy and toxicity profiles. However, their cost and limited survival benefits may compromise incorporation in the Brazilian public healthcare system, the Unified Heath System (Sistema Único de Saúde) (SUS). A cost-effectiveness analysis was conducted using a Markov model from the Brazilian Public health perspective and a lifetime horizon in patients with RAS -wt mCRC. Transition probabilities and mortality rates were extracted from randomized studies. Treatment costs were obtained from price tables regulated by the Brazilian Health Ministry. The World Health Organization recommendation of three times GDP per capita was used to define the cost-effectiveness threshold. The use of cetuximab or panitumumab for chemotherapy-refractory mCRC patients resulted in 0.22 additional life-years relative to BSC, with incremental cost-effectiveness ratios (ICERs) of $58,240 and $52,772 per LY, respectively. That exceeds the pre-specified threshold for cost-effectiveness. Acquisition of biological agents was the major driver of increased costs. Our economic evaluation demonstrates that both cetuximab and panitumumab are not a cost-effective approach in RAS-wt mCRC patients. Discussion about drug price should be prioritized to enable incorporation of these monoclonal antibodies in the SUS.

Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial.

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Li, Jin; Qin, Shukui; Xu, Ruihua; Yau, Thomas C C; Ma, Brigette; Pan, Hongming; Xu, Jianming; Bai, Yuxian; Chi, Yihebali; Wang, Liwei; Yeh, Kun-Huei; Bi, Feng; Cheng, Ying; Le, Anh Tuan; Lin, Jen-Kou; Liu, Tianshu; Ma, Dong; Kappeler, Christian; Kalmus, Joachim; Kim, Tae Won

2015-06-01

In the international randomised phase 3 CORRECT trial (NCT01103323), regorafenib significantly improved overall survival versus placebo in patients with treatment-refractory metastatic colorectal cancer. Of the 760 patients in CORRECT, 111 were Asian (mostly Japanese). This phase 3 trial was done to assess regorafenib in a broader population of Asian patients with refractory metastatic colorectal cancer than was studied in CORRECT. In this randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial done in 25 hospitals in mainland China, Hong Kong, South Korea, Taiwan, and Vietnam, we recruited Asian patients aged 18 years or older with progressive metastatic colorectal cancer who had received at least two previous treatment lines or were unable to tolerate standard treatments. Patients had to have an Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 3 months, and adequate bone marrow, liver, and renal function, without other uncontrolled medical disorders. We randomly allocated patients (2:1; with a computer-generated unicentric randomisation list [prepared by the study funder] and interactive voice response system; block size of six; stratified by metastatic site [single vs multiple organs] and time from diagnosis of metastatic disease [regorafenib 160 mg once daily or placebo on days 1-21 of each 28 day cycle; patients in both groups were also to receive best supportive care. Participants, investigators, and the study funder were masked to treatment assignment. The primary endpoint was overall survival, and we analysed data on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01584830. Between April 29, 2012, and Feb 6, 2013, we screened 243 patients and randomly assigned 204 patients to receive either regorafenib (136 [67%]) or placebo (68 [33%]). After a median follow-up of 7·4 months (IQR 4·3-12·2), overall survival was significantly better with regorafenib

INTEGRATION OF BEVACIZUMAB IN METASTATIC COLORECTAL CANCER CHEMOTHERAPY REGIMENS IN 2 CLINICAL CENTERS IN MOSCOW AND SAINT PETERSBURG

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N. V. Dobrova

2013-01-01

Full Text Available The aim of this study was to estimate efficacy of first line chemotherapy with bevacizumab in metastatic colorectal cancer patients and investigate the impact of different prognostic factors on treatment outcome.Methods.During 2004–2008 48 colorectal cancer patients were included (29 in Russian N.N. Blokhin Cancer Research Center, 19 in St. Petersburg, who had unresectable distant metastases. Primary tumor was resected in 93.8 % patients. 52.1 % had rectal cancer. 87.5 % had liver metastases, 43.8 % had more than 1 organ affected. 66.7 % received chemotherapy with bevacizumab 5 mg/kg biweekly, 33.3 % received bevacizumab 7,5 mg/kg every 3 weeks. 62.5 % patients had oxaliplatin-based regimens, 35.4 % – only fluorpyrimidines, 2.1 % – chemotherapy with irinotecan.Results.Median time of bevacizumab use was 7.8 months. 60.3 % had objective response, 87.4 % had stable diseases during more than 6 months. Median progression-free survival (PFS was 11.5 months. Median overall survival (OS was 24.1 months.Conclusions.Survival and efficacy results are comparable to international experience. Combination of fluorpyrimidines with bevacizumab had comparable efficacy to combined chemotherapy regimens with no impact on quality of life. Integration of bevacizumab in combined treatment regimens reduced the impact of negative prognostic factors on PFS and OS. 

Regorafenib (BAY 73-4506) in advanced colorectal cancer: a phase I study

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Strumberg, D; Scheulen, M E; Schultheis, B; Richly, H; Frost, A; Büchert, M; Christensen, O; Jeffers, M; Heinig, R; Boix, O; Mross, K

2012-01-01

Background: In a phase I dose-escalation study, regorafenib demonstrated tolerability and antitumour activity in solid tumour patients. The study was expanded to focus on patients with metastatic colorectal cancer (CRC). Methods: Patients received oral regorafenib 60–220 mg daily (160 mg daily in the extension cohort) in cycles of 21 days on, 7 days off treatment. Assessments included toxicity, response, pharmacokinetics and pharmacodynamics. Results: Thirty-eight patients with heavily pretreated CRC (median 4 prior lines of therapy, range 0–7) were enrolled in the dose-escalation and extension phases; 26 patients received regorafenib 160 mg daily. Median treatment duration was 53 days (range 7–280 days). The most common treatment-related toxicities included hand–foot skin reaction, fatigue, voice change and rash. Twenty-seven patients were evaluable for response: 1 achieved partial response and 19 had stable disease. Median progression-free survival was 107 days (95% CI, 66–161). At steady state, regorafenib and its active metabolites had similar systemic exposure. Pharmacodynamic assessment indicated decreased tumour perfusion in most patients. Conclusion: Regorafenib showed tolerability and antitumour activity in patients with metastatic CRC. This expanded-cohort phase I study provided the foundation for further clinical trials of regorafenib in this patient population. PMID:22568966

Iodine-131-labelled CDR grafted monoclonal antibody huA33 metastatic colorectal carcinoma: A case study

International Nuclear Information System (INIS)

Thomas, D.L.; Lee, F.T.; Scott, A.M.

1997-01-01

Full text: A 58-year-old woman was diagnosed with metastatic colorectal carcinoma two years after initial surgery for sigmoid carcinoma. As part of the staging work-up she was initially referred for a 18 F-FDG PET scan at the PET Centre. FDG PET scans of the abdomen and pelvis demonstrated multiple hepatic lesions, but there was no evidence of disease outside the liver. On the basis of extensive hepatic disease, the patient was scheduled for a laparotomy for insertion of an hepatic artery catheter for chemotherapy. In view of her clinical presentation, the patient was eligible for a Phase 1 trial with 131 l-labelled huA33, and agreed to participate. HuA33 is a humanised CDR-grafted recombinant monoclonal antibody directed against an antigen found on >95 per cent of all colorectal carcinomas, and on small bowel and colonic mucosa. The phase 1 trial is a protein dose escalation study designed to examine the biodistribution, pharmacokinetics, dosimetry and safety profile of huA33, and sequential gamma camera images of the whole body were obtained daily until seven days post infusion. SPECT images were obtained on day 6. Excellent localisation of 131 l-huA33 was seen in hepatic lesions. Calculation of whole body retention and tumour uptake was performed, and pharmacokinetic analysis also undertaken. Biopsies of tumour obtained at surgery were used to quantitate tumour uptake and cellular trafficking of 131 l-huA33. On the basis of this phase 1 study, future therapeutic trials of 131 I-huA33 are planned

Topoisomerase I copy number alterations as biomarker for irinotecan efficacy in metastatic colorectal cancer

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Palshof, Jesper Andreas; Hogdall, Estrid Vilma Solyom; Poulsen, Tim Svenstrup

2017-01-01

Background No biomarker exists to guide the optimal choice of chemotherapy for patients with metastatic colorectal cancer. We examined the copy numbers (CN) of topoisomerase I (TOP1) as well as the ratios of TOP1/CEN-20 and TOP1/CEN-2 as biomarkers for irinotecan efficacy in patients...... were produced. FISH analysis was performed using two probe-mixes: TOP1/CEN-20 and TOP1/CEN-2. Only samples harboring all three signals (TOP1, CEN-20 and CEN-2) using FISH were included in the analyses. Results In the TOP1/CEN-20 probe-mix the median TOP1- and CEN-20 CN were 4.46 (range: 1.5–9.5) and 2.......00 (range: 0.55–4.55), respectively. The median TOP1- and CEN-2 CN in the TOP1/CEN-2 probe-mix, were 4.57 (range: 1.82–10.43) and 1.98 (range: 1.22–6.14), respectively. The median TOP1/CEN-20 ratio and TOP1/CEN-2 ratio were 1.25 (range: 0.92–2.90) and 2.05 (range: 1.00–6.00), respectively. None...

Clinicopathological features and the value of differential Cytokeratin 7 and 20 expression in resolving diagnostic dilemmas of ovarian involvement by colorectal adenocarcinoma and vice-versa

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Dikshit Rajesh

2008-09-01

Full Text Available Abstract The distinction between metastasis from a colorectal adenocarcinoma into the ovary and an ovarian adenocarcinoma is vital, but challenging at times, due to overlapping morphological features. Similarly, a distinction between an ovarian metastasis into the colorectum and a colorectal adenocarcinoma, although rare; is important and can be daunting. We report an analysis of 20 cases of ovarian involvement by metastatic colorectal adenocarcinomas and colorectal involvement by metastatic ovarian adenocarcinomas, including the value of differential expression of cytokeratins 7 & 20 by immunohistochemistry (IHC, in these cases. Nine cases (45% were identified as colorectal adenocarcinomas metastatic to the ovary. On biopsy, all these cases showed a 'garland-like' tumor necrosis, with desmoplasia and predominantly exhibited a tubuloalveolar pattern (67% cases. On IHC, all 8 of 9 such cases, where staining for cytokeratin 20 was performed, displayed strong positivity and 7 cases, where staining for carcinoembryogenic antigen (CEA was performed, revealed positivity for this marker (100%. Other 11 cases (55% were ovarian adenocarcinomas, metastatic to the colorectum. These showed metachronous presentations, with the ovarian tumor preceding the colorectal tumor deposits. Morphologically, psammomatous calcification was noted in 73% of these cases, whereas 'garland-like' necrosis was absent in all. The chief morphological subtype was serous papillary cystadenocarcinoma (55% cases. On IHC, CK7 and CA 125 were positive in all 6 of 11 such cases, whereas CK 20 was negative in all these cases. In cases of complex presentations like an ovarian involvement by a metastatic colorectal adenocarcinoma and vice-versa, certain clinicopathological features are useful. Differential expression of CK 7 and CK20 is vital in resolving these dilemmas. CK20 positivity and CK7 negativity is associated with a colorectal adenocarcinoma. Markers like CEA and CA-125 have an

Surgical treatment options following chemotherapy plus cetuximab or bevacizumab in metastatic colorectal cancer-central evaluation of FIRE-3.

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Modest, D P; Denecke, T; Pratschke, J; Ricard, I; Lang, H; Bemelmans, M; Becker, T; Rentsch, M; Seehofer, D; Bruns, C J; Gebauer, B; Modest, H I; Held, S; Folprecht, G; Heinemann, V; Neumann, U P

2018-01-01

The FIRE-3 trial investigated combination chemotherapy plus either cetuximab or bevacizumab in patients with untreated metastatic colorectal cancer (mCRC) not scheduled for upfront surgery. We aimed to determine the number of patients who present with potentially resectable disease during systemic first-line therapy and to compare the findings with study reports concerning resections and outcome. This evaluation of 448 patients was performed as central review blinded for treatment, other reviewers' evaluations and conducted interventions. Resectability was defined if at least 50% of the reviewers recommended surgical-based intervention. Overall survival was assessed by Kaplan-Meier method. Resectability increased from 22% (97/448) at baseline before treatment to 53% (238/448) at best response (P < 0.001), compared with an actual secondary resection rate for metastases of 16% (72/448). At baseline (23% versus 20%) and best response (53% versus 53%), potential resectability of metastases in this molecular unselected population was similar in cetuximab-treated patients versus bevacizumab-treated patients and not limited to patients with one-organ disease. The actual resection rate of metastases was significantly associated with treatment setting (P = 0.02; university hospital versus hospital/practice). Overall survival was 51.3 months (95% confidence interval [CI] 35.9-66.7) in patients with resectable disease who received surgery, 30.8 months (95% CI 26.6-34.9) in patients with resectable disease without surgery and 18.6 months (95% CI 15.8-21.3) in patients with unresectable disease (P < 0.001). Our findings illustrate the potential for conversion to resectability in mCRC, certain reluctance towards metastatic resections in clinical practice and the need for pre-planned and continuous evaluation for metastatic resection in high-volume centres. CLINICALTRIALS. NCT00433927. Copyright © 2017 Elsevier Ltd. All rights reserved.

Combination epigenetic therapy in metastatic colorectal cancer (mCRC) with subcutaneous 5-azacitidine and entinostat: a phase 2 consortium/stand up 2 cancer study.

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Azad, Nilofer S; El-Khoueiry, Anthony; Yin, Jun; Oberg, Ann L; Flynn, Patrick; Adkins, Douglas; Sharma, Anup; Weisenberger, Daniel J; Brown, Thomas; Medvari, Prakriti; Jones, Peter A; Easwaran, Hariharan; Kamel, Ihab; Bahary, Nathan; Kim, George; Picus, Joel; Pitot, Henry C; Erlichman, Charles; Donehower, Ross; Shen, Hui; Laird, Peter W; Piekarz, Richard; Baylin, Stephen; Ahuja, Nita

2017-05-23

Therapy with demethylating agent 5-azacitidine and histone deacetylase inhibitor entinostat shows synergistic re-expression of tumor-suppressor genes and growth inhibition in colorectal (CRC) cell lines and in vivo studies. We conducted a phase II, multi-institutional study of the combination in metastatic CRC patients. Subcutaneous azacitidine was administered at 40 mg/m2 days 1-5 and 8-10 and entinostat was given 7 mg orally on days 3 and 10. An interim analysis indicated toxicity crossed the pre-specified safety boundary but was secondary to disease. A 2nd cohort with added eligibility restrictions was accrued: prior therapies were limited to no more than 2 or 3 (KRAS-mutated and KRAS-wildtype cancers, respectively) and <30% of liver involvement. The primary endpoint was RECIST response. Serial biopsies were performed at baseline and after 2 cycles of therapy. Forty-seven patients were enrolled (24:Cohort 1, 23:Cohort 2). Patients were heavily pre-treated (median prior therapies 4: Cohort 1 and 2.5: cohort 2). No responses were observed. Median progression-free survival was 1.9 months; overall survival was 5.6 and 8.3 months in Cohorts 1 and 2, respectively. Toxicity was tolerable and as expected. Unsupervised cluster analysis of serial tumor biopsies suggested greater DNA demethylation in patients with PFS above the median. In this first trial of CRC patients with combination epigenetic therapy, we show tolerable therapy without significant clinical activity as determined by RECIST responses. Reversal of hypermethylation was seen in a subset of patients and correlated with improved PFS.

MicroRNA-126 and epidermal growth factor-like domain 7-an angiogenic couple of importance in metastatic colorectal cancer. Results from the Nordic ACT trial

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Hansen, T F; Christensen, René dePont; Andersen, R F

2013-01-01

Background:This study investigated the clinical importance of linked angiogenetic biomarkers to chemotherapy, combined with the anti-vascular endothelial growth factor A (anti-VEGF-A), as a first-line treatment in patients with metastatic colorectal cancer (mCRC).Methods:A total of 230 patients...... on the prognostic value of miRNA-126 in mCRC and may suggest a relationship between treatment efficacy and EGFL7 expression. As miRNA-126 may target VEGF-A as well as EGFL7, the results may provide predictive information in relation to next-generation anti-angiogenetics....

Circulating Tumor Cell Count Is a Prognostic Factor in Metastatic Colorectal Cancer Patients Receiving First-Line Chemotherapy Plus Bevacizumab: A Spanish Cooperative Group for the Treatment of Digestive Tumors Study

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Maestro, M. Luisa; Gómez-España, Auxiliadora; Rivera, Fernando; Valladares, Manuel; Massuti, Bartomeu; Benavides, Manuel; Gallén, Manuel; Marcuello, Eugenio; Abad, Albert; Arrivi, Antonio; Fernández-Martos, Carlos; González, Encarnación; Tabernero, Josep M.; Vidaurreta, Marta; Aranda, Enrique; Díaz-Rubio, Eduardo

2012-01-01

Background. The Maintenance in Colorectal Cancer trial was a phase III study to assess maintenance therapy with single-agent bevacizumab versus bevacizumab plus chemotherapy in patients with metastatic colorectal cancer. An ancillary study was conducted to evaluate the circulating tumor cell (CTC) count as a prognostic and/or predictive marker for efficacy endpoints. Patients and Methods. One hundred eighty patients were included. Blood samples were obtained at baseline and after three cycles. CTC enumeration was carried out using the CellSearch® System (Veridex LLC, Raritan, NJ). Computed tomography scans were performed at cycle 3 and 6 and every 12 weeks thereafter for tumor response assessment. Results. The median progression-free survival (PFS) interval for patients with a CTC count ≥3 at baseline was 7.8 months, versus the 12.0 months achieved by patients with a CTC count <3 (p = .0002). The median overall survival (OS) time was 17.7 months for patients with a CTC count ≥3, compared with 25.1 months for patients with a lower count (p = .0059). After three cycles, the median PFS interval for patients with a low CTC count was 10.8 months, significantly longer than the 7.5 months for patients with a high CTC count (p = .005). The median OS time for patients with a CTC count <3 was significantly longer than for patients with a CTC count ≥3, 25.1 months versus 16.2 months, respectively (p = .0095). Conclusions. The CTC count is a strong prognostic factor for PFS and OS outcomes in metastatic colorectal cancer patients. PMID:22643538

Adenocarcinoma of the caecum metastatic to the bladder: an unusual cause of haematuria

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Hunt Roger

2006-10-01

Full Text Available Abstract Background Primary malignancies of colorectal origin can metastasise to the bladder. Reports are however extremely rare, particularly from the caecum. Case report The report describes the case of a 45-year old male with Duke's B caecal carcinoma treated with a laparoscopically-assisted right hemicolectomy and adjuvant 5-Fluorouracil chemotherapy. Subsequently, a metastatic lesion to the bladder was demonstrated and successfully excised by partial cystectomy. Conclusion In order that optimal therapeutic options can be determined, it is important for clinicians to distinguish between primary disease of the bladder and other causes of haematuria. Various immunohistochemical techniques attempt to differentiate primary adenocarcinoma of the bladder from secondary colorectal adenocarcinoma. Suspicion of metastatic disease must be raised when histologically unusual bladder tumours are identified.

Pulmonary nodules and metastases in colorectal cancer

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Nordholm-Carstensen, Andreas

2016-01-01

Patients with newly diagnosed colorectal cancer (CRC) are subjected to a preoperative thoraco-abdominal CT scan to determine the cancer stage. This staging is of relevance with regard to treatment and prognosis. About 20% of the patients have distant metastatic spread at the time of diagnosis, i...

Immunomodulatory effects in a phase II study of lenalidomide combined with cetuximab in refractory KRAS-mutant metastatic colorectal cancer patients.

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Anita K Gandhi

Full Text Available This study assessed the immunomodulatory effects in previously treated KRAS-mutant metastatic colorectal cancer patients participating in a phase II multicenter, open-label clinical trial receiving lenalidomide alone or lenalidomide plus cetuximab. The main findings show the T cell immunostimulatory properties of lenalidomide as the drug induced a decrease in the percentage CD45RA(+ naïve T cells 3-fold while increasing the percentage HLA-DR(+ activated T helper cells and percentage total CD45RO(+ CD8(+ memory T cytotoxic cells, 2.6- and 2.1-fold respectively (p<0.0001. In addition, lenalidomide decreased the percentage of circulating CD19(+ B cells 2.6-fold (p<0.0001. Lenalidomide increased a modest, yet significant, 1.4-fold change in the percentage of circulating natural killer cells. Our findings indicate that lenalidomide significantly activates T cells, suggestive of an immunotherapeutic role for this drug in settings of maintenance therapy and tumor immunity. Furthermore, reported for the first time is the effect of lenalidomide in combination with cetuximab on T cell function, including increases in circulating naïve and central memory T cells. In summary, lenalidomide and cetuximab have significant effects on circulating immune cells in patients with colorectal carcinoma.ClinicalTrials.gov NCT01032291.

Individual Patient Data Analysis of Progression-Free Survival Versus Overall Survival As a First-Line End Point for Metastatic Colorectal Cancer in Modern Randomized Trials: Findings From the Analysis and Research in Cancers of the Digestive System Database

NARCIS (Netherlands)

Shi, Qian; de Gramont, Aimery; Grothey, Axel; Zalcberg, John; Chibaudel, Benoist; Schmoll, Hans-Joachim; Seymour, Matthew T.; Adams, Richard; Saltz, Leonard; Goldberg, Richard M.; Punt, Cornelis J. A.; Douillard, Jean-Yves; Hoff, Paulo M.; Hecht, Joel Randolph; Hurwitz, Herbert; Díaz-Rubio, Eduardo; Porschen, Rainer; Tebbutt, Niall C.; Fuchs, Charles; Souglakos, John; Falcone, Alfredo; Tournigand, Christophe; Kabbinavar, Fairooz F.; Heinemann, Volker; van Cutsem, Eric; Bokemeyer, Carsten; Buyse, Marc; Sargent, Daniel J.

2015-01-01

Purpose Progression-free survival (PFS) has previously been established as a surrogate for overall survival (OS) for first-line metastatic colorectal cancer (mCRC). Because mCRC treatment has advanced in the last decade with extended OS, this surrogacy requires re-examination. Methods Individual

KRAS early testing: consensus initiative and cost-effectiveness evaluation for metastatic colorectal patients in an Italian setting.

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Carlo Barone

Full Text Available KRAS testing is relevant for the choice of the most appropriate first-line therapy of metastatic colorectal cancer (CRC. Strategies for preventing unequal access to the test should be implemented, but their relevance in the practice is related to economic sustainability. The study adopted the Delphi technique to reach a consensus on several topics. Issues related to execution of KRAS testing were identified by an expert's board and proposed to 108 Italian oncologists and pathologists through two subsequent questionnaires. The emerging proposal was evaluated by decision analyses models employed by technology assessment agencies in order to assess cost-effectiveness. Alternative therapeutic strategies included most commonly used chemotherapy regimens alone or in combination with cetuximab or bevacizumab. The survey indicated that time interval for obtaining KRAS test should not exceed 15 days, 10 days being an optimal interval. To assure the access to proper treatment, a useful strategy should be to anticipate the test after radical resection in patients at high risk of relapse. Early KRAS testing in high risk CRC patients generates incremental cost-effectiveness ratios between 6,000 and 13,000 Euro per quality adjusted life year (QALY gained. In extensive sensitivity analyses ICER's were always below 15,000 Euro per QALY gained, far within the threshold of 60,000 Euro/QALY gained accepted by regulatory institutions in Italy. In metastatic CRC a time interval higher than 15 days for result of KRAS testing limits access to therapeutic choices. Anticipating KRAS testing before the onset of metastatic disease in patients at high risk does not affect the sustainability and cost-effectiveness profile of cetuximab in first-line mCRC. Early KRAS testing may prevent this inequality in high-risk patients, whether they develop metastases, and is a cost-effective strategy. Based on these results, present joined recommendations of Italian societies of

Pretreatment Neutrophil-Lymphocyte Ratio as a Predictor in Bladder Cancer and Metastatic or Unresectable Urothelial Carcinoma Patients: a Pooled Analysis of Comparative Studies.

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Wu, Shuiqing; Zhao, Xiaokun; Wang, Yinhuai; Zhong, Zhaohui; Zhang, Lei; Cao, Jian; Ai, Kai; Xu, Ran

2018-01-01

Emerging studies have shown that the neutrophil-lymphocyte ratio (NLR) is a potential predictor in various tumors. Our study was conducted to assess the prognostic value of the pretreatment NLR in bladder cancer and metastatic or unresectable urothelial carcinoma (mUC or uUC) patients up to July 2017. The correlation between the pretreatment NLR and pathological characteristics was also evaluated in bladder cancer patients. The hazard ratio (HR) and odds ratio (OR) with the 95% confidence interval (CI) were extracted or calculated from the included studies for further pooled analysis. A total of 21 studies were included in a pooled analysis. The pooled results indicated that a high pretreatment NLR was associated with reduced overall survival (OS) (HR=1.27, 95% CI=1.12-1.43), relapse-free survival (RFS) (HR=1.41, 95% CI=1.23-1.60), progression-free survival (PFS) (HR=1.75, 95% CI=1.36-2.15), disease-specific survival (DSS) and cancer-specific survival (CSS) (HR=1.27, 95% CI=1.19-1.35) in the bladder cancer patients. Additionally, an elevated pretreatment NLR suggested a worse OS rate in the mUC or uUC patients (HR=1.63, 95% CI=1.34-1.91). The pooled ORs and 95% CIs showed that a high pretreatment NLR could be a risk indicator for certain pathological features, such as lymphovascular invasion, a positive margin status and advanced tumor stage. our results showed that a high pretreatment NLR predicted poor prognosis in bladder cancer, mUC and uUC patients. © 2018 The Author(s). Published by S. Karger AG, Basel.

Irinotecan plus folinic acid/continuous 5-fluorouracil as simplified bimonthly FOLFIRI regimen for first-line therapy of metastatic colorectal cancer

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Höhler Thomas

2004-07-01

Full Text Available Abstract Background Combination therapy of irinotecan, folinic acid (FA and 5-fluorouracil (5-FU has been proven to be highly effective for the treatment of metastatic colorectal cancer. However, in light of safety and efficacy concerns, the best combination regimen for first-line therapy still needs to be defined. The current study reports on the bimonthly FOLFIRI protocol consisting of irinotecan with continuous FA/5-FU in five German outpatient clinics, with emphasis on the safety and efficiency, quality of life, management of delayed diarrhea, and secondary resection of regressive liver metastases. Methods A total of 35 patients were treated for metastatic colorectal cancer. All patients received first-line treatment according to the FOLFIRI regimen, consisting of irinotecan (180 mg/m2, L-FA (200 mg/m2 and 5-FU bolus (400 mg/m2 on day 1, followed by a 46-h continuous infusion 5-FU (2400 mg/m2. One cycle contained three fortnightly administrations. Staging was performed after 2 cycles. Dosage was reduced at any time if toxicity NCI CTC grade III/IV was observed. Chemotherapy was administered only to diarrhea-free patients. Results The FOLFIRI regimen was generally well tolerated. It was postponed for one-week in 51 of 415 applications (12.3%. Dose reduction was necessary in ten patients. Grade III/IV toxicity was rare, with diarrhea (14%, nausea/vomiting (12%, leucopenia (3%, neutropenia (9% and mucositis (3%. The overall response rate was 31% (4 CR and 7 PR, with disease control in 74%. After primary chemotherapy, resection of liver metastases was achieved in three patients. In one patient, the CR was confirmed pathologically. Median progression-free and overall survival were seven and 17 months, respectively. Conclusions The FOLFIRI regimen proved to be safe and efficient. Outpatient treatment was well tolerated. Since downstaging was possible, combinations of irinotecan and continuous FA/5-FU should further be investigated in neoadjuvant

Definition and scope of the surgical treatment in patients with pulmonary metastases from colorectal cancer

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B. B. Ahmedov

2016-01-01

Full Text Available Surgical treatment of metastatic colorectal cancer in lungs is a relatively new trend of modern oncology. In this connection, still there are no clearly formulated criteria for patient selection for this type of intervention, approaches to repeated resections and scope of the surgical operation in case of multiple lesions. Established key prognostic factors include lesion of intrathoracic lymph nodes, timing of the development of metastatic disease, baseline level of carcinoembryonic antigen, number of foci and the volume of metastatic lesion, stage of the disease. Options for surgical access include lateral thoracotomy, sternotomy, thoracoscopy and thoracoscopy combined with additional minithoracotomy.If a patient has a single peripheral metastatic lesions, physician should prefer thoracoscopic operations. One of their advantages include minimum development of adhesions and possibility of subsequent re-thoracoscopy. Resection of pulmonary metastases from colorectal cancer (R0 resection rate allows to achieve persistent healing of the tumor process in a significant number of patients.

Cetuximab in first line treatment of metastatic colorectal cancer

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Carlo Barone

2012-07-01

Full Text Available The present health technology assessment report evaluates the clinical and economic profile of cetuximab in first-line metastatic colorectal cancer (mCRC in Italy. The first part of the report addresses the epidemiological, clinical, social and economic impact of mCRC. In the second part, evidence of efficacy, safety and cost-effectiveness of cetuximab and its available alternatives is shown. Finally, a model-based economic evaluation aimed at comparing cetuximab-based re­gimens vs. alternative therapeutic strategies indicated in mCRC in Italy is presented. The model estimates the incremental cost-effectiveness of adding cetuximab to FOLFOX-4 or FOLFIRI based on KRAS status, vs. adding bevacizumab to FOLFOX-4 or vs. FOLFOX-4 or FOLFIRI alone. A theoretical analysis vs. panitumumab has also been performed, despite panitumumab is not yet reimbursed in Italy in first-line mCRC. Survival outcomes, quality of life and costs of patient ma­nagement are estimated through a Markov model, using the Italian National Healthcare Service (NHS perspective, over a 10 year period, taking into account KRAS status of patients. The results of the pharmaco-economic analysis show that cetuximab + FOLFOX-4 and cetuximab + FOLFIRI are associated with increased survival, increased cost and increased quality adjusted survival, compared to all other treatments currently indicated and reimbursed in Italy. Adding cetuximab to FOLFOX-4 or FOLFIRI, based on KRAS status shows favorable incremental cost-effectiveness ratio (ICER vs. adding bevacizumab to FOLFIRI or vs. FOLFOX-4 or FOLFIRI alone. ICER of cetuximab (in combination with FOLFOX-4 or FOLFIRI, compared to currently reimbursed alternatives, is estimated between 6 and 13 thousand Euros per QALY gai­ned, depending on alternative treatment. These estimates are robust in extensive sensitivity analyses. As a final result, both clinical and economic evidence analyzed in this health technology assessment leads to

Cetuximab: clinical results in colorectal cancer.

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Maiello, E; Giuliani, F; Gebbia, V; Piano, A; Agueli, R; Colucci, G

2007-06-01

In recent years, the introduction of targeted therapies into clinical practice seems to offer incremental benefits in the treatment of metastatic colorectal cancer (mCRC), mainly when they are employed in combination with optimal chemotherapy and/or radiotherapy. In this paper, we focus on Cetuximab and its role in the treatment of mCRC.

Beclin 1 Expression is Closely Linked to Colorectal Carcinogenesis and Distant Metastasis of Colorectal Carcinoma

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Mei-Ying Zhang

2014-08-01

Full Text Available Beclin 1 participates in development, autophagy, differentiation, anti- apoptosis, neurodegeneration, tumorigenesis and cancer progression. The roles of Beclin 1 in colorectal carcinogenesis and its subsequent progression are still unclear. Here, the mRNA and protein expression of Beclin 1 were determined in colorectal carcinoma and matched mucosa by Reverse transcriptase-polymerase chain reaction and Western blot. Immunohistochemistry and in situ hybridization (ISH were performed on tissue microarryer with colorectal carcinoma, adenoma and mucosa. The expression of Beclin 1 mRNA and protein was found to be higher in colorectal carcinoma than matched mucosa by real-time PCR and Western blot (p < 0.05. According to the ISH data, Beclin 1 expression was lower in colorectal non-neoplastic mucosa (NNM than adenoma and carcinoma (p < 0.05. Immunohistochemically, primary carcinoma showed stronger Beclin 1 expression than NNM and metastatic carcinoma in the liver (p < 0.05. Beclin 1 protein expression was negatively related to liver and distant metastasis (p < 0.05, but not correlated with age, sex, depth of invasion, lymphatic or venous invasion, lymph node metastasis, tumor-node-metastasis (TNM staging, differentiation or serum carcinoembryonic antigen (CEA concentration (p > 0.05. Survival analysis indicated that Beclin 1 expression was not linked to favorable prognosis of the patients with colorectal carcinoma (p > 0.05. Cox’s model indicated that depth of invasion and distant metastasis were independent prognostic factors for colorectal carcinomas (p < 0.05. It was suggested that Beclin 1 expression is closely linked to colorectal carcinogenesis and distant metastasis of colorectal carcinoma.

Fatal Acute Liver Failure as a Consequence of Regorafenib Treatment in a Metastatic Colon Cancer

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Dominique Béchade

2017-08-01

Full Text Available Regorafenib is a multikinase inhibitor which showed benefits in pretreated metastatic colorectal cancer patients. Hepatotoxicity has been described as a frequent side effect. We report the case of a 65-year-old patient presenting with jaundice, fever, and hepatocellular insufficiency which led to death of the patient. She had previously been treated with several lines of chemotherapy for sub- and diaphragmatic ganglionic metastases of a colon adenocarcinoma. There were no liver metastases. The fatal liver failure occurred at the beginning of treatment with regorafenib at a dosage of 3 tablets per day. No concomitant treatment was given, and other causes of liver damage were eliminated. The liver biopsy showed hepatocyte necrosis with lymphocyte infiltration. This observation illustrates the risk of severe hepatic involvement typically occurring within the first 2 months of treatment. Monitoring liver biology every 2 weeks is essential during the first 2 months to detect any hepatotoxicity.

Trastuzumab and survival of patients with metastatic breast cancer.

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Kast, Karin; Schoffer, Olaf; Link, Theresa; Forberger, Almuth; Petzold, Andrea; Niedostatek, Antje; Werner, Carmen; Klug, Stefanie J; Werner, Andreas; Gatzweiler, Axel; Richter, Barbara; Baretton, Gustavo; Wimberger, Pauline

2017-08-01

Prognosis of Her2-positive breast cancer has changed since the introduction of trastuzumab for treatment in metastatic and early breast cancer. It was described to be even better compared to prognosis of Her2-negative metastatic breast cancer. The purpose of this study was to evaluate the effect of trastuzumab in our cohort. Besides the effect of adjuvant pretreatment with trastuzumab on survival of patients with metastatic Her2-positive breast cancer was analyzed. All patients with primary breast cancer of the Regional Breast Cancer Center Dresden diagnosed during the years 2001-2013 were analyzed for treatment with or without trastuzumab in the adjuvant and in the metastatic treatment setting using Kaplan-Meier survival estimation and Cox regression. Age and tumor stage at time of first diagnosis of breast cancer as well as hormone receptor status, grading, time, and site of metastasis at first diagnosis of distant metastatic disease were analyzed. Of 4.481 female patients with primary breast cancer, 643 presented with metastatic disease. Her2-positive status was documented in 465 patients, including 116 patients with primary or secondary metastases. Median survival of patients with Her2-positive primary metastatic disease was 3.0 years (95% CI 2.3-4.0). After adjustment for other factors, survival was better in patients with Her2-positive breast cancer with trastuzumab therapy compared to Her2-negative metastatic disease (HR 2.10; 95% CI 1.58-2.79). Analysis of influence of adjuvant therapy with and without trastuzumab by Kaplan-Meier showed a trend for better survival in not pretreated patients. Median survival was highest in hormone receptor-positive Her2-positive (triple-positive) primary metastatic breast cancer patients with 3.3 years (95% CI 2.3-4.6). Prognosis of patients with Her2-positive metastatic breast cancer after trastuzumab treatment is more favorable than for Her2-negative breast cancer. The role of adjuvant chemotherapy with or without

Prognostic value of KRAS genotype in metastatic colorectal cancer (MCRC patients treated with intensive triplet chemotherapy plus bevacizumab (FIr-B/FOx according to extension of metastatic disease

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Bruera Gemma

2012-11-01

Full Text Available Abstract Background Bevacizumab (BEV plus triplet chemotherapy can increase efficacy of first-line treatment of metastatic colorectal cancer (MCRC, particularly integrated with secondary liver surgery in liver-limited (L-L patients. The prognostic value of the KRAS genotype in L-L and other or multiple metastatic (O/MM MCRC patients treated with the FIr-B/FOx regimen was retrospectively evaluated. Methods Tumoral and metastatic samples were screened for KRAS codon 12 and 13 and BRAF mutations by SNaPshot and/or direct sequencing. Fit MCRC patients 2, days 1, 2, 8, 9, 15, 16, 22 and 23; irinotecan (CPT-11 160 mg/m2 plus BEV 5 mg/kg, days 1, 15; oxaliplatin (OXP 80 mg/m2, days 8, 22; every 4 weeks. MCRC patients were classified as L-L and O/MM. Activity and efficacy were evaluated and compared using log-rank test. Results In all, 59 patients were evaluated: 31 KRAS wild-type (53%, 28 KRAS mutant (47%. At 21.5 months median follow-up, objective response rate (ORR, progression-free survival (PFS and overall survival (OS were, respectively: KRAS wild-type 90%, 14 months, 38 months; KRAS mutant 67%, 11 months, 20 months. PFS and OS were not significantly different. PFS and OS were significantly different in L-L compared to O/MM evaluable patients. In KRAS wild-type patients, clinical outcome of 12 L-L compared to 18 O/MM was significantly different: PFS 21 versus 12 months and OS 47 versus 28 months, respectively. In KRAS mutant patients, the clinical outcome of 13 L-L compared to 14 O/MM was not significantly different: PFS 11 months equivalently and OS 39 versus 19 months, respectively. Conclusions The KRAS genotype wild-type and mutant does not significantly affect different clinical outcomes for MCRC patients treated with the first-line FIr-B/FOx intensive regimen. KRAS wild-type patients with L-L disease may achieve a significantly prolonged clinical outcome due to integration with secondary liver surgery, with respect to KRAS mutant patients.

Temporal relationship between prostate brachytherapy and the diagnosis of colorectal cancer

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Gutman, Sarah A.; Merrick, Gregory S.; Butler, Wayne M.; Wallner, Kent E.; Allen, Zachariah A.; Galbreath, Robert W.; Adamovich, Edward

2006-01-01

Purpose: To identify the location of pretreatment and posttreatment colorectal malignancies and posttreatment colorectal polyps in patients with clinically localized prostate cancer managed with brachytherapy. Methods and Materials: From April 1995 through July 2004, 1,351 consecutive patients underwent brachytherapy for clinical stage T1b-T3a (American Joint Committee on Cancer, 2002) prostate cancer. Supplemental external beam radiotherapy (XRT) was administered to 699 patients. The median follow-up was 4.6 years. Operative and pathology reports were reviewed for all patients with pretreatment and posttreatment colorectal cancer and posttreatment colorectal polyps. Multiple parameters were evaluated for the development of colorectal cancer or colorectal polyps. Results: Colorectal cancer was diagnosed in 23 and 25 patients before and after prostate brachytherapy, respectively. No differences were identified in the distribution of colorectal cancers either before or after treatment (3 and 4 rectal cancers in the pre- and postbrachytherapy cohorts). Thirty-five of the 48 colorectal cancers (73%) were diagnosed within 5 years of brachytherapy with a peak incidence 1 year after brachytherapy. One hundred ninety-two colorectal polyps were diagnosed after brachytherapy, 160 (83%) occurred within 4 years of brachytherapy, and only 27 (14%) were located in the rectum. In multivariate Cox regression analysis, prostate D 9 (minimum percentage of the dose covering 90% of the target volume) predicted for posttreatment colorectal cancer. Rectal polyps were most closely related to patient age and percent positive biopsies, whereas sigmoid/colon polyps were best predicted by patient age, planning volume, and supplemental XRT. Conclusions: Colorectal cancer was diagnosed with equal frequency before and after brachytherapy with comparable geographic distributions. In addition, the vast majority of postbrachytherapy colorectal polyps were located beyond the confines of the rectum

Impact of Serum Apolipoprotein A-I on Prognosis and Bevacizumab Efficacy in Patients with Metastatic Colorectal Cancer: a Propensity Score-Matched Analysis

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Qi Quan

2017-04-01

Full Text Available PURPOSE: We aimed to investigate the role of apolipoprotein A-I (ApoA-I as a predictor of prognosis and treatment efficacy of bevacizumab in patients with metastatic colorectal cancer (mCRC treated with first-line chemotherapy with or without bevacizumab. METHODS: We conducted a retrospective study on consecutive patients who were diagnosed with mCRC at Sun Yat-sen University Cancer Center. According to their pretreatment ApoA-I level, patients were divided into low– and high–ApoA-I groups. Propensity score-matched method was performed to balance baseline characteristics between two groups. Based on whether they accepted bevacizumab as a first-line therapy, patients were further divided into the chemo + bevacizumab group and the chemo group. Overall survival (OS and progression-free survival (PFS were assessed with Kaplan-Meier method, log-rank test, and Cox regression. RESULTS: The optimal cutoff value for the ApoA-I level was determined to be 1.105 g/l. In the propensity-matched cohort of 508 patients, low ApoA-I was significantly associated with inferior OS (P < .001 and PFS (P < .001 than high ApoA-I. Multivariate analysis showed that ApoA-I level was an independent prognostic maker of OS (P < .001 and PFS (P = .001. PFS (P < .001 in either the high– or low–ApoA-I groups could be extended significantly after the administration of bevacizumab, and patients with a high ApoA-I level also had a better OS in the chemo + bevacizumab group than the chemo group (P = .049. CONCLUSIONS: Patients with a low ApoA-I level have poor prognoses, and they did not display an OS benefit from bevacizumab.

Dai-Kenchu-To, a Herbal Medicine, Attenuates Colorectal Distention-induced Visceromotor Responses in Rats.

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Nakaya, Kumi; Nagura, Yohko; Hasegawa, Ryoko; Ito, Hitomi; Fukudo, Shin

2016-10-30

Dai-kenchu-to (DKT), a traditional Japanese herbal medicine, is known to increase gastrointestinal motility and improve ileal function. We tested our hypotheses that (1) pretreatment with DKT would block the colorectal distention-induced visceromotor response in rats, and (2) pretreatment with DKT would attenuate colorectal distention-induced adrenocorticotropic hormone (ACTH) release and anxiety-related behavior. Rats were pretreated with vehicle or DKT (300 mg/kg/5 mL, per os). Visceromotor responses were analyzed using electromyography in response to colorectal distention (10, 20, 40, 60, and 80 mmHg for 20 seconds at 3-minutes intervals). Anxiety-related behavior was measured during exposure to an elevated-plus maze after colorectal distention. Plasma ACTH and serum corticosterone levels were measured after exposure to the elevated-plus maze. Colorectal distention produced robust contractions of the abdominal musculature, graded according to stimulus intensity, in vehicle-treated rats. At 40, 60, and 80 mmHg of colorectal distention, the visceromotor responses of DKT-treated rats was significantly lower than that of vehicle-treated rats. At 80 mmHg, the amplitude was suppressed to approximately one-third in DKT-treated rats, compared with that in vehicle-treated rats. Smooth muscle compliance and the velocity of accommodation to 60 mmHg of stretching did not significantly differ between the vehicle-treated and DKT-treated rats. Similarly, the DKT did not influence colorectal distention-induced ACTH release, corticosterone levels, or anxiety-related behavior in rats. Our results suggest that DKT attenuates the colorectal distention-induced visceromotor responses, without increasing smooth muscle compliance, ACTH release or anxiety-related behavior in rats.

Combination epigenetic therapy in metastatic colorectal cancer (mCRC) with subcutaneous 5-azacitidine and entinostat: a phase 2 consortium/stand Up 2 cancer study

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Azad, Nilofer S.; el-Khoueiry, Anthony; Yin, Jun; Oberg, Ann L.; Flynn, Patrick; Adkins, Douglas; Sharma, Anup; Weisenberger, Daniel J.; Brown, Thomas; Medvari, Prakriti; Jones, Peter A.; Easwaran, Hariharan; Kamel, Ihab; Bahary, Nathan; Kim, George; Picus, Joel; Pitot, Henry C.; Erlichman, Charles; Donehower, Ross; Shen, Hui; Laird, Peter W.; Piekarz, Richard; Baylin, Stephen; Ahuja, Nita

2017-01-01

Purpose Therapy with demethylating agent 5-azacitidine and histone deacetylase inhibitor entinostat shows synergistic re-expression of tumor-suppressor genes and growth inhibition in colorectal (CRC) cell lines and in vivo studies. Experimental Design We conducted a phase II, multi-institutional study of the combination in metastatic CRC patients. Subcutaneous azacitidine was administered at 40 mg/m2 days 1-5 and 8-10 and entinostat was given 7 mg orally on days 3 and 10. An interim analysis indicated toxicity crossed the pre-specified safety boundary but was secondary to disease. A 2nd cohort with added eligibility restrictions was accrued: prior therapies were limited to no more than 2 or 3 (KRAS-mutated and KRAS-wildtype cancers, respectively) and <30% of liver involvement. The primary endpoint was RECIST response. Serial biopsies were performed at baseline and after 2 cycles of therapy. Results Forty-seven patients were enrolled (24:Cohort 1, 23:Cohort 2). Patients were heavily pre-treated (median prior therapies 4: Cohort 1 and 2.5: cohort 2). No responses were observed. Median progression-free survival was 1.9 months; overall survival was 5.6 and 8.3 months in Cohorts 1 and 2, respectively. Toxicity was tolerable and as expected. Unsupervised cluster analysis of serial tumor biopsies suggested greater DNA demethylation in patients with PFS above the median. Conclusion In this first trial of CRC patients with combination epigenetic therapy, we show tolerable therapy without significant clinical activity as determined by RECIST responses. Reversal of hypermethylation was seen in a subset of patients and correlated with improved PFS. PMID:28186961

Associations between lifestyles and neutrophil-lymphocyte and platelet-lymphocyte ratios in colorectal cancer.

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Hong, Chuyuan; Wei, Yisheng; Jiang, Jianxin; Zhao, Chuxiong; Liang, Guojian; Wang, Guoqiang; Yang, Hui

2014-06-01

To explore the etiology of the neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) abnormalities in colorectal cancer. In total, 230 patients with histopathologically confirmed colorectal cancer from August 2009 to August 2011 were recruited to our study. The associations between lifestyles (smoking, alcohol and pickled food consumption) and pretreatment NLR and PLR were estimated using the Kruskal-Wallis tests and linear regression model. The Kruskal-Wallis test showed a significant association between pickled food intake and pretreatment NLR but not PLR (P = 0.002, 0.057, respectively). Pairwise comparisons showed that, compared with those with a moderately frequent (2-3 times/week) and an infrequent (≤ once a week) intake of pickled food, high frequency (≥ four times/week) consumption of pickled food had a higher pretreatment NLR (P = 0.01, 0.007, respectively). Multivariate linear regression analysis showed pretreatment NLR increased significantly in high frequency (≥ four times/week) consumption of pickled food (P frequency intake of pickled food possibly contributes to higher NLR, which may reflect a systemic inflammatory response in colorectal cancer. © 2013 Wiley Publishing Asia Pty Ltd.

Real-world utilization of molecular diagnostic testing and matched drug therapies in the treatment of metastatic cancers.

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Chawla, Anita; Peeples, Miranda; Li, Nanxin; Anhorn, Rachel; Ryan, Jason; Signorovitch, James

2018-06-01

To assess the frequency of biopsies and molecular diagnostic testing (human DNA/RNA analysis), anti-cancer drug use (genomically-matched targeted therapy [GMTT], unmatched targeted therapy [UTT], endocrine therapy [ET], and chemotherapy [CT]), and medical service costs among adults with metastatic cancer. Adults diagnosed with metastatic breast, non-small cell lung (NSCLC), colorectal, head and neck, ovarian, and uterine cancer (2010Q1-2015Q1) were identified in the OptumHealth Care Solutions claims database and followed from first metastatic diagnosis for ≥1 month and until the end of data availability. Utilization was assessed for each cancer cohort (all and patients aged ≥65 years); per-patient-per-month (PPPM) medical service costs were assessed for all patients. Testing frequency estimates were applied to Surveillance, Epidemiology, and End Results Program data to estimate the number of untested patients (2010-2014). Patients with metastatic cancer (n = 8,193; breast [n = 3,414], NSCLC [n = 2,231], colorectal [n = 1,611], head and neck [n = 511], ovarian [n = 275], and uterine [n = 151]) were 63 years old (mean), with 11.1-22.2 months of observation. Biopsy and molecular diagnostic testing frequencies ranged from 7% (uterine) to 73% (ovarian), and from 34% (head and neck) to 52% (breast), respectively. Few were treated with GMTT (breast, 11%; NSCLC, 9%; colorectal, 6%). Treatment with UTT ranged from 0.7% (uterine) to 21% (colorectal). Biopsy, diagnostic testing, and anti-cancer drug therapy were less frequent for those ≥65 years. Medical service costs (PPPM, mean) ranged from $6,618 (head and neck) to $9,940 (ovarian). The estimated number of untested new patients with metastatic cancer was 636,369 (all) and 341,397 (≥65). In addition to the limitations of claims analyses, diagnostic testing frequency may be under-estimated if patients underwent testing prior to study inclusion. The low frequency of molecular diagnostic

Aminopeptidase A initiates tumorigenesis and enhances tumor cell stemness via TWIST1 upregulation in colorectal cancer

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Chuang, Hui-Yu; Jiang, Jeng-Kae; Yang, Muh-Hwa; Wang, Hsei-Wei; Li, Ming-Chun; Tsai, Chan-Yen; Jhang, Yau-Yun; Huang, Jason C.

2017-01-01

Metastasis accounts for the high mortality rate associated with colorectal cancer (CRC), but metastasis regulators are not fully understood. To identify a novel gene involved in tumor metastasis, we used oligonucleotide microarrays, transcriptome distance analyses, and machine learning algorithms to determine links between primary and metastatic colorectal cancers. Aminopeptidase A (APA; also known as ENPEP) was selected as our focus because its relationship with colorectal cancer requires cl...

Pulmonary nodules and metastases in colorectal cancer

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Nordholm-Carstensen, Andreas

2016-01-01

Patients with newly diagnosed colorectal cancer (CRC) are subjected to a preoperative thoraco-abdominal CT scan to determine the cancer stage. This staging is of relevance with regard to treatment and prognosis. About 20% of the patients have distant metastatic spread at the time of diagnosis, i...... detected in 7.5% of the patients and in 37% of these cases the metastatic spread was confined to the lungs. The prevalence of SPCM increased with the implementation of thoracic CT in CRC staging. SPCM impaired survival significantly and was associated with increasing age and rectal cancer. Resection...

Impact of Primary Tumor Location on First-line Bevacizumab or Cetuximab in Metastatic Colorectal Cancer.

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Snyder, Matthew; Bottiglieri, Sal; Almhanna, Khaldoun

2018-01-01

Colorectal cancer is one of the most common malignancies in the United States, with a large proportion of patients presenting with metastatic disease or developing a recurrence. Systemic chemotherapy is the mainstay of therapy in this setting. There is a clear benefit in the addition of bevacizumab or cetuximab (for rat sarcoma [RAS] wild type tumors) to oxaliplatin- and irinotecan-based regimens which can be considered for first-line therapy. However, many significant questions remain as to which agent reflects best practice. Our review aimed to elucidate the benefit of adding bevacizumab and cetuximab to initial therapy for metastatic colorectal cancer based on primary tumor location and a variety of other disease- and patient-related factors, addressing the paucity of evidence that currently exists in this area and contributing to current literature and clinical practices. The primary endpoints of the study were first Progression-Free Survival (PFS) and Overall Survival (OS). Secondary endpoints included best response to first- and second-line therapies, Treatment- Related Adverse Events (TRAEs), second PFS, cost of therapy, and an assessment of other patient- and disease-related factors affecting PFS and OS. While there were trends towards improved OS in patients with left-sided primary tumors (n=57) compared to those with right-sided disease (n=23), there were no significant differences between the two groups in either primary endpoint. While no differences were found for patients with left- or right- sided tumors stratified by add-on agent, these analyses were limited by the small number of patients receiving cetuximab with first-line therapy (n=4). However, the bevacizumab cohort (n=76) was sizable enough to provide ample data and produce clinically relevant results. Add-on therapy with bevacizumab in our study achieved impressive survival outcomes in both left-sided (median first PFS = 13 months, 95% CI 11-15 months; median OS = 37 months, 95% CI 21

Poor prognostic role of the pretreatment platelet counts in colorectal cancer: A meta-analysis.

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Rao, Xu-Dong; Zhang, Hua; Xu, Zheng-Shui; Cheng, Hua; Shen, Wei; Wang, Xin-Ping

2018-06-01

Recently, a wide variety of studies have suggested that elevated platelet counts are associated with survival in patients with colorectal cancer. On one hand several studies suggest a negative connection in colorectal cancer patients with pre-operative thrombocytosis, on the other hand other studies contradicts this. However, it remains unknown whether elevated platelet counts are associated with survival in colorectal cancer patients. We therefore conducted this meta-analysis to evaluate the prognostic role of platelet counts in colorectal cancer. PubMed, Embase, and the Cochrane Library databases were searched from their inception to October 15, 2016 to identify relevant studies that have explored the prognostic role of platelet counts in colorectal cancer. Studies that examined the association between platelet counts and prognoses in colorectal cancer and that provided a hazard ratio (HR) and 95% confidence interval (CI) for overall survival (OS) and/or disease-free survival (DFS) were included. This meta-analysis included 9 retrospective cohort studies involving 3413 patients with colorectal cancer. OS was shorter in patients with elevated platelet counts than in patients with normal counts (HR 2.11, 95% CI: 1.68-2.65). For DFS, an elevated platelet count was also a poor predictor (HR 2.51, 95% CI: 1.84-3.43). In this meta-analysis, we suggest that an elevated platelet count is a negative predictor of survival in both primary colorectal cancer and resectable colorectal liver metastases.

Some Aspects Of Adjuvant Treatment Of Colorectal Cancer

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Hlavata, Z.

2008-01-01

Colorectal cancer is one of the most common cancers in Europe and in North America. Cornerstone of the treatment of localized colorectal cancer is surgical resection followed by chemotherapy or radio-chemotherapy in indicated cases. For patients with Stage III colon cancer recent data have shown efficacy through the combining fluorouracil-based chemotherapy with oxaliplatin into adjuvant treatment program. For patients with Stage II colon cancer, the use of adjuvant chemotherapy remains controversial, but may be appropriate in a subset of individuals at high risk for disease recurrence. Current randomized clinical trials in the adjuvant therapy of colorectal cancer are examining the value of adding agents known to be active in metastatic disease, including those that modify specific molecular targets. (author)

Intact and cleaved plasma soluble urokinase receptor in patients with metastatic colorectal cancer treated with oxaliplatin with or without cetuximab

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Tarpgaard, Line Schmidt; Christensen, Ib Jarle; Høyer-Hansen, Gunilla

2015-01-01

) in a ligand-independent manner. The purpose of the study was to evaluate whether plasma soluble intact and cleaved uPAR(I-III)+(II-III) levels could identify a subpopulation of patients with metastatic colorectal cancer (mCRC) where treatment with cetuximab would have a beneficial effect. Plasma samples were...... available from 453 patients treated in the NORDIC VII study. Patients were randomized between FLOX and FLOX + cetuximab. The levels of uPAR(I-III)+(II-III) were determined by time-resolved fluorescence immunoassay. We demonstrated that higher baseline plasma uPAR(I-III)+(II-III) levels were significantly...... with FLOX + cetuximab as compared to patients with KRAS wild-type and high levels of suPAR. These results thus support the preclinical findings and should be further tested in an independent clinical data set....

Feasibility and response of helical tomotherapy in patients with metastatic colorectal cancer

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Kim, Yong Ho [Dept. of Radiation Oncology, Catholic Kwandong University International St. Mary' s Hospital, Incheon (Korea, Republic of); Bae, Sun yun; Moon, Seong Kwon; Cho, Kwang Hwan; Shin, Eung Jin; Lee, Moon Sung; Ryu, Chang Beom; Ko, Bong Min; Yun, Ji Na [Soonchunhyang University College of Medicine, Bucheon (Korea, Republic of)

2015-12-15

To investigate the treatment outcome and the toxicity of helical tomotherapy (HT) in patients with metastatic colorectal cancer (mCRC). We retrospectively reviewed 18 patients with 31 lesions from mCRC treated with HT between 2009 and 2013. The liver (9 lesions) and lymph nodes (9 lesions) were the most frequent sites. The planning target volume (PTV) ranged from 12 to 1,110 mL (median, 114 mL). The total doses ranged from 30 to 70 Gy in 10-30 fractions. When the alpha/beta value for the tumor was assumed to be 10 Gy for the biologically equivalent dose (BED), the total doses ranged from 39 to 119 Gy{sub 10} (median, 55 Gy{sub 10}). Nineteen lesions were treated with concurrent chemotherapy (CCRT). With a median follow-up time of 16 months, the median overall survival for 18 patients was 33 months. Eight lesions (26%) achieved complete response. The 1- and 3-year local progression free survival (LPFS) rates for 31 lesions were 45% and 34%, respectively. On univariate analysis, significant parameters influencing LPFS rates were chemotherapy response before HT, aim of HT, CCRT, PTV, BED, and adjuvant chemotherapy. On multivariate analysis, PTV < or =113 mL and BED >48 Gy{sub 10} were associated with a statistically significant improvement in LFPS. During HT, four patients experienced grade 3 hematologic toxicities, each of whom had also received CCRT. The current study demonstrates the efficacy and tolerability of HT for mCRC. To define optimal RT dose according to tumor size of mCRC, further study should be needed.

Underpinning the repurposing of anthracyclines towards colorectal cancer

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Nygård, Sune Boris; Christensen, Ib Jarle; Smith, David Hersi

2013-01-01

Abstract Objective. We propose a repurposing strategy where anthracyclines are reintroduced to a subgroup of patients with metastatic colorectal cancer with the highest likelihood of response. In breast cancer, DNA topoisomerase II alpha gene (TOP2A) alterations predict incremental benefit...... of anthracyclines, but this association has not been investigated in colorectal cancer. Frequency analysis of TOP2A gene alterations in colorectal cancer and the association with prognosis are evaluated and the challenges of using a TOP2A/CEN-17 FISH probe combination are addressed. Material and methods. Formalin......-fixed, paraffin-embedded material from 154 stage III colorectal cancer patients included in the RANX05 clinical trial was retrospectively assessed for TOP2A gene alterations using FISH. The TOP2A/CEN-17 ratio as well as the TOP2A gene copy number alone was used to define gene alterations and associations between...

B cells and ectopic follicular structures: novel players in anti-tumor programming with prognostic power for patients with metastatic colorectal cancer.

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Anastasia Meshcheryakova

Full Text Available Remarkably limited information is available about biological mechanisms that determine the disease entity of metastatic colorectal cancer in the liver (CRCLM with no good clinical parameters to estimate prognosis. For the last few years, understanding the relationship between tumor characteristics and local immune response has gained increasing attention. Given the multifaceted roles of B-cell-driven responses, we aimed to elucidate the immunological imprint of B lymphocytes at the metastatic site, the interrelation with macrophages, and their prognostic relevance. Here we present novel algorithm allowing to assess a link between the local patient-specific immunological capacity and clinical outcome. The microscopy-based imaging platform was used for automated scanning of large-scale tissue sections and subsequent qualitative and quantitative analyses of immune cell subtypes using lineage markers and single-cell recognition strategy. Results indicate massive infiltration of CD45-positive leukocytes confined to the metastatic border. We report for the first time the accumulation of CD20-positive B lymphocytes at the tumor-liver interface comprising the major population within the large CD45-positive aggregates. Strikingly, functionally active, activation-induced cytidine deaminase (AID-positive ectopic lymphoid structures were found to be assembled within the metastatic margin. Furthermore, the CD20-based data set revealed a strong prognostic power: patients with high CD20 content and/or ectopic follicles had significantly lower risk for disease recurrence as revealed by univariate analysis (p<0.001 for both and in models adjusted for clinicopathological variables (p<0.001 and p = 0.01, respectively, and showed prolonged overall survival. In contrast, CD68 staining-derived data set did not show an association with clinical outcome. Taken together, we nominate the magnitude of B lymphocytes, including those organized in ectopic follicles, as

Consensus statement on essential patient characteristics in systemic treatment trials for metastatic colorectal cancer: Supported by the ARCAD Group.

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Goey, Kaitlyn K H; Sørbye, Halfdan; Glimelius, Bengt; Adams, Richard A; André, Thierry; Arnold, Dirk; Berlin, Jordan D; Bodoky, György; de Gramont, Aimery; Díaz-Rubio, Eduardo; Eng, Cathy; Falcone, Alfredo; Grothey, Axel; Heinemann, Volker; Hochster, Howard S; Kaplan, Richard S; Kopetz, Scott; Labianca, Roberto; Lieu, Christopher H; Meropol, Neal J; Price, Timothy J; Schilsky, Richard L; Schmoll, Hans-Joachim; Shacham-Shmueli, Einat; Shi, Qian; Sobrero, Alberto F; Souglakos, John; Van Cutsem, Eric; Zalcberg, John; van Oijen, Martijn G H; Punt, Cornelis J A; Koopman, Miriam

2018-06-21

Patient characteristics and stratification factors are key features influencing trial outcomes. However, there is substantial heterogeneity in reporting of patient characteristics and use of stratification factors in phase 3 trials investigating systemic treatment of metastatic colorectal cancer (mCRC). We aimed to develop a minimum set of essential baseline characteristics and stratification factors to include in such trials. We performed a modified, two-round Delphi survey among international experts with wide experience in the conduct and methodology of phase 3 trials of systemic treatment of mCRC. Thirty mCRC experts from 15 different countries completed both consensus rounds. A total of 14 patient characteristics were included in the recommended set: age, performance status, primary tumour location, primary tumour resection, prior chemotherapy, number of metastatic sites, liver-only disease, liver involvement, surgical resection of metastases, synchronous versus metachronous metastases, (K)RAS and BRAF mutation status, microsatellite instability/mismatch repair status and number of prior treatment lines. A total of five patient characteristics were considered the most relevant stratification factors: RAS/BRAF mutation status, performance status, primary tumour sidedness and liver-only disease. This survey provides a minimum set of essential baseline patient characteristics and stratification factors to include in phase 3 trials of systemic treatment of mCRC. Inclusion of these patient characteristics and strata in study protocols and final study reports will improve interpretation of trial results and facilitate cross-study comparisons. Copyright © 2018 Elsevier Ltd. All rights reserved.

Primary Tumour Resection Could Improve the Survival of Unresectable Metastatic Colorectal Cancer Patients Receiving Bevacizumab-Containing Chemotherapy

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Zhiming Wang

2016-09-01

Full Text Available Background: The effect of primary tumour resection (PTR among metastatic colorectal cancer (mCRC patients remains controversial. Combination chemotherapy with bevacizumab could improve the clinical outcomes of these patients, which might change the importance of PTR in the multi-disciplinary treatment pattern. Methods: We performed a non-randomized prospective controlled study of mCRC pts whose performance status (PS scored ≤2 and who received bevacizumab combination chemotherapy (FOLFOX/XELOX/FOLFIRI as a first-line therapy. These patients were classified into the PTR group and the IPT (intact primary tumour group according to whether they underwent PTR before receiving the systemic therapy. The progression free survival (PFS time and overall survival (OS time, which were recorded from the start of the primary diagnosis until disease progression and death or last follow-up, were analysed. We also compared severe clinical events (such as emergency surgery, radiation therapy, and stent plantation between the two groups. Results: One hundred and nighty-one mCRC pts (108 male patients and 93 female patients were entered in this prospective observational study. The median age was 57.5 years old. The clinical characteristics (age, gender, performance status, primary tumour site, RAS status, and the number of metastatic organs did not significantly differ between the two groups. The median PFS and OS times of the PTR group were superior than those of the IPT group (10.0 vs 7.8 months, p Conclusions: The mCRC patients who received PTR and bevacizumab combination chemotherapy had better clinical outcomes than patients who did not receive PTR. PTR also decreased the incidence of severe clinical events and improved quality of life.

Meeting An Unmet Need in Metastatic Colorectal Carcinoma with Regorafenib

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Barbara Melosky

2016-01-01

Full Text Available Colorectal cancer is a global issue, affecting men and women equally. Over the last 25 years, advances in therapy and multidisciplinary care have led to improvements in survival for those with colorectal cancer. Despite these advances, more therapeutic options are needed for those being treated for this disease.Regorafenib is an oral drug that is a new therapeutic option for our patients. The CORRECT and CONCUR trials demonstrate the efficacy of regorafenib in the last line setting. This article summarizes some of the regorafenib clinical trial data and discusses the strategies to help manage the side effects of this drug including patient education, dose reductions and interruptions, and monitoring hypertension and liver function.

Predictive role of multiple gene alterations in response to cetuximab in metastatic colorectal cancer: A single center study

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Ulivi Paola

2012-05-01

Full Text Available Abstract Background KRAS mutations negatively affect outcome after treatment with cetuximab in metastatic colorectal cancer (mCRC patients. As only 20% of KRAS wild type (WT patients respond to cetuximab it is possible that other mutations, constitutively activating the EGFR pathway, are present in the non-responding KRAS WT patients. We retrospectively analyzed objective tumor response rate, (ORR progression-free (PFS and overall survival (OS with respect to the mutational status of KRAS, BRAF, PIK3CA and PTEN expression in mCRC patients treated with a cetuximab-based regimen. Methods 67 mCRC patients were enrolled onto the study. DNA was extracted from paraffin-embedded sections derived from primary or metastatic lesions. Exon 2 of KRAS and exon 15 of BRAF were analyzed by direct sequencing, PIK3CA was evaluated by pyrosequencing and PTEN expression by immunohistochemistry. Results BRAF and PIK3CA mutations were independently associated with worse PFS (p = 0.006 and p = 0.028, respectively and OS (p = 0.008 and p = 0.029, respectively. No differences in clinical outcome were found between patients who were positive or negative for PTEN expression. Conversely, patients negative for KRAS, BRAF and PIK3CA mutations were characterized by significantly better ORR, PFS and OS than patients with at least one of these mutations. Conclusions BRAF and PIK3CA mutations would seem to be independent predictors of anti-EGFR therapy effectiveness and could be taken into consideration during treatment decision making.

Asymptomatic primary tumour in incurable metastatic colorectal cancer: is there a role for surgical resection prior to systematic therapy or not?

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Samalavicius, Narimantas E; Dulskas, Audrius; Baltruskeviciene, Edita; Smailyte, Giedre; Skuciene, Marija; Mikelenaite, Rasa; Venslovaite, Rasa; Aleknavicius, Eduardas; Samalavicius, Almantas; Lunevicius, Raimundas

2016-01-01

The role of the resection of asymptomatic primary colorectal cancer in patients with incurable disease is questionable. To evaluate the impact of the resection of asymptomatic primary tumour on overall survival in patients with unresectable distant metastases. Patients treated in the National Cancer Institute, Lithuania, in the period 2008-2012, were selected retrospectively. The main inclusion criteria were: metastatic colorectal cancer (mCRC), endoscopically and histologically confirmed adenocarcinoma, without any symptoms for urgent operation, and at least one cycle of palliative chemotherapy administered. Information on patients' age, gender, tumour histology, localization of the tumour, regional lymph node involvement, number of metastatic sites, surgery and systemic treatment was collected prospectively. Eligible patients for the study were divided into two groups according to the initial treatment - surgery (patients who underwent primary tumour resection) and chemotherapy (patients who received chemotherapy without surgery). The impact of initial treatment strategy, tumour size and site, regional lymph nodes, grade of differentiation of adenocarcinoma and application of biotherapy on overall cumulative survival was estimated using the Kaplan-Meier method. To compare survival between groups the log-rank test was used. Cox regression analysis was employed to assess the effects of variables on patient survival. The study group consisted of 183 patients: 103 men and 80 women. The median age was 66 years (range: 37-91). There were no notable imbalances with regard to age, gender, number of metastatic sites, metastases (such as pulmonary, peritoneal, liver, metastases into non-regional lymph nodes and other metastases), the number of received cycles of chemotherapy, first line chemotherapy type or biological therapy. Only 27 (14.8%) patients received biological therapy and the majority of them (n = 25, 92.6%) were treated with bevacizumab. For surgically treated

Mismatch repair status and synchronous metastases in colorectal cancer

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Nordholm-Carstensen, Andreas; Krarup, Peter-Martin; Morton, Dion

2015-01-01

The causality between the metastatic potential, mismatch repair status (MMR) and survival in colorectal cancer (CRC) is complex. This study aimed to investigate the impact of MMR in CRC on the occurrence of synchronous metastases (SCCM) and survival in patients with SCCM on a national basis....... A nationwide cohort study of 6,692 patients diagnosed with CRC between 2010 and 2012 was conducted. Data were prospectively entered into the Danish Colorectal Cancer Group's database and merged with data from the Danish Pathology Registry and the National Patient Registry. Multivariable and multinomial...

Biomarkers for the early detection of relapses in metastatic colorectal cancers.

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Chereches, Gabriela; Barbos, Otilia; Buiga, Rares; Balacescu, Ovidiu; Iancu, Dana; Todor, Nicolae; Balacescu, Loredana; Miron, Nicu; Bejinariu, Nona; Ciuleanu, Tudor-Eliade

2017-01-01

To assess prognostic/predictive value of carcinoembryonic antigen (CEA), transthyretin (TRT), αenolase (NNE), β2-microglobulin (β2-micro), B-cell activating factor (BAFF) and circulating tumor cells (CTCs) in metastatic colorectal cancer (mCRC) patients treated with chemotherapy with or without bevacizumab. 72 histologically confirmed mCRC patients treated at Oncology Institute Cluj were included. Biomarker levels were measured through validated methods. A manual method was used for CTCs, involving hemolysis, cytospin centrifugation and immunocytochemical staining for pan-cytokeratin. Statistical endpoints were response, progression- free survival (PFS) and overall survival (OS). Initial chemotherapy was fluoropyrimidine/oxaliplatin-based in 93.1%; bevacizumab was added in 58.3% of the patients. Median PFS and OS were 16.4 and 24.4 months. Two-year OS for CR & PR vs SD vs PD were 90% vs 48% vs 12%, respectively (p<0.01). Two-year OS for chemo/ bevacizumab vs chemotherapy: 65% vs 42% (p=0.09). Baseline CEA ≥5 ng/ml had a negative prognostic impact on OS and PFS (p<0.01). High baseline CEA was predictive of improved OS when adding bevacizumab (2-year OS chemo/bevacizumab vs chemo: 60% vs 17%, p<0.01); adding bevacizumab in patients with normal CEA did not improve OS (p=0.29). Higher than cut-off values for TRT had a positive OS prognostic value (p<0.01); higher levels for NNE, β2-microglobulin and BAFF had a negative impact (p<0.01). Two-year OS for baseline <1 CTC/ml vs ≥1 CTC/ ml was 74% vs 64% respectively (p=0.15). The evaluated biomarkers could be useful prognostic factors for survival. Baseline CEA also has predictive value, suggesting that patients with low levels do not benefit from bevacizumab. A non-statistically significant correlation was observed between the number of CTCs and outcome.

Chemotherapy ± cetuximab modulates peripheral immune responses in metastatic colorectal cancer.

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Xynos, Ioannis D; Karadima, Maria L; Voutsas, Ioannis F; Amptoulach, Sousana; Skopelitis, Elias; Kosmas, Christos; Gritzapis, Angelos D; Tsavaris, Nikolas

2013-01-01

To identify changes in peripheral immune responses in patients with metastatic colorectal cancer (mCRC) treated with irinotecan/5-fluorouracil/leucovorin (IFL) alone or in combination with cetuximab (C-IFL). Peripheral blood mononuclear cells (PBMCs) collected from healthy donors (n = 20) and patients with mCRC receiving treatment with either IFL (n = 30) or C-IFL (n = 30) were tested for cytokine production upon polyclonal stimulation with anti-CD3 monoclonal antibody, T cell proliferation in the autologous mixed lymphocyte reaction (auto-MLR) and T regulatory cell (Treg) frequency. The respective results were evaluated over two treatment cycles and further assessed in relation to response to treatment. PBMCs prior to treatment exhibited significantly lower production of IL-2, IFN-γ, IL-12 and IL-18 cytokines and lower auto-MLR responses, whereas Treg frequency, IL-4, IL-10 cytokines were increased compared to healthy donors. During treatment, IL-2, IFN-γ, IL-12, IL-18 and auto-MLR responses increased, while Treg frequency and IL-10 secretion decreased significantly compared to the baseline. Responders to treatment exhibited a significantly higher increase in IL-2, IFN-γ, IL-12 and IL-18 production and auto-MLR responses, and higher decrease in IL-4, IL-10 secretion and Treg frequency. Among all patient subgroups analysed, responders to C-IFL demonstrated significantly higher increase in auto-MLR responses, IL-12 and IL-18 secretion and higher decrease in Treg frequency. The disturbed immune parameters observed in patients with mCRC at presentation can be significantly improved during treatment with IFL and this effect can be potentiated by the addition of cetuximab. Monitoring of the peripheral immune system function could be used as surrogate marker in predicting treatment-related outcome. Copyright © 2013 S. Karger AG, Basel.

Primary tumor site is a useful predictor of cetuximab efficacy in the third-line or salvage treatment of KRAS wild-type (exon 2 non-mutant) metastatic colorectal cancer: a nationwide cohort study

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Chen, Kuo-Hsing; Shao, Yu-Yun; Chen, Ho-Min; Lin, Yu-Lin; Lin, Zhong-Zhe; Lai, Mei-Shu; Cheng, Ann-Lii; Yeh, Kun-Huei

2016-01-01

Previous studies have shown left-sided colorectal cancer (LCRC) and right-sided colorectal cancer (RCRC) exhibit different molecular and clinicopathological features. We explored the association between the primary tumor site and cetuximab efficacy in KRAS wild-type colorectal cancer (CRC). This study enrolled a cohort of patients, who had received cetuximab treatment after two or more lines of chemotherapy for KRAS wild-type (exon 2 nonmutant) metastatic CRC, from the databases of Taiwan Cancer Registry (2004–2010) and National Health Insurance (2004–2011). Survival data were obtained from the National Death Registry. Time to treatment discontinuation (TTD) and overall survival (OS) after the start of cetuximab treatment were compared between patients with LCRC (splenic flexure to rectum) and RCRC (cecum to hepatic flexure). A total of 969 CRC patients were enrolled. Among them, 765 (78.9 %) and 136 (14.0 %) patients had LCRC and RCRC, respectively. Patients with LCRC, compared to patients with RCRC, had longer TTD (median, 4.59 vs. 2.75 months, P = .0005) and OS (median, 12.62 vs. 8.07 months, P < .0001) after the start of cetuximab treatment. Multivariate analysis revealed a right-sided primary tumor site was an independent predictor of shorter TTD (adjusted hazard ratio [HR] = 1.32, using the LCRC group as a reference, 95 % confidence interval: 1.08–1.61, P = .0072) and OS (adjusted HR = 1.45, 95 % CI: 1.18–1.78, P = .0003). Our findings demonstrate that a left-sided primary tumor site is a useful predictor of improved cetuximab efficacy in the third-line or salvage treatment of KRAS wild-type (exon 2 nonmutant) metastatic CRC

Aggressive Treatment of Patients with Metastatic Colorectal Cancer Increases Survival: A Scandinavian Single-Center Experience

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Kristoffer Watten Brudvik

2013-01-01

Full Text Available Background. We examined overall and disease-free survivals in a cohort of patients subjected to resection of liver metastasis from colorectal cancer (CRLM in a 10-year period when new treatment strategies were implemented. Methods. Data from 239 consecutive patients selected for liver resection of CRLM during the period from 2002 to 2011 at a single center were used to estimate overall and disease-free survival. The results were assessed against new treatment strategies and established risk factors. Results. The 5-year cumulative overall and disease-free survivals were 46 and 24%. The overall survival was the same after reresection, independently of the number of prior resections and irrespectively of the location of the recurrent disease. The time intervals between each recurrence were similar (11 ± 1 months. Patients with high tumor load given neoadjuvant chemotherapy had comparable survival to those with less extensive disease without neoadjuvant chemotherapy. Positive resection margin or resectable extrahepatic disease did not affect overall survival. Conclusion. Our data support that one still, and perhaps to an even greater extent, should seek an aggressive therapeutic strategy to achieve resectable status for recurrent hepatic and extrahepatic metastases. The data should be viewed in the context of recent advances in the understanding of cancer biology and the metastatic process.

Human monoclonal antibody 99mTc-88BV59: detection of colorectal cancer, recurrent or metastatic disease and immunogenicity assessment.

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Krause, B J; Baum, R P; Staib-Sebler, E; Lorenz, M; Niesen, A; Hör, G

1997-01-01

This study presents immunoscintigraphic results in 24 patients suffering from primary colorectal cancer, recurrent or metastatic disease after the injection of 1197-1351 MBq technetium-99m labelled totally human monoclonal antibody 88BV59. Labelling efficacy of 99mTc-88BV59 ranged from 97% to 99%. Immunoscintigraphy was performed 18-20 h after injection. Scintigraphic findings were compared with those of computed tomography (CT). Patients underwent surgery in order to evaluate immunoscintigraphic findings histologically. Sera of the patients (before injection and 1 and 3 months post infusion) were analysed for the presence of human anti-human antibodies (HAHA). None of the patients showed a HAHA response as assessed by a solid-phase ELISA assay. The antibody scan detected about 25% more lesions than CT. In the detection of extrahepatic disease, the sensitivity of the antibody scan proved to be 68%, whereas the sensitivity of CT was 41%.

Propensity Score Analysis of Regorafenib Versus Trifluridine/Tipiracil in Patients with Metastatic Colorectal Cancer Refractory to Standard Chemotherapy (REGOTAS): A Japanese Society for Cancer of the Colon and Rectum Multicenter Observational Study.

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Moriwaki, Toshikazu; Fukuoka, Shota; Taniguchi, Hiroya; Takashima, Atsuo; Kumekawa, Yusuke; Kajiwara, Takeshi; Yamazaki, Kentaro; Esaki, Taito; Makiyama, Chinatsu; Denda, Tadamichi; Satake, Hironaga; Suto, Takeshi; Sugimoto, Naotoshi; Enomoto, Masanobu; Ishikawa, Toshiaki; Kashiwada, Tomomi; Sugiyama, Masahiko; Komatsu, Yoshito; Okuyama, Hiroyuki; Baba, Eishi; Sakai, Daisuke; Watanabe, Tomoki; Tamura, Takao; Yamashita, Kimihiro; Gosho, Masahiko; Shimada, Yasuhiro

2018-01-01

This study compared the efficacy of regorafenib and trifluridine/tipiracil (TFTD) in patients with metastatic colorectal cancer (mCRC) who are refractory to standard chemotherapy, because despite their clinical approval, it still remains unclear which of these two drugs should be used as initial treatment. The clinical data of patients with mCRC who were treated with regorafenib or TFTD and those of drug-naive patients, between June 2014 and September 2015, were retrospectively collected from 24 institutions in Japan. Overall survival (OS) was evaluated using the Cox's proportional hazard models based on propensity score adjustment for baseline characteristics. A total of 550 patients (223 patients in the regorafenib group and 327 patients in the TFTD group) met all criteria. The median OS was 7.9 months (95% confidence interval [CI], 6.8-9.2) in the regorafenib group and 7.4 months (95% CI, 6.6-8.3) in the TFTD group. The propensity score adjusted analysis showed that OS was similar between the two groups (adjusted hazard ratio [HR], 0.96; 95% CI, 0.78-1.18). In the subgroup analysis, a significant interaction with age was observed. Regorafenib showed favorable survival in patients aged regorafenib and TFTD was observed in patients with mCRC. Although the choice of the drug by age might affect survival, a clearly predictive biomarker to distinguish the two drugs should be identified in further studies. Previous studies of patients with metastatic colorectal cancer refractory to standard chemotherapy had demonstrated that both regorafenib and trifluridine/tipiracil could result in increased overall survival compared with placebo, but there are no head-to-head trials. This large, multicenter, observational study retrospectively compared the efficacy of regorafenib and trifluridine/tipiracil in 550 patients with metastatic colorectal cancer refractory to standard chemotherapy who had access to both drugs. Although no difference in overall survival was found between

Peptidomimetic inhibitors of APC-Asef interaction block colorectal cancer migration.

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Jiang, Haiming; Deng, Rong; Yang, Xiuyan; Shang, Jialin; Lu, Shaoyong; Zhao, Yanlong; Song, Kun; Liu, Xinyi; Zhang, Qiufen; Chen, Yu; Chinn, Y Eugene; Wu, Geng; Li, Jian; Chen, Guoqiang; Yu, Jianxiu; Zhang, Jian

2017-09-01

The binding of adenomatous polyposis coli (APC) to its receptor Asef relieves the negative intramolecular regulation of Asef and leads to aberrant cell migration in human colorectal cancer. Because of its crucial role in metastatic dissemination, the interaction between APC and Asef is an attractive target for anti-colorectal-cancer therapy. We rationally designed a series of peptidomimetics that act as potent inhibitors of the APC interface. Crystal structures and biochemical and cellular assays showed that the peptidomimetics in the APC pocket inhibited the migration of colorectal cells by disrupting APC-Asef interaction. By using the peptidomimetic inhibitor as a chemical probe, we found that CDC42 was the downstream GTPase involved in APC-stimulated Asef activation in colorectal cancer cells. Our work demonstrates the feasibility of exploiting APC-Asef interaction to regulate the migration of colorectal cancer cells, and provides what to our knowledge is the first class of protein-protein interaction inhibitors available for the development of cancer therapeutics targeting APC-Asef signaling.

Health-related quality of life in patients with metastatic colorectal cancer, association with systemic inflammatory response and RAS and BRAF mutation status

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Thomsen, Maria; Guren, Marianne Grønlie; Skovlund, Eva

2017-01-01

Background The aim of this study was to evaluate the effect of cetuximab on health-related quality of life (HRQoL) in the NORDIC-VII trial on metastatic colorectal cancer (mCRC), and to assess HRQoL in relation to RAS and BRAF mutation status and inflammatory biomarkers. Patient and methods HRQo....... There was a statistically significant association between reduction in IL-6 and CRP levels and improvement in HRQoL during treatment from baseline to cycle 4. Conclusion The addition of cetuximab to chemotherapy did not affect HRQoL in mCRC patients. Patients with BRAF-mutated tumours have both a worse prognosis and a poor...

Safety and efficacy of the addition of simvastatin to panitumumab in previously treated KRAS mutant metastatic colorectal cancer patients.

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Baas, Jara M; Krens, Lisanne L; Bos, Monique M; Portielje, Johanneke E A; Batman, Erdogan; van Wezel, Tom; Morreau, Hans; Guchelaar, Henk-Jan; Gelderblom, Hans

2015-09-01

Panitumumab has proven efficacy in patients with metastatic or locally advanced colorectal cancer patients, provided that they have no activating KRAS mutation in their tumour. Simvastatin blocks the mevalonate pathway and thereby interferes with the post-translational modification of KRAS. We hypothesize that the activity of the RAS-induced pathway in patients with a KRAS mutation might be inhibited by simvastatin. This would theoretically result in increased sensitivity to panitumumab, potentially comparable with tumours with wild-type KRAS. A Simon two-stage design single-arm, phase II study was designed to test the safety and efficacy of the addition of simvastatin to panitumumab in colorectal cancer patients with a KRAS mutation after failing fluoropyrimidine-based, oxaliplatin-based and irinotecan-based therapy. The primary endpoint of this study was the proportion of patients alive and free from progression 11 weeks after the first administration of panitumumab, aiming for at least 40%, which is comparable with, although slightly lower than, that in KRAS wild-type patients in this setting. If this 40% was reached, then the study would continue into the second step up to 46 patients. Explorative correlative analysis for mutations in the KRAS and related pathways was carried out. One of 14 patients was free from progression at the primary endpoint time. The median progression-free survival was 8.4 weeks and the median overall survival status was 19.6 weeks. We conclude that the concept of mutant KRAS phenotype expression modulation with simvastatin was not applicable in the clinic.

Metastatic Renal Cell Carcinoma to the Pancreas: A Review.

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Cheng, Shaun Kian Hong; Chuah, Khoon Leong

2016-06-01

The pancreas is an unusual site for tumor metastasis, accounting for only 2% to 5% of all malignancies affecting the pancreas. The more common metastases affecting the pancreas include renal cell carcinomas, melanomas, colorectal carcinomas, breast carcinomas, and sarcomas. Although pancreatic involvement by nonrenal malignancies indicates widespread systemic disease, metastatic renal cell carcinoma to the pancreas often represents an isolated event and is thus amenable to surgical resection, which is associated with long-term survival. As such, it is important to accurately diagnose pancreatic involvement by metastatic renal cell carcinoma on histology, especially given that renal cell carcinoma metastasis may manifest more than a decade after its initial presentation and diagnosis. In this review, we discuss the clinicopathologic findings of isolated renal cell carcinoma metastases of the pancreas, with special emphasis on separating metastatic renal cell carcinoma and its various differential diagnoses in the pancreas.

5-Fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) plus sunitinib or bevacizumab as first-line treatment for metastatic colorectal cancer: a randomized Phase IIb study

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Hecht, J Randolph; Mitchell, Edith P; Yoshino, Takayuki; Welslau, Manfred; Lin, Xun; Chow Maneval, Edna; Paolini, Jolanda; Lechuga, Maria Jose; Kretzschmar, Albrecht

2015-01-01

Background Sunitinib is an oral inhibitor of tyrosine kinase receptors implicated in tumor proliferation, angiogenesis, and metastasis. In this randomized, multicenter, open-label Phase IIb study, sunitinib plus mFOLFOX6 (oxaliplatin plus leucovorin plus 5-fluorouracil) was compared with bevacizumab plus mFOLFOX6 as first-line therapy in patients with metastatic colorectal cancer. Methods Patients were stratified by performance status, baseline lactate dehydrogenase level, and prior adjuvant treatment, and randomized 1:1 to receive sunitinib 37.5 mg/day for 4 weeks on and 2 weeks off plus mFOLFOX6 every 2 weeks or bevacizumab 5 mg/kg every 2 weeks plus mFOLFOX6 every 2 weeks. The primary endpoint was progression-free survival. Secondary endpoints included objective response rate, overall survival, safety, and quality of life. Results Enrollment was closed early following accrual of 191 patients, based on an interim analysis showing an inferior trend in the primary progression-free survival efficacy endpoint for sunitinib. Ninety-six patients were randomized to sunitinib plus mFOLFOX6 and 95 to bevacizumab plus mFOLFOX6. Median progression-free survival was 9.3 months and 15.4 months, respectively, but the objective response rate was similar between the study arms. Median overall survival was 23.7 months and 34.1 months, respectively. Dose reductions and interruptions were more common with sunitinib. Hematologic toxicity was more common in the sunitinib arm. Conclusion While the results of the sunitinib arm are comparable with those of previously reported FOLFOX combinations, the sunitinib-based combination was associated with more toxicity than that observed with bevacizumab and mFOLFOX6. The bevacizumab arm had an unexpectedly good outcome, and was much better than that seen in the Phase III trials. Combination therapy with sunitinib plus mFOLFOX6 is not recommended for patients with metastatic colorectal cancer. PMID:26109878

5-Fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) plus sunitinib or bevacizumab as first-line treatment for metastatic colorectal cancer: a randomized Phase IIb study

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Hecht, J Randolph; Mitchell, Edith P; Yoshino, Takayuki; Welslau, Manfred; Lin, Xun; Chow Maneval, Edna; Paolini, Jolanda; Lechuga, Maria Jose; Kretzschmar, Albrecht

2015-01-01

Sunitinib is an oral inhibitor of tyrosine kinase receptors implicated in tumor proliferation, angiogenesis, and metastasis. In this randomized, multicenter, open-label Phase IIb study, sunitinib plus mFOLFOX6 (oxaliplatin plus leucovorin plus 5-fluorouracil) was compared with bevacizumab plus mFOLFOX6 as first-line therapy in patients with metastatic colorectal cancer. Patients were stratified by performance status, baseline lactate dehydrogenase level, and prior adjuvant treatment, and randomized 1:1 to receive sunitinib 37.5 mg/day for 4 weeks on and 2 weeks off plus mFOLFOX6 every 2 weeks or bevacizumab 5 mg/kg every 2 weeks plus mFOLFOX6 every 2 weeks. The primary endpoint was progression-free survival. Secondary endpoints included objective response rate, overall survival, safety, and quality of life. Enrollment was closed early following accrual of 191 patients, based on an interim analysis showing an inferior trend in the primary progression-free survival efficacy endpoint for sunitinib. Ninety-six patients were randomized to sunitinib plus mFOLFOX6 and 95 to bevacizumab plus mFOLFOX6. Median progression-free survival was 9.3 months and 15.4 months, respectively, but the objective response rate was similar between the study arms. Median overall survival was 23.7 months and 34.1 months, respectively. Dose reductions and interruptions were more common with sunitinib. Hematologic toxicity was more common in the sunitinib arm. While the results of the sunitinib arm are comparable with those of previously reported FOLFOX combinations, the sunitinib-based combination was associated with more toxicity than that observed with bevacizumab and mFOLFOX6. The bevacizumab arm had an unexpectedly good outcome, and was much better than that seen in the Phase III trials. Combination therapy with sunitinib plus mFOLFOX6 is not recommended for patients with metastatic colorectal cancer

EMAST is associated with a poor prognosis in microsatellite instable metastatic colorectal cancer.

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Sabine Venderbosch

Full Text Available To determine the frequency and prognostic value of elevated microsatellite alterations at selected tetranucleotide repeats (EMAST in metastatic colorectal cancer (mCRC patients in relation to microsatellite instability (MSI status and MSH3 protein expression.The frequency of EMAST was evaluated in mCRC patients with MSI tumors and microsatellite stable (MSS tumors. A literature overview was performed to compare the frequency of EMAST in our study with existing data. Immunohistochemistry for MSH3 was compared with EMAST status. Outcome was studied in terms of overall survival (OS of mCRC patients with MSI and MSS tumors.EMAST was evaluated in 89 patients with MSI tumors (including 39 patients with Lynch syndrome and 94 patients with MSS tumors. EMAST was observed in 45.9% (84 out of 183 of patients, with an increased frequency in MSI tumors (79.8% versus 13.8%, p < 0.001. We found no correlation between EMAST and MSH3 protein expression. There was no effect of EMAST on prognosis in patients with MSS tumors, but patients with MSI / non-EMAST tumors had a significantly better prognosis than patients with MSI / EMAST tumors (OS: HR 3.22, 95% CI 1.25-8.30.Frequency of EMAST was increased in mCRC patients with MSI tumors, compared to MSS tumors. Our data suggest that the presence of EMAST correlates with worse OS in these patients. There was no effect of EMAST on the prognosis of patients with MSS tumors. A limitation of our study is the small number of patients in our subgroup analysis.

Association of pretreatment neutrophil-lymphocyte ratio and outcome in emergency colorectal cancer care.

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Palin, R P; Devine, A T; Hicks, G; Burke, D

2018-04-01

Introduction The association between the neutrophil-lymphocyte ratio (NLR) and outcome in elective colorectal cancer surgery is well established; the relationship between NLR and the emergency colorectal cancer patient is, as yet, unexplored. This paper evaluates the predictive quality of the NLR for outcome in the emergency colorectal cancer patient. Materials and Methods A total of 187 consecutive patients who underwent emergency surgery for colorectal cancer were included in the study. NLR was calculated from the haematological tests done on admission. Receiver operating characteristic analyses were used to determine the most suitable cut-off for NLR. Outcomes were assessed by mortality at 30 and 90 days using stepwise Cox proportional hazards regression. Results An NLR cut-off of 5 was found to have the highest sensitivity and specificity. At 30 days, age and time from admission to surgery were associated with increased mortality; a high NLR was associated with an increased risk of mortality in univariate but not multivariate analysis. At 90 days, age, NLR, time from admission to surgery and nodal status were all significantly associated with increased mortality on multivariate analysis. Conclusions Pre-operative NLR is a cheap, easily performed and useful clinical tool to aid prediction of outcome in the emergency colorectal cancer patient.

Elevated serum cytokines correlated with altered behavior, serum cortisol rhythm, and dampened 24-hour rest-activity patterns in patients with metastatic colorectal cancer.

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Rich, Tyvin; Innominato, Pasquale F; Boerner, Julie; Mormont, M Christine; Iacobelli, Stefano; Baron, Benoit; Jasmin, Claude; Lévi, Francis

2005-03-01

Incapacitating symptom burden in cancer patients contributes to poor quality of life (QOL) and can influence treatment outcomes because of poor tolerance to therapy. In this study, the role of circulating cytokines in the production symptoms in cancer patients is evaluated. Eighty patients with metastatic colorectal cancer with either normal (group I, n = 40) or dampened (group II, n = 40) 24-hour rest/activity patterns measured by actigraphy were identified. Actigraphy patterns were correlated with QOL indices, serum cortisol obtained at 8:00 a.m. and 4:00 p.m. and with serum levels of transforming growth factor-alpha, tumor necrosis factor-alpha, and interleukin 6 (IL-6) obtained at 8:00 a.m. and analyzed in duplicate by ELISA. Cytokine levels and survival were also correlated. Group II patients had significantly higher pre treatment levels of all three cytokines, displayed significantly poorer emotional and social functioning, had higher fatigue, more appetite loss, and poorer performance status compared with group I patients. Transforming growth factor-alpha (TGF-alpha) and IL-6 were significantly increased in the patients with WHO performance status >1 and in those with appetite loss. Fatigue was significantly associated with elevated TGF-alpha only. IL-6 was increased in those patients with extensive liver involvement and multiple organ replacement, and it was significantly correlated with dampened cortisol rhythm. In a multivariate analysis, IL-6 was correlated with poor treatment outcome. Significant correlations were found between serum levels of TGF-alpha and IL-6, circadian patterns in wrist activity and serum cortisol and tumor-related symptoms in patients with metastatic colorectal cancer. These data support the hypothesis that some cancer patient's symptoms of fatigue, poor QOL, and treatment outcome are related to tumor or host generated cytokines and could reflect cytokine effects on the circadian timing system. This interplay between cytokine

Evaluation of dual energy spectral CT in differentiating metastatic from non-metastatic lymph nodes in rectal cancer: Initial experience

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Liu, Huanhuan [Department of Radiology, Ruijin Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai 200025 (China); Department of Radiology, Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine (China); Yan, Fuhua; Pan, Zilai; Lin, Xiaozhu; Luo, Xianfu; Shi, Cen [Department of Radiology, Ruijin Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai 200025 (China); Chen, Xiaoyan [Department of Pathology, Ruijin Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai 200025 (China); Wang, Baisong [Department of Biomedical Statistics, Shanghai Jiaotong University, School of Medicine, Shanghai 200025 (China); Zhang, Huan, E-mail: huanzhangy@126.com [Department of Radiology, Ruijin Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai 200025 (China)

2015-02-15

Highlights: • Colorectal cancer is the third most prevalent cancer and the status of the regional lymph nodes in rectal cancer is considered to be one of the most powerful prognostic factor in the absence of distant metastatic disease. Detecting LNs metastasis is still a challenging problem due to the presence of microscopic metastasis or inflammatory swelling of LNs. • We investigated the value of dual energy spectral CT in differentiating metastatic from non-metastatic lymph nodes in rectal cancer. Our study demonstrated that the quantitative normalized iodine concentration (nIC) could be useful for differentiating metastatic and non-metastatic lymph nodes. The combination of nIC in portal venous phase and conventional size criterion could improve the diagnostic accuracy, sensitivity, specificity, positive predictive value and negative predictive value of rectal cancer. - Abstract: Objectives: To investigate the value of dual energy spectral CT (DEsCT) imaging in differentiating metastatic from non-metastatic lymph nodes in rectal cancer. Methods: Fifty-five patients with rectal cancer underwent the arterial phase (AP) and portal venous phase (PP) contrast-enhanced DEsCT imaging. The virtual monochromatic images and iodine-based material decomposition images derived from DEsCT imaging were interpreted for lymph nodes (LNs) measurement. The short axis diameter and the normalized iodine concentration (nIC) of metastatic and non-metastatic LNs were measured. The two-sample t test was used to compare the short axis diameters and nIC values of metastatic and non-metastatic LNs. ROC analysis was performed to assess the diagnostic performance. Results: One hundred and fifty two LNs including 92 non-metastatic LNs and 60 metastatic LNs were matched using the radiological-pathological correlation. The mean short axis diameter of metastatic LNs was significantly larger than that of the non-metastatic LNs (7.28 ± 2.28 mm vs. 4.90 ± 1.64 mm, P < 0.001). The mean n

Correlations of {sup 18}F-fluorothymidine uptake with pathological tumour size, Ki-67 and thymidine kinase 1 expressions in primary and metastatic lymph node colorectal cancer foci

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Nakajo, Masatoyo; Nakajo, Masayuki [Kagoshima University, Department of Radiology, Graduate School of Medical and Dental Sciences, Kagoshima (Japan); Nanpuh Hospital, Department of Radiology, Kagoshima (Japan); Kajiya, Yoriko; Tani, Atsushi [Nanpuh Hospital, Department of Radiology, Kagoshima (Japan); Goto, Yuko; Higashi, Michiyo [Kagoshima University, Department of Human Pathology, Graduate School of Medical and Dental Sciences, Kagoshima, 890-8544 (Japan); Jinguji, Megumi; Fukukura, Yoshihiko [Kagoshima University, Department of Radiology, Graduate School of Medical and Dental Sciences, Kagoshima (Japan); Tanaka, Sadao [Nanpuh Hospital, Department of Pathology, Kagoshima (Japan)

2014-12-15

To examine correlations of {sup 18}F-fluorothymidine (FLT) uptake with pathological tumour size and immunohistochemical Ki-67, and thymidine kinase 1 (TK-1) expressions in primary and metastatic node colorectal cancer foci. Thirty primary cancers (PCs) and 37 metastatic nodes (MNs) were included. FLT uptake was assessed by visual scores (non-visible: 0-1 and visible: 2-4), standardized uptake value (SUV), and correlated with size, Ki-67, and TK-1. SUV was measured in visible lesions. FLT heterogeneity was assessed by visual scores (no heterogeneous uptake: 0 and heterogeneous uptake: 1-4). Forty-two lesions were visible. The visible group showed significantly higher values than the non-visible group in size, Ki-67, and TK-1 (each p < 0.05). Size correlated significantly with visual score (PC; ρ = 0.74 and MN; ρ = 0.63), SUVmax (PC; ρ = 0.49, and MN; ρ = 0.76), and SUVmean (PC; ρ = 0.40 and MN; ρ = 0.76) (each p < 0.05). Visual score correlated significantly with size (ρ = 0.86), Ki-67max (ρ = 0.35), Ki-67mean (ρ = 0.38), TK-1max (ρ = 0.35) and TK-1mean (ρ = 0.25) (each p < 0.05). No significant correlations were found between FLT uptake and Ki-67 or TK-1 in 42 visible lesions (each p > 0.05). Heterogeneous FLT uptake was noted in 73 % (22/30) of PCs. FLT uptake correlated with size. Heterogeneous FLT distribution in colorectal cancers may be one of the causes of weak or lack of FLT uptake/Ki-67 or TK-1 correlation. (orig.)

Inhibition of tumor necrosis factor alpha reduces the outgrowth of hepatic micrometastasis of colorectal tumors in a mouse model of liver ischemia-reperfusion injury.

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Jiao, Shu-Fan; Sun, Kai; Chen, Xiao-Jing; Zhao, Xue; Cai, Ning; Liu, Yan-Jun; Xu, Long-Mei; Kong, Xian-Ming; Wei, Li-Xin

2014-01-08

Patients with colorectal cancer (CRC) often develop liver metastases, in which case surgery is considered the only potentially curative treatment option. However, liver surgery is associated with a risk of ischemia-reperfusion (IR) injury, which is thought to promote the growth of colorectal liver metastases. The influence of IR-induced tumor necrosis factor alpha (TNF-α) elevation in the process still is unknown. To investigate the role of TNF-α in the growth of pre-existing micrometastases in the liver following IR, we used a mouse model of colorectal liver metastases. In this model, mice received IR treatment seven days after intrasplenic injections of colorectal CT26 cells. Prior to IR treatment, either TNF-α blocker Enbrel or low-dose TNF-α, which could inhibit IR-induced TNF-α elevation, was administered by intraperitoneal injection. Hepatic IR treatment significantly promoted CT26 tumor growth in the liver, but either Enbrel or low-dose TNF-α pretreatment reversed this trend. Further studies showed that the CT26 + IR group prominently increased the levels of ALT and AST, liver necrosis, inflammatory infiltration and the expressions of hepatic IL-6, MMP9 and E-selectin compared to those of CT26 group. Inhibition of TNF-α elevation remarkably attenuated the increases of these liver inflammatory damage indicators and tumor-promoting factors. These findings suggested that inhibition of TNF-α elevation delayed the IR-enhanced outgrowth of colorectal liver metastases by reducing IR-induced inflammatory damage and the formation of tumor-promoting microenvironments. Both Enbrel and low-dose TNF-α represented the potential therapeutic approaches for the protection of colorectal liver metastatic patients against IR injury-induced growth of liver micrometastases foci.

Biochemical liver function test parameter levels in relation to treatment response in liver metastatic colorectal patients treated with FOLFOX4 with or without bevacizumab

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Denić Kristina

2016-01-01

Full Text Available Introduction. Combined use of bevacizumab and conventional anticancer drugs leads to a significant improvement of treatment response in patients with metastatic colorectal carcinoma (CRC. Conventional treatment protocols exert undesired effects on the liver tissue. Hepatotoxic effects are manifested as a disturbance of liver function test parameters. The relation between clinical outcome and disorder of biochemical parameters has not been completely evaluated. Objective. The objective of our study was to examine whether clinical outcome in patients with liver metastatic CRC correlates with the level of liver function test parameters. Methods. The study included 96 patients with untreated liver metastatic CRC who received FOLFOX4 protocol with or without bevacizumab. Biochemical liver parameters were performed before and after the treatment completion. Treatment response was evaluated as disease regression, stable disease, and disease progression. The patients were divided into three groups according to the accomplished treatment response. Results. In the group of patients with disease regression the post-treatment levels of aspartate aminotransferase, alanine aminotransferase, and bilirubin were statistically significantly increased. In contrast to this, gamma-glutamyltransferase and protein post-treatment values were significantly lower in relation to initial values. In patients with stable disease, difference was found only in the level of proteins being lower after the treatment. In patients with disease progression, values of aspartate aminotransferase and bilirubin were significantly increased after completed treatment. Conclusion. Treatment responses are not completely associated with the level of liver function test parameters. The only parameter which correlated with treatment response is gamma-glutamyltransferase. Its decrease is accompanied with disease regression.

Human monoclonal antibody 99mTc-88BV59: detection of colorectal cancer, recurrent or metastatic disease and immunogenicity assessment

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Krause, B.J.; Baum, R.P.; Staib-Sebler, E.; Lorenz, M.; Niesen, A.; Hoer, G.

1997-01-01

This study presents immunoscintigraphic results in 24 patients suffering from primary colorectal cancer, recurrent or metastatic disease after the injection of 1197-1351 MBq technetium-99m labelled totally human monoclonal antibody 88BV59. Labelling efficacy of 99m Tc-88BV59 ranged from 97% to 99%. Immunoscintigraphy was performed 18-20 h after injection. Scintigraphic findings were compared with those of computed tomography (CT). Patients underwent surgery in order to evaluate immunoscintigraphic findings histologically. Sera of the patients (before injection and 1 and 3 months post infusion) were analysed for the presence of human anti-human antibodies (HAHA). None of the patients showed a HAHA response as assessed by a solid-phase ELISA assay. The antibody scan detected about 25% more lesions than CT. In the detection of extrahepatic disease, the sensitivity of the antibody scan proved to be 68%, whereas the sensitivity of CT was 41%. (orig.). With 3 figs., 1 tab

Increased platelet-lymphocyte ratio closely relates to inferior clinical features and worse long-term survival in both resected and metastatic colorectal cancer: an updated systematic review and meta-analysis of 24 studies.

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Chen, Nan; Li, Wanling; Huang, Kexin; Yang, Wenhao; Huang, Lin; Cong, Tianxin; Li, Qingfang; Qiu, Meng

2017-05-09

Colorectal cancer (CRC) is one of the most common cancers worldwide. However, the prognostic and clinical value of platelet-lymphocyte ratio (PLR) in colorectal cancer was still unclear, which attracted more and more researchers' considerable attention. We performed a systematic review and meta-analysis to investigate the relationship between PLR and survival as well as clinical features of CRC update to September 2016. The hazard ratio (HR) or odds ratio (OR) with 95% confidence interval (CI) were calculated to access the association. We included 24 eligible studies with a total of 13719 patients. Elevated PLR predicted shorter overall survival (OS) (HR=1.47; 95%CI, 1.28-1.68; p<0.001), poorer disease-free survival (DFS) (HR=1.51; 95% CI, 1.2-1.91; p=0.001), and worse recurrence-free survival (RFS) (HR=1.39; 95% CI, 1.03-1.86; p=0.03), but had nothing to do with Cancer-specific survival (CSS) (HR=1.14; 95% CI, 0.92-1.42; p=0.223). After trim and fill method, the connection between PLR and DFS disappeared (HR=1.143; 95%CI, 0.903-1.447; p=0.267). By subgroup analyze, we found that increased PLR predicated a worse OS and DFS in patients who underwent surgery, and this prognostic role also shown both in metastatic and nonmetastatic patients. In addition, elevated PLR was associated with poorly differentiated tumor (OR=1.51; 95% CI, 1.26-1.81; p<0.001), higher tumor stage (OR=1.25; 95% CI, 1.05-1.49; p=0.012), lymphovascular invasion (LVI) (OR=1.25; 95% CI, 1.09-1.43; p=0.001), and the recurrence of CRC (OR=2.78; 95% CI, 1.36-5.68; p=0.005). We indicated that pretreatment PLR was a good prognostic marker for CRC patients. High PLR was related to worse OS, RFS and poor clinical characteristics.

Resilience and hope during advanced disease: a pilot study with metastatic colorectal cancer patients.

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Solano, Joao Paulo Consentino; da Silva, Amanda Gomes; Soares, Ivan Agurtov; Ashmawi, Hazem Adel; Vieira, Joaquim Edson

2016-08-02

The balance between hope-hopelessness plays an important role in the way terminally ill patients report quality of life, and personal resilience may be related to hope at the end of life. The objective of this study was to explore associations between personal resilience, hope, and other possible predictors of hope in advanced cancer patients. A cross-sectional pilot study was carried out with metastatic colorectal cancer patients in a tertiary hospital. The patients answered the Connor-Davidson Resilience Scale, Herth Hope Index, Barthel Index, an instrument addressing family and social support, visual-numeric scales for pain and suffering, a two-item screening for depression, socio-demographic and socio-economic information about the family. Forty-four patients were interviewed (mean age 56 years; range 29-86). A strong correlation was noted between resilience and hope (0.63; p hope and independence for activities of daily living, support from family and community, and pain and suffering levels. Of the 44 patients, 20 presented with depressive symptoms. These depressive patients had lower resilience (p = 0.005) and hope (p = 0.003), and higher scores of suffering (p hope kept stable after adjusting for age, gender, and presence of depression (p hope, resilience-fostering interventions should be most valued in palliative care settings and should be commenced as soon as possible with cancer patients. Patients with advanced stages of non-malignant conditions would also probably benefit from such interventions.

Tumour gene expression predicts response to cetuximab in patients with KRAS wild-type metastatic colorectal cancer.

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Baker, J B; Dutta, D; Watson, D; Maddala, T; Munneke, B M; Shak, S; Rowinsky, E K; Xu, L-A; Harbison, C T; Clark, E A; Mauro, D J; Khambata-Ford, S

2011-02-01

Although it is accepted that metastatic colorectal cancers (mCRCs) that carry activating mutations in KRAS are unresponsive to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies, a significant fraction of KRAS wild-type (wt) mCRCs are also unresponsive to anti-EGFR therapy. Genes encoding EGFR ligands amphiregulin (AREG) and epiregulin (EREG) are promising gene expression-based markers but have not been incorporated into a test to dichotomise KRAS wt mCRC patients with respect to sensitivity to anti-EGFR treatment. We used RT-PCR to test 110 candidate gene expression markers in primary tumours from 144 KRAS wt mCRC patients who received monotherapy with the anti-EGFR antibody cetuximab. Results were correlated with multiple clinical endpoints: disease control, objective response, and progression-free survival (PFS). Expression of many of the tested candidate genes, including EREG and AREG, strongly associate with all clinical endpoints. Using multivariate analysis with two-layer five-fold cross-validation, we constructed a four-gene predictive classifier. Strikingly, patients below the classifier cutpoint had PFS and disease control rates similar to those of patients with KRAS mutant mCRC. Gene expression appears to identify KRAS wt mCRC patients who receive little benefit from cetuximab. It will be important to test this model in an independent validation study.

Symptom burden & quality of life among patients receiving second-line treatment of metastatic colorectal cancer

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Walker Mark S

2012-06-01

Full Text Available Abstract Background Bevacizumab (B and cetuximab (C are both approved for use in the treatment of metastatic colorectal cancer (mCRC in the second-line. We examined patient reported symptom burden during second-line treatment of mCRC. Methods Adult mCRC patients treated in the second-line setting with a regimen that included B, C, or chemotherapy only (O and who had completed ≥ 1 Patient Care Monitor (PCM surveys as part of routine clinical care were drawn from the ACORN Data Warehouse. Primary endpoints were rash, dry skin, itching, nail changes, nausea, vomiting, fatigue, burning in hands/feet, and diarrhea. Linear mixed models examined change in PCM scores across B, C and O (B = reference. Results 182 patients were enrolled (B: n = 106, C: n = 38, O: n = 38. Patients were 51% female, 67% Caucasian, with mean age of 62.0 (SD = 12.6. Groups did not differ on demographic or clinical characteristics. The most common second-line regimens were FOLFIRI ± B or C (23.1% and FOLFOX ± B or C (22.5%. Results showed baseline scores to be strongly predictive of second-line symptoms across all PCM items (all p’s  Conclusions Patients receiving second-line treatment for mCRC with B report less symptom burden, especially dermatologic, compared to patients treated with C.

Bevacizumab Demonstrates Prolonged Disease Stabilization in Patients with Heavily Pretreated Metastatic Renal Cell Carcinoma: A Case Series and Review of the Literature

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Nicole M. Agostino

2010-01-01

Full Text Available There are now a variety of therapies approved for the treatment of metastatic renal cell carcinoma (RCC. These include the immunotherapeutics, alfa-interferon, and interleukin-2, and agents that target the vascular endothelial growth factor receptor (VEGFR via its tyrosine kinase, such as sorafenib, sunitinib, and pazopanib, or the mammalian target of rapamycin (mTOR, such as temsirolimus and everolimus. Bevacizumab, a monoclonal antibody directed against the ligand, VEGF, has shown activity against RCC as a single agent in patients who had failed prior cytokine therapy and as first line therapy in combination with interferon. The activity of bevacizumab in patients who had received and failed prior therapy has not been described. We report our experience in 4 patients with metastatic RCC who had failed prior cytokine, TKI, and mTOR inhibitors who were treated with bevacizumab as single agent therapy. These heavily pretreated patients sustained very prolonged periods of stable disease (median of 12 months with very little toxicity and excellent quality of life. The activity of this agent in patients who had failed prior therapies directed against the VEGFR and mTOR suggests that therapy targeting the ligand, VEGF, is still a viable approach in these patients and deserves further study.

Regorafenib Versus Trifluridine/Tipiracil for Refractory Metastatic Colorectal Cancer: A Retrospective Comparison.

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Masuishi, Toshiki; Taniguchi, Hiroya; Hamauchi, Satoshi; Komori, Azusa; Kito, Yosuke; Narita, Yukiya; Tsushima, Takahiro; Ishihara, Makoto; Todaka, Akiko; Tanaka, Tsutomu; Yokota, Tomoya; Kadowaki, Shigenori; Machida, Nozomu; Ura, Takashi; Fukutomi, Akira; Ando, Masashi; Onozawa, Yusuke; Tajika, Masahiro; Yasui, Hirofumi; Muro, Kei; Mori, Keita; Yamazaki, Kentaro

2017-06-01

Regorafenib and trifluridine/tipiracil (TAS-102) both prolong survival for patients with refractory metastatic colorectal cancer. However, it is unclear which drug should be administered first. We retrospectively evaluated the data from patients who had received regorafenib or TAS-102 at 2 institutions from May 2013 to March 2015. The inclusion criteria were disease refractory or intolerant to fluoropyrimidines, oxaliplatin, irinotecan, anti-vascular endothelial growth factor antibodies, and anti-epidermal growth factor receptor (EGFR) antibodies (if KRAS exon 2 wild-type), and no previous treatment with regorafenib or TAS-102. A total of 146 and 54 patients received regorafenib and TAS-102, respectively. The baseline characteristics were similar between the 2 groups, except for a history of irinotecan and anti-EGFR therapy and high alkaline phosphatase levels. The median progression-free survival and overall survival were 2.1 months and 6.7 months, respectively, with regorafenib and 2.1 months and 6.5 months, respectively, with TAS-102 (progression-free survival hazard ratio 1.20, P = .27; overall survival hazard ratio, 1.01, P = .97). The analysis of overall survival for patients after the approval of TAS-102 in Japan was similar to the overall survival for the entire population. The frequency of hand-foot syndrome and increased aspartate aminotransferase, alanine aminotransferase, and bilirubin levels was higher and the frequency of neutropenia, leukopenia, anemia, nausea, and febrile neutropenia was lower with regorafenib than with TAS-102. No remarkable differences were found in the efficacy and safety of TAS-102 between patients with and without previous regorafenib and vice versa. Regorafenib and TAS-102 had similar efficacy but resulted in different toxicities, which could guide the agent choice. Copyright © 2016 Elsevier Inc. All rights reserved.

Vorinostat and hydroxychloroquine improve immunity and inhibit autophagy in metastatic colorectal cancer.

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Patel, Sukeshi; Hurez, Vincent; Nawrocki, Steffan T; Goros, Martin; Michalek, Joel; Sarantopoulos, John; Curiel, Tyler; Mahalingam, Devalingam

2016-09-13

Hydroxychloroquine (HCQ) enhances the anti-cancer activity of the histone deacetylase inhibitor, vorinostat (VOR), in pre-clinical models and early phase clinical studies of metastatic colorectal cancer (mCRC). Mechanisms could include autophagy inhibition, accumulation of ubiquitinated proteins, and subsequent tumor cell apoptosis. There is growing evidence that autophagy inhibition could lead to improved anti-cancer immunity. To date, effects of autophagy on immunity have not been reported in cancer patients. To address this, we expanded an ongoing clinical study to include patients with advanced, refractory mCRC to evaluate further the clinical efficacy and immune effects of VOR plus HCQ. Refractory mCRC patients received VOR 400 milligrams orally with HCQ 600 milligrams orally daily, in a 3-week cycle. The primary endpoint was median progression-free survival (mPFS). Secondary endpoints include median overall survival (mOS), adverse events (AE), pharmacodynamic of inhibition of autophagy in primary tumors, immune cell analyses, and cytokine levels. Twenty patients were enrolled (19 evaluable for survival) with a mPFS of 2.8 months and mOS of 6.7 months. Treatment-related grade 3-4 AEs occurred in 8 patients (40%), with fatigue, nausea/vomiting, and anemia being the most common. Treatment significantly reduced CD4+CD25hiFoxp3+ regulatory and PD-1+ (exhausted) CD4+ and CD8+ T cells and decreased CD45RO-CD62L+ (naive) T cells, consistent with improved anti-tumor immunity. On-study tumor biopsies showed increases in lysosomal protease cathepsin D and p62 accumulation, consistent with autophagy inhibition. Taken together, VOR plus HCQ is active, safe and well tolerated in refractory CRC patients, resulting in potentially improved anti-tumor immunity and inhibition of autophagy.

Outcomes of colon resection in patients with metastatic colon cancer.

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Moghadamyeghaneh, Zhobin; Hanna, Mark H; Hwang, Grace; Mills, Steven; Pigazzi, Alessio; Stamos, Michael J; Carmichael, Joseph C

2016-08-01

Patients with advanced colorectal cancer have a high incidence of postoperative complications. We sought to identify outcomes of patients who underwent resection for colon cancer by cancer stage. The National Surgical Quality Improvement Program database was used to evaluate all patients who underwent colon resection with a diagnosis of colon cancer from 2012 to 2014. Multivariate logistic regression analysis was performed to investigate patient outcomes by cancer stage. A total of 7,786 colon cancer patients who underwent colon resection were identified. Of these, 10.8% had metastasis at the time of operation. Patients with metastatic disease had significantly increased risks of perioperative morbidity (adjusted odds ratio [AOR]: 1.44, P = .01) and mortality (AOR: 3.72, P = .01). Patients with metastatic disease were significantly younger (AOR: .99, P colon cancer have metastatic disease. Postoperative morbidity and mortality are significantly higher than in patients with localized disease. Published by Elsevier Inc.

Schedule-selective biochemical modulation of 5-fluorouracil in advanced colorectal cancer – a phase II study

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Savage Paul

2002-05-01

Full Text Available Abstract Background 5-fluorouracil remains the standard therapy for patients with advanced/metastatic colorectal cancer. Pre-clinical studies have demonstrated the biological modulation of 5-fluorouracil by methotrexate and leucovorin. This phase II study was initiated to determine the activity and toxicity of sequential methotrexate – leucovorin and 5-fluorouracil chemotherapy in patients with advanced colorectal cancer. Methods Ninety-seven patients with metastatic colorectal cancer were enrolled onto the study. Methotrexate – 30 mg/m2 was administered every 6 hours for 6 doses followed by a 2 hour infusion of LV – 500 mg/m2. Midway through the leucovorin infusion, patients received 5-fluorouracil – 600 mg/m2. This constituted a cycle of therapy and was repeated every 2 weeks until progression. Results The median age was 64 yrs (34–84 and the Eastern Cooperative Group Oncology performance score was 0 in 37%, 1 in 55% and 2 in 8% of patients. Partial and complete responses were seen in 31% of patients with a median duration of response of 6.4 months. The overall median survival was 13.0 months. The estimated 1-year survival was 53.7%. Grade III and IV toxic effects were modest and included mucositis, nausea and vomiting. Conclusions This phase II study supports previously reported data demonstrating the modest clinical benefit of 5-FU modulation utilizing methotrexate and leucovorin in patients with metastatic colorectal cancer. Ongoing studies evaluating 5-fluorouracil modulation with more novel agents (Irinotecan and/or oxaliplatin are in progress and may prove encouraging.

Combination Effect of Nimotuzumab with Radiation in Colorectal Cancer Cells

International Nuclear Information System (INIS)

Shin, Hye Kyung; Kim, Mi Sook; Jeong, Jae Hoon

2010-01-01

To investigate the radiosensitizing effect of the selective epidermal growth factor receptor (EGFR) inhibitor nimotuzumab in human colorectal cancer cell lines. Four human colorectal cancer cell lines, HCT-8, LoVo, WiDr, and HCT-116 were treated with nimotuzumab and/or radiation. The effects on cell proliferation, viability, and cell cycle progression were measured by MTT, clonogenic survival assay, flow cytometry, and Western blot. An immunoblot analysis revealed that EGFR phosphorylation was inhibited by nimotuzumab in colorectal cancer cell lines. Under these experimental conditions, pre-treatment with nimotuzumab increased radiosensitivity of colorectal cancer cell lines, except for cell line HCT-116. However, cell proliferation or cell cycle progression was not affected by the addition of nimotuzumab, irrespective of irradiation. Nimotuzumab enhanced the radiosensitivity of colorectal cancer cells in vitro by inhibiting EGFR-mediated cell survival signaling. This study provided a rationale for the clinical application of the selective EGFR inhibitor, nimotuzumab in combination with radiation in colorectal cancer cells.

Putative contribution of CD56 positive cells in cetuximab treatment efficacy in first-line metastatic colorectal cancer patients

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Maréchal, Raphaël; De Schutter, Jef; Nagy, Nathalie; Demetter, Pieter; Lemmers, Arnaud; Devière, Jacques; Salmon, Isabelle; Tejpar, Sabine; Van Laethem, Jean-Luc

2010-01-01

Activity of cetuximab, a chimeric monoclonal antibody targeting the epidermal growth factor receptor, is largely attributed to its direct antiproliferative and proapoptotic effects. Antibody-dependent cell-mediated cytotoxicity (ADCC) could be another possible mechanism of cetuximab antitumor effects and its specific contribution on the clinical activity of cetuximab is unknown. We assessed immune cells infiltrate (CD56, CD68, CD3, CD4, CD8, Foxp3) in the primary tumor of metastatic colorectal cancer (mCRC) patients treated with a first-line cetuximab-based chemotherapy in the framework of prospective trials (treatment group) and in a matched group of mCRC patients who received the same chemotherapy regimen without cetuximab (control group). The relationship between intra-tumoral immune effector cells, the K-ras status and the efficacy of the treatment were investigated. We also evaluated in vitro, the ADCC activity in healthy donors and chemonaive mCRC patients and the specific contribution of CD56 + cells. ADCC activity against DLD1 CRC cell line is maintained in cancer patients and significantly declined after CD56 + cells depletion. In multivariate analysis, K-ras wild-type (HR: 4.7 (95% CI 1.8-12.3), p = 0.001) and tumor infiltrating CD56 + cells (HR: 2.6, (95%CI:1.14-6.0), p = 0.019) were independent favourable prognostic factors for PFS and response only in the cetuximab treatment group. By contrast CD56 + cells failed to predict PFS and response in the control group. CD56 + cells, mainly NK cells, may be the major effector of ADCC related-cetuximab activity. Assessment of CD56 + cells infiltrate in primary colorectal adenocarcinoma may provide additional information to K-ras status in predicting response and PFS in mCRC patients treated with first-line cetuximab-based chemotherapy

Cetuximab plus FOLFOX for Patients with Metastatic Colorectal Cancer with Poor Performance Status and/or Severe Tumor-Related Complications

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Shitara, Kohei; Yokota, Tomoya; Takahari, Daisuke; Shibata, Takashi; Sato, Yozo; Tajika, Masahiro; Ura, Takashi; Muro, Kei

2010-01-01

Introduction Cetuximab-based chemotherapy showed a statistically significantly higher response rate compared with chemotherapy such as FOLFOX. Therefore, FOLFOX plus cetuximab is suspected to be the best regimen to alleviate tumor-related symptoms with a high response rate. Case Report Here we present the results of 8 consecutive patients with metastatic colorectal cancer with poor performance status and/or severe complications who were treated with first-line FOLFOX with cetuximab. Six of 8 patients achieved an apparent clinical benefit, including radiological response and symptoms improvement. Two patients with BRAF mutation could achieve neither clinical benefit nor radiological response. Conclusion Although an optimal line of therapy with cetuximab is unclear yet with bevacizumab in mind, we propose that patients who need a tumor response to alleviate their symptoms due to advanced disease might be candidates for first-line cetuximab-based therapy as shown in our cases. Additionally, patients with BRAF mutant tumors might be important candidates for novel targeted therapy in the future to improve their poor prognosis. PMID:21347194

Cetuximab plus FOLFOX for Patients with Metastatic Colorectal Cancer with Poor Performance Status and/or Severe Tumor-Related Complications

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Kohei Shitara

2010-07-01

Full Text Available Introduction: Cetuximab-based chemotherapy showed a statistically significantly higher response rate compared with chemotherapy such as FOLFOX. Therefore, FOLFOX plus cetuximab is suspected to be the best regimen to alleviate tumor-related symptoms with a high response rate. Case Report: Here we present the results of 8 consecutive patients with metastatic colorectal cancer with poor performance status and/or severe complications who were treated with first-line FOLFOX with cetuximab. Six of 8 patients achieved an apparent clinical benefit, including radiological response and symptoms improvement. Two patients with BRAF mutation could achieve neither clinical benefit nor radiological response. Conclusion: Although an optimal line of therapy with cetuximab is unclear yet with bevacizumab in mind, we propose that patients who need a tumor response to alleviate their symptoms due to advanced disease might be candidates for first-line cetuximab-based therapy as shown in our cases. Additionally, patients with BRAF mutant tumors might be important candidates for novel targeted therapy in the future to improve their poor prognosis.

Tandem repeat variation near the HIC1 (hypermethylated in cancer 1) promoter predicts outcome of oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer.

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Okazaki, Satoshi; Schirripa, Marta; Loupakis, Fotios; Cao, Shu; Zhang, Wu; Yang, Dongyun; Ning, Yan; Berger, Martin D; Miyamoto, Yuji; Suenaga, Mitsukuni; Iqubal, Syma; Barzi, Afsaneh; Cremolini, Chiara; Falcone, Alfredo; Battaglin, Francesca; Salvatore, Lisa; Borelli, Beatrice; Helentjaris, Timothy G; Lenz, Heinz-Josef

2017-11-15

The hypermethylated in cancer 1/sirtuin 1 (HIC1/SIRT1) axis plays an important role in regulating the nucleotide excision repair pathway, which is the main oxaliplatin-induced damage-repair system. On the basis of prior evidence that the variable number of tandem repeat (VNTR) sequence located near the promoter lesion of HIC1 is associated with HIC1 gene expression, the authors tested the hypothesis that this VNTR is associated with clinical outcome in patients with metastatic colorectal cancer who receive oxaliplatin-based chemotherapy. Four independent cohorts were tested. Patients who received oxaliplatin-based chemotherapy served as the training cohort (n = 218), and those who received treatment without oxaliplatin served as the control cohort (n = 215). Two cohorts of patients who received oxaliplatin-based chemotherapy were used for validation studies (n = 176 and n = 73). The VNTR sequence near HIC1 was analyzed by polymerase chain reaction analysis and gel electrophoresis and was tested for associations with the response rate, progression-free survival, and overall survival. In the training cohort, patients who harbored at least 5 tandem repeats (TRs) in both alleles had a significantly shorter PFS compared with those who had fewer than 4 TRs in at least 1 allele (9.5 vs 11.6 months; hazard ratio, 1.93; P = .012), and these findings remained statistically significant after multivariate analysis (hazard ratio, 2.00; 95% confidence interval, 1.13-3.54; P = .018). This preliminary association was confirmed in the validation cohort, and patients who had at least 5 TRs in both alleles had a worse PFS compared with the other cohort (7.9 vs 9.8 months; hazard ratio, 1.85; P = .044). The current findings suggest that the VNTR sequence near HIC1 could be a predictive marker for oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Cancer 2017;123:4506-14. © 2017 American Cancer Society. © 2017 American Cancer Society.

Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) as second-line chemotherapy in HER2-negative, taxane-pretreated metastatic breast cancer patients: prospective evaluation of activity, safety, and quality of life.

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Palumbo, Raffaella; Sottotetti, Federico; Trifirò, Giuseppe; Piazza, Elena; Ferzi, Antonella; Gambaro, Anna; Spinapolice, Elena Giulia; Pozzi, Emma; Tagliaferri, Barbara; Teragni, Cristina; Bernardo, Antonio

2015-01-01

A prospective, multicenter trial was undertaken to assess the activity, safety, and quality of life of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) as second-line chemotherapy in HER2-negative, taxane-pretreated metastatic breast cancer (MBC). Fifty-two women with HER2-negative MBC who were candidates for second-line chemotherapy for the metastatic disease were enrolled and treated at three centers in Northern Italy. All patients had previously received taxane-based chemotherapy in the adjuvant or first-line metastatic setting. Single-agent nab-paclitaxel was given at the dose of 260 mg/m(2) as a 30-minute intravenous infusion on day 1 each treatment cycle, which lasted 3 weeks, in the outpatient setting. No steroid or antihistamine premedication was provided. Treatment was stopped for documented disease progression, unacceptable toxicity, or patient refusal. All of the enrolled patients were evaluable for the study endpoints. The objective response rate was 48% (95% CI, 31.5%-61.3%) and included complete responses from 13.5%. Disease stabilization was obtained in 19 patients and lasted >6 months in 15 of them; the overall clinical benefit rate was 77%. The median time to response was 70 days (range 52-86 days). The median progression-free survival time was 8.9 months (95% CI, 8.0-11.6 months, range 5-21+ months). The median overall survival point has not yet been reached. Toxicities were expected and manageable with good patient compliance and preserved quality of life in patients given long-term treatment. Our results showed that single-agent nab-paclitaxel 260 mg/m(2) every 3 weeks is an effective and well tolerated regimen as second-line chemotherapy in HER2-negative, taxane-pretreated MBC patients, and that it produced interesting values of objective response rate and progression-free survival without the concern of significant toxicity. Specifically, the present study shows that such a regimen is a valid therapeutic option for that 'difficult to

Associations between deepness of response and clinical outcomes among Japanese patients with metastatic colorectal cancer treated with second-line FOLFIRI plus cetuximab

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Osumi H

2015-08-01

Full Text Available Hiroki Osumi, Satoshi Matsusaka, Mitsukuni Suenaga, Eiji Shinozaki, Nobuyuki Mizunuma Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan Background: In the FIRE-3 trial, overall survival (OS was significantly longer in patients treated with FOLFIRI plus cetuximab (C-mab than in those treated with FOLFIRI plus bevacizumab (Bev, but progression-free survival (PFS was not significantly different. This may be associated with the deepness of response (DpR in patients treated with FOLFIRI plus C-mab. We aimed to evaluate the relationship between clinical outcome and DpR in metastatic colorectal cancer (mCRC patients treated with second-line FOLFIRI plus C-mab.Methods: A total of 112 patients with histopathologically confirmed mCRC treated with second-line FOLFIRI in combination with C-mab (N=42 or Bev (N=70 were retrospectively enrolled between October 2008 and June 2013. The relationship between DpR and clinical outcome in patients treated with FOLFIRI plus C-mab or Bev was determined.Results: Forty-two patients treated with FOLFIRI plus C-mab had a mean DpR of 6.1% (interquartile range: -13.7%, 20.8% and a minimum DpR of -62.7%. On the other hand, 70 patients treated with FOLFIRI plus Bev had a mean DpR of 0% (interquartile range: -16%, 10% and a minimum DpR of -111%. DpR ≥30% was associated with significantly longer OS and PFS when compared with DpR ≤30% in patients given FOLFIRI plus C-mab. DpR (≥30% was independently associated with prolongation of OS and PFS. In patients treated with FOLFIRI plus C-mab, there was a moderate positive correlation between DpR and clinical outcomes (OS: r=0.51, P<0.001; PFS: r=0.54, P<0.001.Conclusion: FOLFIRI plus C-mab yielded a stronger correlation between DpR and clinical outcomes. These results indicate the potential of DpR as a new measure of efficacy in mCRC patients treated with second-line chemotherapy plus C-mab. Keywords: deepness of

Colorectal Stenting in Malignant Large Bowel Obstruction: The Learning Curve

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D. Williams

2011-01-01

Full Text Available Aim. Self-expanding metal stents (SEMSs are increasingly used for the palliation of metastatic colorectal cancer and as a bridge to surgery for obstructing tumours. This case series analyses the learning curve and changes in practice of colorectal stenting over a three year period. Methods. A study of 40 patients who underwent placement of SEMS for the management of colorectal cancer. Patients spanned the learning curve of a single surgeon endoscopist. Results. Technical success rates increased from 82% initially, using an average of 1.7 stents per procedure, to a 94% success rate where all patients were stented using a single stent. There has been a change in practice from elective palliative stenting toward emergency preoperative stenting. Conclusion. There is a steep learning curve for the use of SEMS in the management of malignant colorectal bowel obstruction. We suggest that at least 20 cases are required for an operator to be considered experienced.

The Hedgehog Inhibitor Cyclopamine Reduces β-Catenin-Tcf Transcriptional Activity, Induces E-Cadherin Expression, and Reduces Invasion in Colorectal Cancer Cells

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Qualtrough, David, E-mail: david.qualtrough@uwe.ac.uk [Department of Biological, Biomedical & Analytical Sciences, University of the West of England, Faculty of Health and Applied Sciences, University of the West of England, Frenchay, Bristol BS16 1QY (United Kingdom); Rees, Phil; Speight, Beverley; Williams, Ann C.; Paraskeva, Christos [School of Cellular & Molecular Medicine, University of Bristol, Medical Sciences Building, University Walk, Bristol BS8 1TD (United Kingdom)

2015-09-17

Colorectal cancer is a major global health problem resulting in over 600,000 deaths world-wide every year with the majority of these due to metastatic disease. Wnt signalling, and more specifically β-catenin-related transcription, has been shown to drive both tumorigenesis and the metastatic process in colorectal neoplasia, yet its complex interactions with other key signalling pathways, such as hedgehog, remain to be elucidated. We have previously shown that the Hedgehog (HH) signalling pathway is active in cells from colorectal tumours, and that inhibition of the pathway with cyclopamine induces apoptosis. We now show that cyclopamine treatment reduces β-catenin related transcription in colorectal cancer cell lines, and that this effect can be reversed by addition of Sonic Hedgehog protein. We also show that cyclopamine concomitantly induces expression of the tumour suppressor and prognostic indicator E-cadherin. Consistent with a role for HH in regulating the invasive potential we show that cyclopamine reduces the expression of transcription factors (Slug, Snail and Twist) associated with the epithelial-mesenchymal transition and reduces the invasiveness of colorectal cancer cells in vitro. Taken together, these data show that pharmacological inhibition of the hedgehog pathway has therapeutic potential in the treatment of colorectal cancer.

The Hedgehog Inhibitor Cyclopamine Reduces β-Catenin-Tcf Transcriptional Activity, Induces E-Cadherin Expression, and Reduces Invasion in Colorectal Cancer Cells

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David Qualtrough

2015-09-01

Full Text Available Colorectal cancer is a major global health problem resulting in over 600,000 deaths world-wide every year with the majority of these due to metastatic disease. Wnt signalling, and more specifically β-catenin-related transcription, has been shown to drive both tumorigenesis and the metastatic process in colorectal neoplasia, yet its complex interactions with other key signalling pathways, such as hedgehog, remain to be elucidated. We have previously shown that the Hedgehog (HH signalling pathway is active in cells from colorectal tumours, and that inhibition of the pathway with cyclopamine induces apoptosis. We now show that cyclopamine treatment reduces β-catenin related transcription in colorectal cancer cell lines, and that this effect can be reversed by addition of Sonic Hedgehog protein. We also show that cyclopamine concomitantly induces expression of the tumour suppressor and prognostic indicator E-cadherin. Consistent with a role for HH in regulating the invasive potential we show that cyclopamine reduces the expression of transcription factors (Slug, Snail and Twist associated with the epithelial-mesenchymal transition and reduces the invasiveness of colorectal cancer cells in vitro. Taken together, Cancers 2015, 7 1886 these data show that pharmacological inhibition of the hedgehog pathway has therapeutic potential in the treatment of colorectal cancer.

The Hedgehog Inhibitor Cyclopamine Reduces β-Catenin-Tcf Transcriptional Activity, Induces E-Cadherin Expression, and Reduces Invasion in Colorectal Cancer Cells

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Qualtrough, David; Rees, Phil; Speight, Beverley; Williams, Ann C.; Paraskeva, Christos

2015-01-01

Colorectal cancer is a major global health problem resulting in over 600,000 deaths world-wide every year with the majority of these due to metastatic disease. Wnt signalling, and more specifically β-catenin-related transcription, has been shown to drive both tumorigenesis and the metastatic process in colorectal neoplasia, yet its complex interactions with other key signalling pathways, such as hedgehog, remain to be elucidated. We have previously shown that the Hedgehog (HH) signalling pathway is active in cells from colorectal tumours, and that inhibition of the pathway with cyclopamine induces apoptosis. We now show that cyclopamine treatment reduces β-catenin related transcription in colorectal cancer cell lines, and that this effect can be reversed by addition of Sonic Hedgehog protein. We also show that cyclopamine concomitantly induces expression of the tumour suppressor and prognostic indicator E-cadherin. Consistent with a role for HH in regulating the invasive potential we show that cyclopamine reduces the expression of transcription factors (Slug, Snail and Twist) associated with the epithelial-mesenchymal transition and reduces the invasiveness of colorectal cancer cells in vitro. Taken together, these data show that pharmacological inhibition of the hedgehog pathway has therapeutic potential in the treatment of colorectal cancer

Evolving role of cetuximab in the treatment of colorectal cancer

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Gunter Schuch

2009-07-01

Full Text Available Gunter Schuch, Sebastian Kobold, Carsten BokemeyerDepartment of Oncology, Hematology, and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyAbstract: In recent years, the monoclonal epidermal growth factor receptor (EGFR-targeting antibody cetuximab was introduced into systemic therapy of colorectal cancer and gained an established role in the treatment of this disease. Cetuximab was shown to be active as a single agent in chemorefractory metastatic disease as well as in combination with varying chemotherapies. Recently, randomized trials demonstrated the activity of cetuximab combinations in the first-line setting of metastatic colorectal cancer. Interestingly, the activity of cetuximab was restricted to patients with KRAS wildtype tumors, as was seen with panitumumab, another EGFR antibody. While 60%–70% of tumors harbor KRAS wildtype genes, 30%–40% of tumors express oncogenic KRAS with mutations in codons 12 and 13 causing constitutive activation of signaling cascades downstream of EGFR and resistance to EGFR blockade. Since proof of KRAS wildtype status became a prerequisite for cetuximab treatment, KRAS testing is being established throughout the world. Future trials will address the question which part of the KRAS wildtype cohort will benefit from EGFR inhibition and how to identify those patients. Additionally, new strategies for treatment of KRAS mutated tumors are strongly needed. Recent developments and future strategies will be summarized.Keywords: cetuximab, colorectal cancer, KRAS

Beneficial Treatment Management with Trifluridine/Tipiracil in a Patient with Metastatic Colorectal Cancer and Pronounced Hematological Event History during Previous Treatments

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Volker Kaechele

2018-01-01

Full Text Available Trifluridine/tipiracil (FTD/TPI significantly improves overall survival in patients with metastatic colorectal cancer (mCRC. The most common treatment-related event (grade ≥3 was hematological toxicity. We here report long-term disease-stabilizing FTD/TPI treatment of an mCRC patient (KRAS wild-type, ECOG performance status 1 at baseline and at the end of FTD/TPI therapy with multifocal synchronous metastases and a longstanding history of extensive hematological events during previous treatments. Finally, this 62-year-old male patient was treated for 10 months with FTD/TPI by consecutive alteration of treatment parameters: (i initial daily dose reduction to 80 mg (72% of the recommended dose, (ii 20 days dose delay, (iii a second and later third dose reduction to 70 mg and 60 mg (about 64% and 55%, respectively, of the recommended dose, and (iv 30 µg per day of granulocyte colony-stimulating factor administration first for 3 days, and later for 5 days, for each treatment cycle.

Human monoclonal antibody {sup 99m}Tc-88BV59: detection of colorectal cancer, recurrent or metastatic disease and immunogenicity assessment

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Krause, B.J. [Department of Nuclear Medicine, Johann Wolfgang Goethe University Medical Center, Frankfurt/Main (Germany); Baum, R.P. [Department of Nuclear Medicine, Johann Wolfgang Goethe University Medical Center, Frankfurt/Main (Germany); Staib-Sebler, E. [Department of General and Abdominal Surgery, Johann Wolfgang Goethe University Medical Center, Frankfurt/Main (Germany); Lorenz, M. [Department of General and Abdominal Surgery, Johann Wolfgang Goethe University Medical Center, Frankfurt/Main (Germany); Niesen, A. [Department of Nuclear Medicine, Johann Wolfgang Goethe University Medical Center, Frankfurt/Main (Germany); Hoer, G. [Department of Nuclear Medicine, Johann Wolfgang Goethe University Medical Center, Frankfurt/Main (Germany)

1997-01-01

This study presents immunoscintigraphic results in 24 patients suffering from primary colorectal cancer, recurrent or metastatic disease after the injection of 1197-1351 MBq technetium-99m labelled totally human monoclonal antibody 88BV59. Labelling efficacy of {sup 99m}Tc-88BV59 ranged from 97% to 99%. Immunoscintigraphy was performed 18-20 h after injection. Scintigraphic findings were compared with those of computed tomography (CT). Patients underwent surgery in order to evaluate immunoscintigraphic findings histologically. Sera of the patients (before injection and 1 and 3 months post infusion) were analysed for the presence of human anti-human antibodies (HAHA). None of the patients showed a HAHA response as assessed by a solid-phase ELISA assay. The antibody scan detected about 25% more lesions than CT. In the detection of extrahepatic disease, the sensitivity of the antibody scan proved to be 68%, whereas the sensitivity of CT was 41%. (orig.). With 3 figs., 1 tab.

High expression of microRNA-625-3p is associated with poor response to first-line oxaliplatin based treatment of metastatic colorectal cancer

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Rasmussen, Mads Heilskov; Jensen, Niels; Tarpgaard, Line Schmidt

2013-01-01

The backbone of current cytotoxic treatment of metastatic colorectal cancer (mCRC) consists of a fluoropyrimidine together with either oxaliplatin (XELOX/FOLFOX) or irinotecan (XELIRI/FOLFIRI). With an overall objective response rate of approximately 50% for either treatment combination, a major...... analyses showed that miR-625-3p was not dysregulated between normal and cancer samples, nor was its expression associated with recurrence of stage II or III disease, indicating that miR-625-3p solely is a response marker. Finally, we also found that these miRNAs were up-regulated in oxaliplatin resistant...... unsolved problem is that no predictors of response to these treatments are available. To address this issue, we profiled 742 microRNAs in laser-capture microdissected cancer cells from responding and non-responding patients receiving XELOX/FOLFOX as first-line treatment for mCRC, and identified, among...

Resection Of Hepatal Metastases In Patients With Colorectal Carcinoma - Multidisciplinary Approach

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Hlavata, Z.

2007-01-01

Recent developments in the treatment of colorectal cancer have focused on the role of chemotherapy as systemic treatment in an attempt to prolong survival and improve treatment outcomes for patients. Despite the use of systemic chemotherapy, however, the median survival of patients with metastatic disease has been reported 33 months in maximum. It is important to underline the role of surgery not only by the elimination of the primary tumor, but also of metastasis in the liver. Using correct combination of surgery and chemotherapy for the treatment of metastatic disease, substantial prolongation in the survival can be achieved. Communication between oncologist, surgeon and radiologist as the multidisciplinary approach is crucial for correct management of patients with metastatic liver disease with respect to their maximal benefit. (author)

Intermediate Monocytes but Not TIE2-Expressing Monocytes Are a Sensitive Diagnostic Indicator for Colorectal Cancer

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Schauer, Dominic; Starlinger, Patrick; Reiter, Christian; Jahn, Nikolaus; Zajc, Philipp; Buchberger, Elisabeth; Bachleitner-Hofmann, Thomas; Bergmann, Michael; Stift, Anton; Gruenberger, Thomas; Brostjan, Christine

2012-01-01

We have conducted the first study to determine the diagnostic potential of the CD14++CD16+ intermediate monocytes as compared to the pro-angiogenic subset of CD14++CD16+TIE2+ TIE2-expressing monocytes (TEMs) in cancer. These monocyte populations were investigated by flow cytometry in healthy volunteers (N = 32) and in colorectal carcinoma patients with localized (N = 24) or metastatic (N = 37) disease. We further determined blood levels of cytokines associated with monocyte regulation. The results revealed the intermediate monocyte subset to be significantly elevated in colorectal cancer patients and to show the highest frequencies in localized disease. Multivariate regression analysis identified intermediate monocytes as a significant independent variable in cancer prediction. With a cut-off value at 0.37% (intermediate monocytes of total leukocytes) the diagnostic sensitivity and specificity ranged at 69% and 81%, respectively. In contrast, TEM levels were elevated in localized cancer but did not differ significantly between groups and none of the cytokines correlated with monocyte subpopulations. Of interest, in vitro analyses supported the observation that intermediate monocytes were more potently induced by primary as opposed to metastatic cancer cells which may relate to the immunosuppressive milieu established in the advanced stage of metastatic disease. In conclusion, intermediate monocytes as compared to TIE2-expressing monocytes are a more sensitive diagnostic indicator of colorectal cancer. PMID:22973451

Intermediate monocytes but not TIE2-expressing monocytes are a sensitive diagnostic indicator for colorectal cancer.

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Dominic Schauer

Full Text Available We have conducted the first study to determine the diagnostic potential of the CD14++CD16+ intermediate monocytes as compared to the pro-angiogenic subset of CD14++CD16+TIE2+ TIE2-expressing monocytes (TEMs in cancer. These monocyte populations were investigated by flow cytometry in healthy volunteers (N = 32 and in colorectal carcinoma patients with localized (N = 24 or metastatic (N = 37 disease. We further determined blood levels of cytokines associated with monocyte regulation. The results revealed the intermediate monocyte subset to be significantly elevated in colorectal cancer patients and to show the highest frequencies in localized disease. Multivariate regression analysis identified intermediate monocytes as a significant independent variable in cancer prediction. With a cut-off value at 0.37% (intermediate monocytes of total leukocytes the diagnostic sensitivity and specificity ranged at 69% and 81%, respectively. In contrast, TEM levels were elevated in localized cancer but did not differ significantly between groups and none of the cytokines correlated with monocyte subpopulations. Of interest, in vitro analyses supported the observation that intermediate monocytes were more potently induced by primary as opposed to metastatic cancer cells which may relate to the immunosuppressive milieu established in the advanced stage of metastatic disease. In conclusion, intermediate monocytes as compared to TIE2-expressing monocytes are a more sensitive diagnostic indicator of colorectal cancer.

Urothelial-Type adenocarcinoma of the prostate mimicking metastatic colorectal adenocarcinoma

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Brian P. Adley

2006-12-01

Full Text Available Adenocarcinoma arising in urinary bladder or prostatic urethra is uncommon. When they occur, the tumor can be mistaken for metastatic lesions, especially from the colon. Here we report the fifth case of a primary urothelial-type adenocarcinoma arising in the prostate which showed enteric differentiation. The patient was a 55 year-old male whose prostatic needle core biopsy showed a high grade adenocarcinoma which was initially thought to be metastatic colon cancer. A follow-up colonoscopy was unremarkable. Subsequent prostatectomy revealed a high grade adenocarcinoma which was positive for cytokeratins 7 and 20, carcinoembryonic antigen, CDX2, and high molecular weight cytokeratin, and negative for prostate specific antigen, prostate specific acid phosphatase and AMACR. A diagnosis of urothelial-type adenocarcinoma of the prostate was rendered. We review the literature regarding this entity, and discuss the differential diagnosis, emphasizing utility of immunohistochemistry in making the diagnosis. Finally, we speculate on the behavior of these rare tumors.

Colorectal cancer patients with low abundance of KRAS mutation may benefit from EGFR antibody therapy.

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Shaorong Yu

Full Text Available Epidermal growth factor receptor monoclonal antibody was approved for treatment of metastatic colorectal cancer patients carrying KRAS wild type DNA. However, recent studies showed that patients with KRAS G13D mutation may benefit from EGFR antibody therapy. In this study we tried to explore whether the abundance of KRAS mutation could affect the efficacy of EGFR antibody therapy. We firstly established a PNA-PCR method which could calculate the percentage of KRAS mutation in total DNA and proved its ability on 47 colorectal cancer samples bearing KRAS mutations. Then we analyzed the correlation between the abundance of KRAS mutations and efficacy of EGFR antibody therapy in another 35 metastatic colorectal cancer patients. We proved that PNA-PCR assay could calculate the abundance of KRAS mutation and the percentage of mutant DNA in tumor cells varied a lot (10.8%∼98.3% on the 47 colorectal cancer patients. The efficacy of EGFR antibody correlated with the abundance of KRAS mutations: in the KRAS mutation less than 30% group, the disease control rate was 44.4% (4/9; the disease control rate of 30∼80% group was 5.6% (1/18 and the >80% group was 12.5% (1/8 (P = 0.038. In summary, our study showed that PNA-PCR method could easily detect the percentage of KRAS mutation in tumor cells and colorectal cancer patients with low abundance of KRAS mutation might benefit from EGFR antibody therapy.

Developments in treating metastatic colorectal cancer: Recent international reports from ASCO 2007 and 2008

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Michel Ducreux

2009-02-01

Full Text Available Michel DucreuxGastro-Intestinal Unit, Institut Gustave-Roussy, Villejuif Cedex, France; Department of Oncology, Paul Brousse University Hospital, Villejuif, France; Paris-Sud XI University, Le Kremlin Bicêtre, FranceIntroduction: Treatment for metastatic colorectal cancer (mCRC, employing various schedules, combinations, and regimens utilizing 5-fluorouracil (5-FU, irinotecan, oxaliplatin, capecitabine, bevacizumab, and cetuximab, currently achieves an overall survival that extends to approximately two years. Major questions regarding optimal management of mCRC await resolution.Methods: A thorough review was conducted of all mCRC abstracts, posters, and other presentations at the 2007 meeting of the American Society of Clinical Oncology (ASCO. Information was analyzed in relationship to previously published research to determine the potential impact of new data on current and future mCRC management strategies and patient outcomes. Updated data presented at ASCO 2008 relevant to these findings was also analyzed.Discussion: Ongoing challenges in mCRC treatment include defining the optimal role of targeted agents such as cetuximab and bevacizumab, elaborating the mechanisms underlying their toxicities, resolving the benefits of adjuvant and neoadjuvant chemotherapy in patients who are candidates for surgical resection, establishing whether there are substantive differences between sequential and combination chemotherapy regimens, and determining the safety and tolerability of chemotherapy in elderly subjects.Conclusion: Recent reports presented at ASCO 2007 and 2008 indicate incremental improvements in care of patients with mCRC. Nevertheless, irinotecan, oxaliplatin, 5-FU, and to an increasing extent the targeted biologic agents bevacizumab and cetuximab continue unchallenged as first-line and later selections.Keywords: chemotherapy, combination chemotherapy, irinotecan, bevacizumab, cetuximab

Dual-specificity tyrosine-regulated kinase 2 is a suppressor and potential prognostic marker for liver metastasis of colorectal cancer.

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Ito, Daisuke; Yogosawa, Satomi; Mimoto, Rei; Hirooka, Shinichi; Horiuchi, Takashi; Eto, Ken; Yanaga, Katsuhiko; Yoshida, Kiyotsugu

2017-08-01

Colorectal cancer is a common cancer and a leading cause of cancer-related death worldwide. The liver is a dominant metastatic site for patients with colorectal cancer. Molecular mechanisms that allow colorectal cancer cells to form liver metastases are largely unknown. Activation of epithelial-mesenchymal transition is the key step for metastasis of cancer cells. We recently reported that dual-specificity tyrosine-regulated kinase 2 (DYRK2) controls epithelial-mesenchymal transition in breast cancer and ovarian serous adenocarcinoma. The aim of this study is to clarify whether DYRK2 regulates liver metastases of colorectal cancer. We show that the ability of cell invasion and migration was abrogated in DYRK2-overexpressing cells. In an in vivo xenograft model, liver metastatic lesions were markedly diminished by ectopic expression of DYRK2. Furthermore, we found that patients whose liver metastases expressed low DYRK2 levels had significantly worse overall and disease-free survival. Given the findings that DYRK2 regulates cancer cell metastasis, we concluded that the expression status of DYRK2 could be a predictive marker for liver metastases of colorectal cancer. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

High Intra- and Inter-Tumoral Heterogeneity of RAS Mutations in Colorectal Cancer

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Marion Jeantet

2016-12-01

Full Text Available Approximately 30% of patients with wild type RAS metastatic colorectal cancer are non-responders to anti-epidermal growth factor receptor monoclonal antibodies (anti-EGFR mAbs, possibly due to undetected tumoral subclones harboring RAS mutations. The aim of this study was to analyze the distribution of RAS mutations in different areas of the primary tumor, metastatic lymph nodes and distant metastasis. A retrospective cohort of 18 patients with a colorectal cancer (CRC was included in the study. Multiregion analysis was performed in 60 spatially separated tumor areas according to the pathological tumor node metastasis (pTNM staging and KRAS, NRAS and BRAF mutations were tested using pyrosequencing. In primary tumors, intra-tumoral heterogeneity for RAS mutation was found in 33% of cases. Inter-tumoral heterogeneity for RAS mutation between primary tumors and metastatic lymph nodes or distant metastasis was found in 36% of cases. Moreover, 28% of tumors had multiple RAS mutated subclones in the same tumor. A high proportion of CRCs presented intra- and/or inter-tumoral heterogeneity, which has relevant clinical implications for anti-EGFR mAbs prescription. These results suggest the need for multiple RAS testing in different parts of the same tumor and/or more sensitive techniques.

A metastatic colon adenocarcinoma harboring BRAF V600E has a durable major response to dabrafenib/trametinib and chemotherapy

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Williams CB

2015-12-01

Full Text Available Casey B Williams,1,* Caitlin McMahon,2,* Siraj M Ali,2 Mark Abramovitz,1 Kirstin A Williams,1 Jessica Klein,1 Heidi McKean,1 Roman Yelensky,2 Thomas J George Jr,3 Julia A Elvin,2 Salil Soman,4 Doron Lipson,2 Juliann Chmielecki,2 Deborah Morosini,2 Vincent A Miller,2 Philip J Stephens,2 Jeffrey S Ross,2,5 Brian Leyland-Jones1 1Avera Cancer Institute, Sioux Falls, SD, USA; 2Foundation Medicine, Inc., Cambridge, MA, USA; 3University of Florida College of Medicine, Gainesville, FL, USA; 4Beth Israel Deaconess Medical Center, Boston, MA, USA; 5Albany Medical College, Albany, NY, USA *These authors contributed equally to this work Abstract: The subset of metastatic colorectal adenocarcinomas that harbor BRAF V600E mutations are aggressive tumors with significantly shortened survival and limited treatment options. Here we present a colorectal cancer patient whose disease progressed through standard chemotherapy and who developed liver metastasis. Comprehensive genomic profiling (FoundationOne® identified a BRAF V600E mutation in the liver lesion, as well as other genomic alterations consistent with colorectal cancers. Combination therapy of dabrafenib and trametinib with standard cytotoxic chemotherapy resulted in a durable major ongoing response for the patient. This report illustrates the utility of comprehensive genomic profiling with personalized targeted therapy for aggressive metastatic colorectal adenocarcinomas. Keywords: oxaliplatin, colorectal adenocarcinoma, combination targeted therapy, BRAF mutations

Hedgehog Signals Mediate Anti-Cancer Drug Resistance in Three-Dimensional Primary Colorectal Cancer Organoid Culture

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Tatsuya Usui

2018-04-01

Full Text Available Colorectal cancer is one of the most common causes of cancer death worldwide. In patients with metastatic colorectal cancer, combination treatment with several anti-cancer drugs is employed and improves overall survival in some patients. Nevertheless, most patients with metastatic disease are not cured owing to the drug resistance. Cancer stem cells are known to regulate resistance to chemotherapy. In the previous study, we established a novel three-dimensional organoid culture model from tumor colorectal tissues of human patients using an air–liquid interface (ALI method, which contained numerous cancer stem cells and showed resistance to 5-fluorouracil (5-FU and Irinotecan. Here, we investigate which inhibitor for stem cell-related signal improves the sensitivity for anti-cancer drug treatment in tumor ALI organoids. Treatment with Hedgehog signal inhibitors (AY9944, GANT61 decreases the cell viability of organoids compared with Notch (YO-01027, DAPT and Wnt (WAV939, Wnt-C59 signal inhibitors. Combination treatment of AY9944 or GANT61 with 5-FU, Irinotecan or Oxaliplatin decreases the cell viability of tumor organoids compared with each anti-cancer drug alone treatment. Treatment with AY9944 or GANT61 inhibits expression of stem cell markers c-Myc, CD44 and Nanog, likely through the decrease of their transcription factor, GLI-1 expression. Combination treatment of AY9944 or GANT61 with 5-FU or Irinotecan also prevents colony formation of colorectal cancer cell lines HCT116 and SW480. These findings suggest that Hedgehog signals mediate anti-cancer drug resistance in colorectal tumor patient-derived ALI organoids and that the inhibitors are useful as a combinational therapeutic strategy against colorectal cancer.

Efficacy and Safety of Regorafenib With 2/1 Schedule for Patients ≥ 75 Years With Metastatic Colorectal Cancer (mCRC) After Failure of 2 Lines of Chemotherapy.

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Petrioli, Roberto; Chirra, Martina; Messuti, Luciana; Fiaschi, Anna Ida; Savelli, Vinno; Martellucci, Ignazio; Francini, Edoardo

2018-02-21

In the CORRECT (patients with metastatic COloRectal Cancer treated with REgorafenib or plaCebo after failure of standard Therapy) trial, regorafenib was proven to extend survival of patients with metastatic colorectal cancer (mCRC) that progressed after all available therapies. Grade 3 to 4 toxicity occurred in 54% of patients, and data on the activity and tolerability of regorafenib in elderly patients were scarce. The aim of this study was to evaluate the efficacy and safety of an alternative schedule, 2-week-on treatment and 1 week-off (2/1 schedule), of regorafenib for elderly patients with mCRC. Patients ≥ 75 years with mCRC who progressed after oxaliplatin- and irinotecan-based chemotherapy received regorafenib on a 2/1 schedule. Potentially frail subjects were identified by G8 screening tool and excluded. The 2-month disease-control rate was the primary endpoint, and the secondary endpoints included safety, progression-free survival (PFS), overall survival (OS), and objective response rate. Between February 2014 and May 2017, 23 patients with mCRC were recruited at our institution. No partial or complete responses were observed, and the stable disease and disease-control rate were 52.2%. The median PFS was 4.8 months (95% confidence interval, 3.8-6.3 months), and the median OS was 8.9 months (95% confidence interval, 6.9-10.6 months). Adverse events were uncommon, and the most frequent grade 3 toxicity adverse events were hand-foot skin reaction (9%) and fatigue (9%). Toxicity-related dose reductions and discontinuations occurred in 5 and 2 patients, respectively. Regorafenib administered with a modified 2/1 schedule to patients who were aged ≥ 75 years and non-frail with treatment-refractory mCRC seems to be tolerable and achieve encouraging results in terms of PFS and OS. Copyright © 2018. Published by Elsevier Inc.

Salinomycin inhibits metastatic colorectal cancer growth and interferes with Wnt/β-catenin signaling in CD133+ human colorectal cancer cells

International Nuclear Information System (INIS)

Klose, Johannes; Eissele, Jana; Volz, Claudia; Schmitt, Steffen; Ritter, Alina; Ying, Shen; Schmidt, Thomas; Heger, Ulrike; Schneider, Martin; Ulrich, Alexis

2016-01-01

The polyether antibiotic Salinomycin (Sal) is regarded as an inhibitor of cancer stem cells. Its effectiveness on human colorectal cancer (CRC) cells in vitro has been demonstrated before. The aim of this study was to establish a murine model to investigate the effectiveness of Sal in vivo. Furthermore, we investigated the impact of Sal on Wnt/β-catenin signaling in human CD133 + CRC cells. The two murine CRC cell lines MC38 and CT26 were used to analyze the impact of Sal on tumor cell proliferation, viability, migration, cell cycle progression and cell death in vitro. For in vivo studies, CT26 cells were injected into syngeneic BALB/c mice to initiate (i) subcutaneous, (ii) orthotopic, or (iii) metastatic CRC growth. Sal was administered daily, 5-Fluoruracil served as a control. For mechanistic studies, the CD133 + and CD133 - subpopulations of human CRC cells were separated by flow cytometry and separately exposed to increasing concentrations of Sal. The impact on Wnt/β-catenin signaling was determined by Western blotting and quantitative PCR. Sal markedly impaired tumor cell viability, proliferation and migration, and induced necrotic cell death in vitro. CRC growth in vivo was likewise inhibited upon Sal treatment. Interference with Wnt signaling and reduced expression of the Wnt target genes Fibronectin and Lgr5 indicates a novel molecular mechanism, mediating anti-tumoral effects of Sal in CRC. Sal effectively impairs CRC growth in vivo. Furthermore, Sal acts as an inhibitor of Wnt/β-catenin signaling. Thus, Salinomycin represents a promising candidate for clinical CRC treatment. The online version of this article (doi:10.1186/s12885-016-2879-8) contains supplementary material, which is available to authorized users

Associations between primary tumor RAS, BRAF and PIK3CA mutation status and metastatic site in patients with chemo-resistant metastatic colorectal cancer

DEFF Research Database (Denmark)

Christensen, Troels Dreier; Palshof, Jesper Andreas; Larsen, Finn Ole

2018-01-01

investigated the association between RAS (KRAS or NRAS), BRAF, PIK3CA mutations and metastatic pattern in patients with metastatic (m) CRC. MATERIAL AND METHODS: This study reviewed Danish biobank and database of patients with mCRC who received cetuximab and irinotecan, independent of RAS mutation status...

Oxidative stress may cause metastatic disease in patients with colorectal cancer

DEFF Research Database (Denmark)

Søndergaard, Edith Smed; Gögenur, Ismail

2014-01-01

Despite surgical treatment of stage II colorectal cancer many patients will experience relapse. Inflammatory and immunologic reactions created due to the surgical stress response result in the production of reactive oxygen species. Oxidative stress in turn, may result in the stimulation of cancer...

The role of microRNA-200 in progression of human colorectal and breast cancer.

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Linda Bojmar

Full Text Available The role of the epithelial-mesenchymal transition (EMT in cancer has been studied extensively in vitro, but involvement of the EMT in tumorigenesis in vivo is largely unknown. We investigated the potential of microRNAs as clinical markers and analyzed participation of the EMT-associated microRNA-200-ZEB-E-cadherin pathway in cancer progression. Expression of the microRNA-200 family was quantified by real-time RT-PCR analysis of fresh-frozen and microdissected formalin-fixed paraffin-embedded primary colorectal tumors, normal colon mucosa, and matched liver metastases. MicroRNA expression was validated by in situ hybridization and after in vitro culture of the malignant cells. To assess EMT as a predictive marker, factors considered relevant in colorectal cancer were investigated in 98 primary breast tumors from a treatment-randomized study. Associations between the studied EMT-markers were found in primary breast tumors and in colorectal liver metastases. MicroRNA-200 expression in epithelial cells was lower in malignant mucosa than in normal mucosa, and was also decreased in metastatic compared to non-metastatic colorectal cancer. Low microRNA-200 expression in colorectal liver metastases was associated with bad prognosis. In breast cancer, low levels of microRNA-200 were related to reduced survival and high expression of microRNA-200 was predictive of benefit from radiotheraphy. MicroRNA-200 was associated with ER positive status, and inversely correlated to HER2 and overactivation of the PI3K/AKT pathway, that was associated with high ZEB1 mRNA expression. Our findings suggest that the stability of microRNAs makes them suitable as clinical markers and that the EMT-related microRNA-200-ZEB-E-cadherin signaling pathway is connected to established clinical characteristics and can give useful prognostic and treatment-predictive information in progressive breast and colorectal cancers.

Circulating tumor cells and their relationship with clinical and morphological characteristics of colorectal cancer

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O I Kit

2018-02-01

Full Text Available Aim. To investigate the dependence of the number of circulating tumor cells in peripheral blood of colorectal cancer patients on the clinical and morphological characteristics of underlying disease. Methods. 91 patients with verified metastatic colorectal cancer Т3-4N1-2М1 were included in the study. The average age of the patients was 61.5±1.7 years. The patients were divided into the study group (laparoscopic surgical treatment, n=44 and control group (open surgical intervention, n=47. The number of circulating tumor cells was determined in CellSearch™ system in the peripheral blood drawn before the intervention. The study of the association of attributes by constructing contingency tables consisted in calculating Pearson’s contingency coefficient c2 with Mantel-Haenszel correction for likelihood (nonparametric correction, estimating statistical significance of contingency and analyzing the tightness of the association by A. Chuprov’s mutual contingency coefficient. Results. We found contingency of the number of circulating tumor cells with clinical and morphological parameters of patients with colorectal cancer. The relationship between potential risk factors and increase of the number of circulating tumor cells in the peripheral blood was observed in all colorectal cancer patients, regardless of the surgical intervention method. The most pronounced association of the number of circulating tumor cells in the peripheral blood of metastatic colorectal cancer patients before surgery according to the mutual contingency coefficient (K was shown to be with present distant metastases (status M1b; K=0.63, p=0.0001 and stage T4 (K=0.56, p=0.0009. Conclusion. The obtained results emphasize the important predictive significance of the circulating tumor cells level in peripheral blood for assessment of the potential for colorectal cancer progression.

Immunotherapy and immunoescape in colorectal cancer

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Mazzolini, Guillermo; Murillo, Oihana; Atorrasagasti, Catalina; Dubrot, Juan; Tirapu, Iñigo; Rizzo, Miguel; Arina, Ainhoa; Alfaro, Carlos; Azpilicueta, Arantza; Berasain, Carmen; Perez-Gracia, José L; Gonzalez, Alvaro; Melero, Ignacio

2007-01-01

Immunotherapy encompasses a variety of interventions and techniques with the common goal of eliciting tumor cell destructive immune responses. Colorectal carcinoma often presents as metastatic disease that impedes curative surgery. Novel strategies such as active immunization with dendritic cells (DCs), gene transfer of cytokines into tumor cells or administration of immunostimulatory monoclonal antibodies (such as anti-CD137 or anti-CTLA-4) have been assessed in preclinical studies and are at an early clinical development stage. Importantly, there is accumulating evidence that chemotherapy and immunotherapy can be combined in the treatment of some cases with colorectal cancer, with synergistic potentiation as a result of antigens cross-presented by dendritic cells and/or elimination of competitor or suppressive T lymphocyte populations (regulatory T-cells). However, genetic and epigenetic unstable carcinoma cells frequently evolve mechanisms of immunoevasion that are the result of either loss of antigen presentation, or an active expression of immunosuppressive substances. Some of these actively immunosuppressive mechanisms are inducible by cytokines that signify the arrival of an effector immune response. For example, induction of 2, 3 indoleamine dioxygenase (IDO) by IFNγ in colorectal carcinoma cells. Combinational and balanced strategies fostering antigen presentation, T-cell costimulation and interference with immune regulatory mechanisms will probably take the stage in translational research in the treatment of colorectal carcinoma. PMID:17990348

Pulmonary metastasectomy in colorectal cancer: a prospective study of demography and clinical characteristics of 543 patients in the Spanish colorectal metastasectomy registry (GECMP-CCR).

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Embún, R; Fiorentino, F; Treasure, T; Rivas, J J; Molins, L

2013-05-28

To capture an accurate contemporary description of the practice of pulmonary metastasectomy for colorectal carcinoma in one national healthcare system. A national registry set up in Spain by Grupo Español de Cirugía Metástasis Pulmonares de Carcinoma Colo-Rectal (GECMP-CCR). 32 Spanish thoracic units. All patients with one or more histologically proven lung metastasis removed by surgery between March 2008 and February 2010. Pulmonary metastasectomy for one or more pulmonary nodules proven to be metastatic colorectal carcinoma. The age and sex of the patients having this surgery were recorded with the number of metastases removed, the interval between the primary colorectal cancer operation and the pulmonary metastasectomy, and the carcinoembryonic antigen level. Also recorded were the practices with respect to mediastinal lymphadenopathy and coexisting liver metastases. Data were available on 543 patients from 32 units (6-43/unit). They were aged 32-88 (mean 65) years, and 65% were men. In 55% of patients, there was a solitary metastasis. The median interval between the primary cancer resection and metastasectomy was 28 months and the serum carcinoembryonic antigen was low/normal in the majority. Liver metastatic disease was present in 29% of patients at some point prior to pulmonary metastasectomy. Mediastinal lymphadenectomy varied from 9% to 100% of patients. The data represent a prospective comprehensive national data collection on pulmonary metastasectomy. The practice is more conservative than the impression gained when members of the European Society of Thoracic Surgeons were surveyed in 2006/2007 but is more inclusive than would be recommended on the basis of recent outcome analyses. Further analyses on the morbidity associated with this surgery and the correlation between imaging studies and pathological findings are being published separately by GECMP-CCR.

Effect of HK2, PKM2 and LDHA on Cetuximab efficacy in metastatic colorectal cancer.

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Wang, Haohua; Peng, Roujun; Chen, Xiuxing; Jia, Rui; Huang, Chunyue; Huang, Yuanyuan; Xia, Liangping; Guo, Guifang

2018-04-01

Although hexokinase (HK) 2, pyruvate kinase muscle (PKM) isozyme 2 and lactate dehydrogenase (LDH) A predict the efficacy of medicines in various solid tumors, their ability to predict the efficacy of cetuximab in metastatic colorectal cancer (mCRC) remains unclear. mCRC patients with pathological specimens who received cetuximab and chemotherapy from 2005 to 2015 in the present institution were enrolled. Immunohistochemistry was used to detect HK2, PKM2 and LDHA expression. SPSS20 was used for statistical analysis. A total of 68 patients were included; 33 received cetuximab plus chemotherapy as first-line therapy, and the rest, as second- or later-line therapy. HK2 expression levels were increased in cancer compared with normal tissue (75.4% vs. 40%; P<0.001), however PKM2 (P=0.243) and LDHA (P=0.067) expression levels were not. For progression-free survival (PFS) with first-line cetuximab plus chemotherapy, patients with high HK2 expression exhibited longer PFS compared with those with low HK2 expression (23.9 months vs. 6.9 months; P=0.021). However, this positive association was absent in 35 cases administered first-line chemotherapy alone (13.4 months vs. 13.5 months; P=0.539). LDHA expression was associated with the PFS of patients receiving first-line chemotherapy (18.3 and 10.1 months for high and low expression, respectively; P=0.005), whereas this association was absent in cetuximab plus chemotherapy cases (19.9 months vs. 12 months; P=0.522). Furthermore, high LDHA expression correlated with high overall response rate (ORR) (72.2% vs. 15.4%, P=0.006) for chemotherapy, however not disease control rate (DCR) (P=0.074). Neither DCR nor ORR were associated with HK2 expression. PKM2 expression did not affect PFS, DCR or ORR. LDHA expression (P=0.005), pathological differentiation (P=0.019) and synchronous/metachronous metastasis (P=0.014) were independent predictive factors of PFS for all first-line patients, and tumor differentiation (P=0.002) was associated

Aflibercept as a second-line therapy in metastatic colorectal cancer: A limited Indian experience

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Govind Babu

2016-01-01

Full Text Available Introduction: Aflibercept in combination with FOLFIRI has been shown to improve overall survival in the pivotal VELOUR study. Aflibercept has not yet been marketed in India. Sanofi has made available this drug for Indian patients under a program called Named Patient Access Program (NPP. We present a limited clinical experience with the use of aflibercept at our center. Materials and Methods: We analyzed the data of the patients who received aflibercept under NPP. Aflibercept was given in combination with FOLFIRI as second-line for patients who progressed on oxaliplatin based therapy. Aflibercept was given at 4 mg/kg intravenous (IV every 15 days. Chemotoxicities were assessed as per CTCAE. Response evaluation was done every four cycles. Results: Five patients were enrolled. The median age was 34 years. The median number of aflibercept cycles administered was 12. Common grade 2/3 toxicities were mucositis, diarrhea, neutropenia thrombocytopenia, and hypertension seen in three (60%, three (60%, two (40%, two (40%, and one patient respectively. After four cycles, the response was assessed as: One complete remission (CR, three partial remissions (PR, and one progressive disease (PD. Three patients completed 12 cycles of chemotherapy and aflibercept. At the end of 12 cycles, one patient still in CR and two patients were in PR. Four patients were alive till date. Conclusion: As we had very less number of patients, it was very difficult to compare it with VELOUR data. It is one of option as second-line in metastatic colorectal cancer (mCRC who progressed on oxaliplatin chemotherapy. Mucositis, diarrhea, and hematological toxicity were the most common toxicity in our patient.

Skin toxicity and quality of life in patients with metastatic colorectal cancer during first-line panitumumab plus FOLFIRI treatment in a single-arm phase II study

International Nuclear Information System (INIS)

Thaler, Josef; Köhne, Claus-Henning; Karthaus, Meinolf; Mineur, Laurent; Greil, Richard; Letocha, Henry; Hofheinz, Ralf; Fernebro, Eva; Gamelin, Erick; Baños, Ana

2012-01-01

Integument-related toxicities are common during epidermal growth factor receptor (EGFR)-targeted therapy. Panitumumab is a fully human monoclonal antibody targeting the EGFR that significantly improves progression-free survival when added to chemotherapy in patients with metastatic colorectal cancer who have wild-type (WT) KRAS tumours. Primary efficacy and tolerability results from a phase II single-arm study of first-line panitumumab plus FOLFIRI in patients with metastatic colorectal cancer have been reported. Here we report additional descriptive tolerability and quality of life data from this trial. Integument-related toxicities and quality of life were analysed; toxicities were graded using modified National Cancer Institute Common Toxicity Criteria. Kaplan-Meier estimates of time to and duration of first integument-related toxicity were prepared. Quality of life was measured using EuroQoL EQ-5D and EORTC QLQ-C30. Best overall response was analysed by skin toxicity grade and baseline quality of life. Change in quality of life was analysed by skin toxicity severity. 154 patients were enrolled (WT KRAS n = 86; mutant KRAS n = 59); most (98%) experienced integument-related toxicities (most commonly rash [42%], dry skin [40%] and acne [36%]). Median time to first integument-related toxicity was 8 days; median duration was 334 days. Overall, proportionally more patients with grade 2+ skin toxicity responded (56%) compared with those with grade 0/1 (29%). Mean overall EQ-5D health state index scores (0.81 vs. 0.78), health rating scores (72.5 vs. 71.0) and QLQ-C30 global health status scores (65.8 vs. 66.7) were comparable at baseline vs. safety follow-up (8 weeks after completion), respectively and appeared unaffected by skin toxicity severity. First-line panitumumab plus FOLFIRI has acceptable tolerability and appears to have little impact on quality of life, despite the high incidence of integument-related toxicity. ClinicalTrials.gov NCT00508404

Skin toxicity and quality of life in patients with metastatic colorectal cancer during first-line panitumumab plus FOLFIRI treatment in a single-arm phase II study

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Thaler Josef

2012-09-01

Full Text Available Abstract Background Integument-related toxicities are common during epidermal growth factor receptor (EGFR-targeted therapy. Panitumumab is a fully human monoclonal antibody targeting the EGFR that significantly improves progression-free survival when added to chemotherapy in patients with metastatic colorectal cancer who have wild-type (WT KRAS tumours. Primary efficacy and tolerability results from a phase II single-arm study of first-line panitumumab plus FOLFIRI in patients with metastatic colorectal cancer have been reported. Here we report additional descriptive tolerability and quality of life data from this trial. Methods Integument-related toxicities and quality of life were analysed; toxicities were graded using modified National Cancer Institute Common Toxicity Criteria. Kaplan-Meier estimates of time to and duration of first integument-related toxicity were prepared. Quality of life was measured using EuroQoL EQ-5D and EORTC QLQ-C30. Best overall response was analysed by skin toxicity grade and baseline quality of life. Change in quality of life was analysed by skin toxicity severity. Results 154 patients were enrolled (WT KRAS n = 86; mutant KRAS n = 59; most (98% experienced integument-related toxicities (most commonly rash [42%], dry skin [40%] and acne [36%]. Median time to first integument-related toxicity was 8 days; median duration was 334 days. Overall, proportionally more patients with grade 2+ skin toxicity responded (56% compared with those with grade 0/1 (29%. Mean overall EQ-5D health state index scores (0.81 vs. 0.78, health rating scores (72.5 vs. 71.0 and QLQ-C30 global health status scores (65.8 vs. 66.7 were comparable at baseline vs. safety follow-up (8 weeks after completion, respectively and appeared unaffected by skin toxicity severity. Conclusions First-line panitumumab plus FOLFIRI has acceptable tolerability and appears to have little impact on quality of life, despite the high incidence of integument

Effect of cordycepin (3'-deoxyadenosine) on hematogenic lung metastatic model mice.

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Nakamura, Kazuki; Konoha, Keiko; Yoshikawa, Noriko; Yamaguchi, Yu; Kagota, Satomi; Shinozuka, Kazumasa; Kunitomo, Masaru

2005-01-01

We investigated the anti-metastatic effect of cordycepin (3'-deoxyadenosine) on a hematogenic metastatic mouse model which was intravenously injected with B16-BL6 melanoma cells. A 3-hour exposure to various concentrations of cordycepin (0.3, 1 and 3 microg/ml) dose-dependently reduced the number of nodules formed in lung at 15 days after the tumor injection. To elucidate the mechanism of this anti-metastatic effect, we examined the effect of cordycepin on the invasiveness of B16-BL6 cells using a chemo-invasion chamber in vitro. The B16-BL6 cells pretreated with cordycepin (3 microg/ml) for 3 hours showed a significant decrease in invasiveness. Under the same conditions, however, cordycepin did not influence the growth curve of B16-BL6 cells at concentrations up to 3 microg/ml. These results suggest that cordycepin exerts an anti-metastatic action, in part, by inhibiting the invasiveness of mouse melanoma cells.

Prognostic value of baseline seric Syndecan-1 in initially unresectable metastatic colorectal cancer patients: a simple biological score.

Science.gov (United States)

Jary, Marine; Lecomte, Thierry; Bouché, Olivier; Kim, Stefano; Dobi, Erion; Queiroz, Lise; Ghiringhelli, Francois; Etienne, Hélène; Léger, Julie; Godet, Yann; Balland, Jérémy; Lakkis, Zaher; Adotevi, Olivier; Bonnetain, Franck; Borg, Christophe; Vernerey, Dewi

2016-11-15

In first-line metastatic colorectal cancer (mCRC), baseline prognostic factors allowing death risk and treatment strategy stratification are lacking. Syndecan-1 (CD138) soluble form was never described as a prognostic biomarker in mCRC. We investigated its additional prognostic value for overall survival (OS). mCRC patients with unresectable disease at diagnosis were treated with bevacizumab-based chemotherapy in two independent prospective clinical trials (development set: n = 126, validation set: n = 51, study NCT00489697 and study NCT00544011, respectively). Serums were collected at baseline for CD138 measurement. OS determinants were assessed and, based on the final multivariate model, a prognostic score was proposed. Two independent OS prognostic factors were identified: Lactate Dehydrogenase (LDH) high level (p = 0.0066) and log-CD138 high level (p = 0.0190). The determination of CD138 binary information (cutoff: 75 ng/mL) allowed the assessment of a biological prognostic score with CD138 and LDH values, identifying three risk groups for death (median OS= 38.9, 30.1 and 19.8 months for the low, intermediate and high risk groups, respectively; p value for OS, in mCRC patients. A simple biological scoring system is proposed including LDH and CD138 binary status values. © 2016 UICC.

Colorectal Cancer Liver Metastasis: Evolving Paradigms and Future DirectionsSummary

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Luai R. Zarour

2017-03-01

Full Text Available In patients with colorectal cancer (CRC that metastasizes to the liver, there are several key goals for improving outcomes including early detection, effective prognostic indicators of treatment response, and accurate identification of patients at high risk for recurrence. Although new therapeutic regimens developed over the past decade have increased survival, there is substantial room for improvement in selecting targeted treatment regimens for the patients who will derive the most benefit. Recently, there have been exciting developments in identifying high-risk patient cohorts, refinements in the understanding of systemic vs localized drug delivery to metastatic niches, liquid biomarker development, and dramatic advances in tumor immune therapy, all of which promise new and innovative approaches to tackling the problem of detecting and treating the metastatic spread of CRC to the liver. Our multidisciplinary group held a state-of-the-science symposium this past year to review advances in this rapidly evolving field. Herein, we present a discussion around the issues facing treatment of patients with CRC liver metastases, including the relationship of discrete gene signatures with prognosis. We also discuss the latest advances to maximize regional and systemic therapies aimed at decreasing intrahepatic recurrence, review recent insights into the tumor microenvironment, and summarize advances in noninvasive multimodal biomarkers for early detection of primary and recurrent disease. As we continue to advance clinically and technologically in the field of colorectal tumor biology, our goal should be continued refinement of predictive and prognostic studies to decrease recurrence after curative resection and minimize treatment toxicity to patients through a tailored multidisciplinary approach to cancer care. Keywords: Colorectal Cancer Liver Metastasis, Biomarkers, Hepatic Arterial Infusion, High-Risk Colorectal

Evolving role of cetuximab in the treatment of colorectal cancer

International Nuclear Information System (INIS)

Schuch, Gunter; Kobold, Sebastian; Bokemeyer, Carsten

2009-01-01

In recent years, the monoclonal epidermal growth factor receptor (EGFR)-targeting antibody cetuximab was introduced into systemic therapy of colorectal cancer and gained an established role in the treatment of this disease. Cetuximab was shown to be active as a single agent in chemorefractory metastatic disease as well as in combination with varying chemotherapies. Recently, randomized trials demonstrated the activity of cetuximab combinations in the first-line setting of metastatic colorectal cancer. Interestingly, the activity of cetuximab was restricted to patients with KRAS wildtype tumors, as was seen with panitumumab, another EGFR antibody. While 60%–70% of tumors harbor KRAS wildtype genes, 30%–40% of tumors express oncogenic KRAS with mutations in codons 12 and 13 causing constitutive activation of signaling cascades downstream of EGFR and resistance to EGFR blockade. Since proof of KRAS wildtype status became a prerequisite for cetuximab treatment, KRAS testing is being established throughout the world. Future trials will address the question which part of the KRAS wildtype cohort will benefit from EGFR inhibition and how to identify those patients. Additionally, new strategies for treatment of KRAS mutated tumors are strongly needed. Recent developments and future strategies will be summarized

MicroRNA-126 and epidermal growth factor-like domain 7-an angiogenic couple of importance in metastatic colorectal cancer. Results from the Nordic ACT trial

DEFF Research Database (Denmark)

Hansen, T F; Christensen, René dePont; Andersen, R F

2013-01-01

Background:This study investigated the clinical importance of linked angiogenetic biomarkers to chemotherapy, combined with the anti-vascular endothelial growth factor A (anti-VEGF-A), as a first-line treatment in patients with metastatic colorectal cancer (mCRC).Methods:A total of 230 patients......-like domain 7 (EGFL7) protein was visualised and quantified using immunohistochemistry.Results:High tumour expression of miRNA-126 was significantly related to a longer progression-free survival. The independent prognostic value of miRNA-126 was confirmed using a Cox regression analysis (hazard ratio=0.49, 95...... on the prognostic value of miRNA-126 in mCRC and may suggest a relationship between treatment efficacy and EGFL7 expression. As miRNA-126 may target VEGF-A as well as EGFL7, the results may provide predictive information in relation to next-generation anti-angiogenetics....

Clinical significance of the BRAFV600E mutation in Asian patients with colorectal cancer.

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Cheng, Hou-Hsuan; Lin, Jen-Kou; Chen, Wei-Shone; Jiang, Jeng-Kai; Yang, Shung-Haur; Chang, Shih-Ching

2018-06-04

To investigate the clinicopathological features and prognostic significance of the BRAFV600E mutation in Asian patients with colorectal cancer. We retrospectively reviewed the medical records of 1969 patients with colorectal cancer admitted to Taipei Veterans General Hospital for surgical treatment between 2000 and 2013. The measured endpoint was overall survival after surgery. The prognostic value of the BRAFV600E mutation was analyzed using the log-rank test and Cox regression analysis. The BRAFV600E mutation was detected in 106 (5.4%) patients and associated with female gender, abnormal cancer antigen (CA)19-9 at diagnosis, microsatellite status, right-sided primary tumors, mucinous histology, poor differentiation, and lymphovascular invasion. Metastatic patterns were more common in non-regional lymph node metastasis (20.8 vs. 7.4%, p = 0.06) and peritoneal seeding (41. vs. 21.2%, p = 0.04). Mutations were not prognostic in the overall survival of the entire study group but only in specific patients: age < 65, normal carcinoembryonic antigen at diagnosis, and stage IV disease. The BRAFV600E mutation was associated with distinct clinicopathological features and metastatic patterns. The overall survival rate was lower in selected colorectal patients with the BRAFV600E mutation.

Cell-free DNA in healthy individuals, noncancerous disease and strong prognostic value in colorectal cancer

DEFF Research Database (Denmark)

Spindler, Karen-Lise Garm; Appelt, Ane L; Pallisgaard, Niels

2014-01-01

The purpose was to investigate total cell-free DNA (cfDNA) in colorectal cancer (CRC) patients during treatment with second-line chemotherapy and in healthy controls and patients with different comorbidities. Patient treated with second-line irinotecan for metastatic CRC (n = 100), a cohort...

GUCY2C-directed CAR-T cells oppose colorectal cancer metastases without autoimmunity.

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Magee, Michael S; Kraft, Crystal L; Abraham, Tara S; Baybutt, Trevor R; Marszalowicz, Glen P; Li, Peng; Waldman, Scott A; Snook, Adam E

2016-01-01

Adoptive T-cell therapy (ACT) is an emerging paradigm in which T cells are genetically modified to target cancer-associated antigens and eradicate tumors. However, challenges treating epithelial cancers with ACT reflect antigen targets that are not tumor-specific, permitting immune damage to normal tissues, and preclinical testing in artificial xenogeneic models, preventing prediction of toxicities in patients. In that context, mucosa-restricted antigens expressed by cancers exploit anatomical compartmentalization which shields mucosae from systemic antitumor immunity. This shielding may be amplified with ACT platforms employing antibody-based chimeric antigen receptors (CARs), which mediate MHC-independent recog-nition of antigens. GUCY2C is a cancer mucosa antigen expressed on the luminal surfaces of the intestinal mucosa in mice and humans, and universally overexpressed by colorectal tumors, suggesting its unique utility as an ACT target. T cells expressing CARs directed by a GUCY2C-specific antibody fragment recognized GUCY2C, quantified by expression of activation markers and cytokines. Further, GUCY2C CAR-T cells lysed GUCY2C-expressing, but not GUCY2C-deficient, mouse colorectal cancer cells. Moreover, GUCY2C CAR-T cells reduced tumor number and morbidity and improved survival in mice harboring GUCY2C-expressing colorectal cancer metastases. GUCY2C-directed T cell efficacy reflected CAR affinity and surface expression and was achieved without immune-mediated damage to normal tissues in syngeneic mice. These observations highlight the potential for therapeutic translation of GUCY2C-directed CAR-T cells to treat metastatic tumors, without collateral autoimmunity, in patients with metastatic colorectal cancer.

Role of physical activity and diet after colorectal cancer diagnosis.

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Van Blarigan, Erin L; Meyerhardt, Jeffrey A

2015-06-01

This review summarizes the evidence regarding physical activity and diet after colorectal cancer diagnosis in relation to quality of life, disease recurrence, and survival. There have been extensive reports on adiposity, inactivity, and certain diets, particularly those high in red and processed meats, and increased risk of colorectal cancer. Only in the past decade have data emerged on how such lifestyle factors are associated with outcomes in colorectal cancer survivors. Prospective observational studies have consistently reported that physical activity after colorectal cancer diagnosis reduces mortality. A meta-analysis estimated that each 15 metabolic equivalent task-hour per week increase in physical activity after colorectal cancer diagnosis was associated with a 38% lower risk of mortality. No randomized controlled trials have been completed to confirm that physical activity lowers risk of mortality among colorectal cancer survivors; however, trials have shown that physical activity, including structured exercise, is safe for colorectal cancer survivors (localized to metastatic stage, during and after treatment) and improves cardiorespiratory fitness and physical function. In addition, prospective observational studies have suggested that a Western dietary pattern, high carbohydrate intake, and consuming sugar-sweetened beverages after diagnosis may increase risk of colorectal cancer recurrence and mortality, but these data are limited to single analyses from one of two US cohorts. Additional data from prospective studies and randomized controlled trials are needed. Nonetheless, on the basis of the available evidence, it is reasonable to counsel colorectal cancer survivors to engage in regular physical activity and limit consumption of refined carbohydrates, red and processed meats, and sugar-sweetened beverages. © 2015 by American Society of Clinical Oncology.

Activity and toxicity of oxaliplatin and bolus fluorouracil plus leucovorin in pretreated colorectal cancer patients: a phase 2. study

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Ferraresi, V.; Buccilli, A.; Giannarelli, D.; Ciccarese, M. [Regina Elena Cancer Institute, Rome (Italy). Dept. of Medical Oncology; Giampaolo, M.A.; Gabriele, A.; Buccilli, A.; Gamucci, T. [Azienda Sanitaria Locale, Frosinone (Italy). Complex Operative Unit of Medical Oncology

2005-06-15

The aim of the current study was to evaluate the activity and toxicity of a combination of oxaliplatin with bolus fluorouracil and leucovorin in colorectal cancer (CRC) patients pretreated for advanced disease with various schedules including continuous fluorouracil infusion. Thirty consecutive patients with pretreated advanced CRC received oxaliplatin 130 mg/m{sup 2} by 2-h infusion dl, leucovorin 100 mg/m{sup 2} by 1-h infusion followed by fluorouracil 425 mg/m{sup 2} i.v. bolus from day 1 to 3 every 3 weeks for a maximum of 6 cycles. The best overall response rate in an intent-to-treat analysis was 13% (2 complete responses and 2 partial responses) (95% CI, 1.2-25.5%) and 37% of patients obtained stable disease with a tumor growth control rate of 50% (95% CI, 32.1-67.9%). The median progression-free survival was 4.0 months (95% CI, 1.4-6.5 months) and median overall survival was 12.0 months (95% CI, 9.9-14.1 months). The independent prognostic factors for improved overall survival were a good performance status and a response/stabilization of disease to chemotherapy. Severe neutropenia was quite common (43.3% of patients and 14.4% of cycles), although complicated by fever only in one case (3.3% of patients). There was one toxic death. In conclusion, the study combination showed an interesting rate of tumor growth control in a cohort of patients previously treated for advanced disease with various schedules including continuous fluorouracil infusion.

Let-7 miRNA-binding site polymorphism in the KRAS 3′UTR; colorectal cancer screening population prevalence and influence on clinical outcome in patients with metastatic colorectal cancer treated with 5-fluorouracil and oxaliplatin +/− cetuximab

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Kjersem Janne B

2012-11-01

Full Text Available Abstract Background Recent studies have reported associations between a variant allele in a let-7 microRNA complementary site (LCS6 within the 3′untranslated region (3′UTR of KRAS (rs61764370 and clinical outcome in metastatic colorectal cancer (mCRC patients receiving cetuximab. The variant allele has also been associated with increased cancer risk. We aimed to reveal the incidence of the variant allele in a colorectal cancer screening population and to investigate the clinical relevance of the variant allele in mCRC patients treated with 1st line Nordic FLOX (bolus 5-fluorouracil/folinic acid and oxaliplatin +/− cetuximab. Methods The feasibility of the variant allele as a risk factor for CRC was investigated by comparing the LCS6 gene frequencies in 197 CRC patients, 1060 individuals with colorectal polyps, and 358 healthy controls. The relationship between clinical outcome and LCS6 genotype was analyzed in 180 mCRC patients receiving Nordic FLOX and 355 patients receiving Nordic FLOX + cetuximab in the NORDIC-VII trial (NCT00145314. Results LCS6 frequencies did not vary between CRC patients (23%, individuals with polyps (20%, and healthy controls (20% (P = 0.50. No statistically significant differences were demonstrated in the NORDIC-VII cohort even if numerically increased progression-free survival (PFS and overall survival (OS were found in patients with the LCS6 variant allele (8.5 (95% CI: 7.3-9.7 months versus 7.8 months (95% CI: 7.4-8.3 months, P = 0.16 and 23.5 (95% CI: 21.6-25.4 months versus 19.5 months (95% CI: 17.8-21.2 months, P = 0.31, respectively. Addition of cetuximab seemed to improve response rate more in variant carriers than in wild-type carriers (from 35% to 57% versus 44% to 47%, however the difference was not statistically significant (interaction P = 0.16. Conclusions The LCS6 variant allele does not seem to be a risk factor for development of colorectal polyps or CRC. No statistically significant effect of the

Contemporary surgical management of synchronous colorectal liver metastases [version 1; referees: 2 approved

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Danielle Collins

2017-04-01

Full Text Available Historically, the 5-year survival rates for patients with stage 4 (metastatic colorectal cancer were extremely poor (5%; however, with advances in systemic chemotherapy combined with an ability to push the boundaries of surgical resection, survival rates in the range of 25–40% can be achieved. This multimodal approach of combining neo-adjuvant strategies with surgical resection has raised a number of questions regarding the optimal management and timing of surgery. For the purpose of this review, we will focus on the treatment of stage 4 colorectal cancer with synchronous liver metastases.

Predictive factors of long-term colorectal cancer survival after ultrasound-controlled ablation of hepatic metastases.

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Hernández-Socorro, Carmen Rosa; Saavedra, Pedro; Ramírez Felipe, José; Bohn Sarmiento, Uriel; Ruiz-Santana, Sergio

2017-04-21

The risk factors associated to long-term survival were assessed in patients with liver metastases of colorectal carcinoma undergoing ablative therapies. Single-centre cohort study, retrospectively analysed and prospectively collected consecutive patients with unresectable metastatic liver disease of colorectal carcinoma treated with ablative therapies between 1996 and 2013. Factors associated with survival time were identified using Cox's proportional hazard model with time-dependent covariates. A forward variable selection based on Akaike information criterion was performed. Relative risk and 95% confidence intervals for each factor were calculated. Statistical significance was set as P<.05. Seventy-five patients with liver metastases of colorectal cancer, with a mean age of 65.6 (10.3) underwent 106 treatments. Variables selected were good quality of life (RR 0.308, 95% CI 0.150-0.632) and tumour extension (RR 3.070, 95% CI 1.776-5.308). The median overall survival was 18.5 months (95% CI 17.4-24.4). The survival prognosis in median was 13.5 vs. 23.4 months for patients with and without tumour extension, and 23.0 vs. 12.8 months for patients with good and fair or poor quality of life, respectively. Good quality of life and tumour extension were the only statistically significant predictors of long-term survival in patients of colorectal carcinoma with liver metastatic disease undergoing ablative treatment with ultrasound. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

Granulocyte-macrophage stimulating factor (GM-CSF increases circulating dendritic cells but does not abrogate suppression of adaptive cellular immunity in patients with metastatic colorectal cancer receiving chemotherapy

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Martinez Micaela

2012-01-01

Full Text Available Abstract Background Advanced cancer and chemotherapy are both associated with immune system suppression. We initiated a clinical trial in patients receiving chemotherapy for metastatic colorectal cancer to determine if administration of GM-CSF in this setting was immunostimulatory. Methods Between June, 2003 and January, 2007, 20 patients were enrolled in a clinical trial (NCT00257322 in which they received 500 ug GM-CSF daily for 4 days starting 24 hours after each chemotherapy cycle. There were no toxicities or adverse events reported. Blood was obtained before chemotherapy/GM-CSF administration and 24 hours following the final dose of GM-CSF and evaluated for circulating dendritic cells and adaptive immune cellular subsets by flow cytometry. Peripheral blood mononuclear cell (PBMC expression of γ-interferon and T-bet transcription factor (Tbx21 by quantitative real-time PCR was performed as a measure of Th1 adaptive cellular immunity. Pre- and post-treatment (i.e., chemotherapy and GM-CSF samples were evaluable for 16 patients, ranging from 1 to 5 cycles (median 3 cycles, 6 biologic sample time points. Dendritic cells were defined as lineage (- and MHC class II high (+. Results 73% of patients had significant increases in circulating dendritic cells of ~3x for the overall group (5.8% to 13.6%, p = 0.02 and ~5x excluding non-responders (3.2% to 14.5%, p Tbx21 levels declined by 75% following each chemotherapy cycle despite administration of GM-CSF (p = 0.02. PBMC γ-interferon expression, however was unchanged. Conclusions This clinical trial confirms the suppressive effects of chemotherapy on Th1 cellular immunity in patients with metastatic colorectal cancer but demonstrates that mid-cycle administration of GM-CSF can significantly increase the proportion of circulating dendritic cells. As the role of dendritic cells in anti-tumor immunity becomes better defined, GM-CSF administration may provide a non-toxic intervention to augment this arm

A gene expression predictor of response to EGFR-targeted therapy stratifies progression-free survival to cetuximab in KRAS wild-type metastatic colorectal cancer

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Black Esther P

2009-05-01

Full Text Available Abstract Background The anti-EGFR monoclonal antibody cetuximab is used in metastatic colorectal cancer (CRC, and predicting responsive patients garners great interest, due to the high cost of therapy. Mutations in the KRAS gene occur in ~40% of CRC and are a negative predictor of response to cetuximab. However, many KRAS-wildtype patients do not benefit from cetuximab. We previously published a gene expression predictor of sensitivity to erlotinib, an EGFR inhibitor. The purpose of this study was to determine if this predictor could identify KRAS-wildtype CRC patients who will benefit from cetuximab therapy. Methods Microarray data from 80 metastatic CRC patients subsequently treated with cetuximab were extracted from the study by Khambata-Ford et al. The study included KRAS status, response, and PFS for each patient. The gene expression data were scaled and analyzed using our predictive model. An improved predictive model of response was identified by removing features in the 180-gene predictor that introduced noise. Results Forty-three of eighty patients were identified as harboring wildtype-KRAS. When the model was applied to these patients, the predicted-sensitive group had significantly longer PFS than the predicted-resistant group (median 88 days vs. 56 days; mean 117 days vs. 63 days, respectively, p = 0.008. Kaplan-Meier curves were also significantly improved in the predicted-sensitive group (p = 0.0059, HR = 0.4109. The model was simplified to 26 of the original 180 genes and this further improved stratification of PFS (median 147 days vs. 56.5 days in the predicted sensitive and resistant groups, respectively, p Conclusion Our model of sensitivity to EGFR inhibition stratified PFS following cetuximab in KRAS-wildtype CRC patients. This study represents the first true external validation of a molecular predictor of response to cetuximab in KRAS-WT metastatic CRC. Our model may hold clinical utility for identifying patients responsive

Anticoagulant therapy for venous thromboembolism detected by Doppler ultrasound in patients with metastatic colorectal cancer receiving bevacizumab

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Suenaga M

2015-01-01

Full Text Available Mitsukuni Suenaga, Nobuyuki Mizunuma, Eiji Shinozaki, Satoshi Matsusaka, Masato Ozaka, Mariko Ogura, Keisho Chin, Toshiharu Yamaguchi Department of Gastroenterology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan Background: Doppler ultrasound imaging is useful for management of venous thromboembolism associated with a subclavicular implantable central venous access system in patients receiving bevacizumab (Bev. We investigated the efficacy and safety of our anticoagulant regimen based on Doppler findings.Methods: Patients aged ≤75 years with metastatic colorectal cancer, no history of thromboembolism, and no prior use of Bev received chemotherapy plus Bev. Doppler ultrasound imaging of the deep venous system to detect thrombosis was performed after the first course of Bev and repeated after the third course in patients with asymptomatic thrombosis. Indications for anticoagulant therapy in patients with asymptomatic thrombosis were as follows: enlarging thrombus (E, thrombus >40 mm in diameter (S, thrombus involving the superior vena cava (C, and decreased blood flow (V.Results: Among 79 patients enrolled in this study, asymptomatic thrombosis was detected in 56 patients (70.9% by Doppler ultrasound imaging after the first course of Bev and there was no thrombus in 23 patients (29.1%. Of these 56 patients, 11 (19.6% received anticoagulant therapy with warfarin, including eight after the first course and three after follow-up imaging. S + V was observed in four of 11 patients (36.4%, as well as V in two (18.2%, S + V + C in one (9.1%, E + S + V in one (9.1%, E + C in one (9.1%, E in one (9.1%, and C in one (9.1%. All patients resumed chemotherapy, including seven who resumed Bev. Improvement or stabilization of thrombi was achieved in ten patients (90.9%. Only one patient had symptomatic thromboembolism. Mild bleeding due to anticoagulant therapy occurred in six patients (54.5%, but there were no treatment

Colorectal cancer in younger population: our experience

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Amini, A.Q.; Samo, K.A.; Memon, A.S.

2013-01-01

Objective: To promote awareness regarding increased occurrence of colorectal cancer in younger population and its clinicopathological features compared to older patients. Methods: The cross-sectional study was conducted from February 2010 to January 2011 on patients with diagnosis of colorectal carcinoma admitted through emergency or outpatient departments to Surgical Unit 5, Civil Hospital, Karachi. Data regarding age, gender, presentation, site of tumour, surgery performed and Dukes staging was collected and analysed. Results: A total of 23 patients were operated during the study period: 13 (56.52%) males and 10 (43.47%) females. Of them 12 (52.17%) were below the age of 40 years, while 3 (13.04%) patients were in the 11-20 age group. In 7 (30.4%) patients, tumour was irresectable at the time of presentation so a palliative procedure (diversion colostomy or ileostomy) was performed. There was a higher proportion of younger patients with metastatic disease at the time of presentation (n=9; 75%) while 10 out of 12 patients in the younger age group (83.3%) had a tumour of left colon, particularly rectum. Conclusion: Although colorectal cancer is usually a disease of older patients, it is increasingly becoming more common in younger population. Data suggests a leftward distribution for colorectal carcinoma and that younger patients present with more advanced disease and poorer prognosis. (author)

Revaluation on detection of metastatic cancer of the colorectum with barium enema. Comparison with computed tomography and colonoscopy

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Watari, Jiro; Mizukami, Yusuke; Tanabe, Hirotaka

1996-01-01

The findings with barium enema were analyzed and compared to those with computed tomography and colonoscopy in 15 patients with metastatic cancer of the colorectum, which were from 8 gastric, 2 colonic, 2 ovarian, 1 pancreatic, 1 prostatic carcinomas and 1 unknown origin. Primary cancers of intra-abdominal cavity origin tended to make multiple colorectal metastases (91.7%). With barium enema colonic and rectal involvement was mostly expressed as the tethered type and the diffuse type by Ishikawa's classification, respectively. Computed tomography detected direct tumor invasion to the colorectum in 4 cases. Of the other 11 cases, 8 patients (72.3%) showed abnormally thickened colorectal wall. Colonoscopy detected only 3 (37.5%) out of 8 lesions seen in 4 patients who had undergone colonoscopy before barium enema. Many of the lesions missed were the tethered type involvement. Barium enema is the most sensitive method to detect metastatic cancer of the colorectum. (author)

ALPPS Improves Resectability Compared With Conventional Two-stage Hepatectomy in Patients With Advanced Colorectal Liver Metastasis

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Sandström, Per; Røsok, Bård I; Sparrelid, Ernesto

2018-01-01

resection offers the only chance of a cure for patients with metastatic colorectal cancer. Patients with colorectal liver metastasis (CRLM) and an insufficient future liver remnant (FLR) volume are traditionally treated with chemotherapy with portal vein embolization or ligation followed by hepatectomy (TSH...... of patients completing both stages of the treatment. Secondary outcomes were complications, radicality, and 90-day mortality measured from the final intervention. RESULTS: Baseline characteristics, besides body mass index, did not differ between the groups. The RR was 92% [95% confidence interval (CI) 84...

Degradation Rate of 5-Fluorouracil in Metastatic Colorectal Cancer: A New Predictive Outcome Biomarker?

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Andrea Botticelli

Full Text Available 5-FU based chemotherapy is the most common first line regimen used for metastatic colorectal cancer (mCRC. Identification of predictive markers of response to chemotherapy is a challenging approach for drug selection. The present study analyzes the predictive role of 5-FU degradation rate (5-FUDR and genetic polymorphisms (MTHFR, TSER, DPYD on survival.Genetic polymorphisms of MTHFR, TSER and DPYD, and the 5-FUDR of homogenous patients with mCRC were retrospectively studied. Genetic markers and the 5-FUDR were correlated with clinical outcome.133 patients affected by mCRC, treated with fluoropyrimidine-based chemotherapy from 2009 to 2014, were evaluated. Patients were classified into three metabolic classes, according to normal distribution of 5-FUDR in more than 1000 patients, as previously published: poor-metabolizer (PM with 5-FU-DR ≤ 0,85 ng/ml/106 cells/min (8 pts; normal metabolizer with 0,85 < 5-FU-DR < 2,2 ng/ml/106 cells/min (119 pts; ultra-rapid metabolizer (UM with 5-FU-DR ≥ 2,2 ng/ml/106 cells/min (6 pts. PM and UM groups showed a longer PFS respect to normal metabolizer group (14.5 and 11 months respectively vs 8 months; p = 0.029. A higher G3-4 toxicity rate was observed in PM and UM, respect to normal metabolizer (50% in both PM and UM vs 18%; p = 0.019. No significant associations between genes polymorphisms and outcomes or toxicities were observed.5-FUDR seems to be significantly involved in predicting survival of patients who underwent 5-FU based CHT for mCRC. Although our findings require confirmation in large prospective studies, they reinforce the concept that individual genetic variation may allow personalized selection of chemotherapy to optimize clinical outcomes.

Results of CT in the diagnosis of recurrence of colorectal carcinomas

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Majewski, A.; Haubitz, B.; Laprell, H.

1983-06-01

Postoperative CT was performed in 179 colo-rectal carcinoma patients who had undergone abdominoperineal extirpation (n = 71), resection and rectosigmoid anastomosis (n = 37), hemicolectomy (n = 32), resection of sigma (n = 31), and others (n = 8). Normal CT-findings were found in 25% only, in more than 75% of all cases pathological CT-findings were seen. CT detected loxal recurrence in 87 patients. Based on CT findings local recurrent colo-rectal carcinoma was classified as Stage 0, or intraluminal mass, in 2 patients (2%). Stage 1, or extraluminal mass without invasion of adjacent organs, was found in 38 (44%) patients; Stage 2a, tumor mass with direct invasions of adjacent organs but not the pelvic side walls could be demonstrated in 13 (15%) of the cases; Stage 2b, for extension of mass to pelvic side walls, and Stage 3, or distant metastatic disease, was found in 14 (16%) and 20 (23%) patients. CT was negative in 2 patients with local recurrence (beside Stage 0), an incorrect diagnosis of recurrence due postoperative scarring was found in 4 patients. CT detected exclusive also metastatic disease of the liver in 23 patients and intraabdominal lymph node involvement in 8 patients.

Randomized phase III trial of regorafenib in metastatic colorectal cancer: analysis of the CORRECT Japanese and non-Japanese subpopulations.

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Yoshino, Takayuki; Komatsu, Yoshito; Yamada, Yasuhide; Yamazaki, Kentaro; Tsuji, Akihito; Ura, Takashi; Grothey, Axel; Van Cutsem, Eric; Wagner, Andrea; Cihon, Frank; Hamada, Yoko; Ohtsu, Atsushi

2015-06-01

In the international, phase III, randomized, double-blind CORRECT trial, regorafenib significantly prolonged overall survival (OS) versus placebo in patients with metastatic colorectal cancer (mCRC) that had progressed on all standard therapies. This post hoc analysis evaluated the efficacy and safety of regorafenib in Japanese and non-Japanese subpopulations in the CORRECT trial. Patients were randomized 2 : 1 to regorafenib 160 mg once daily or placebo for weeks 1-3 of each 4-week cycle. The primary endpoint was OS. Outcomes were assessed using descriptive statistics. One hundred Japanese and 660 non-Japanese patients were randomized to regorafenib (n = 67 and n = 438) or placebo (n = 33 and n = 222). Regorafenib had a consistent OS benefit in the Japanese and non-Japanese subpopulations, with hazard ratios of 0.81 (95 % confidence interval [CI] 0.43-1.51) and 0.77 (95 % CI 0.62-0.94), respectively. Regorafenib-associated hand-foot skin reaction, hypertension, proteinuria, thrombocytopenia, and lipase elevations occurred more frequently in the Japanese subpopulation than in the non-Japanese subpopulation, but were generally manageable. Regorafenib appears to have comparable efficacy in Japanese and non-Japanese subpopulations, with a manageable adverse-event profile, suggesting that this agent could potentially become a standard of care in patients with mCRC.

Phospholipid ether analogs for the detection of colorectal tumors.

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Dustin A Deming

Full Text Available The treatment of localized colorectal cancer (CRC depends on resection of the primary tumor with adequate margins and sufficient lymph node sampling. A novel imaging agent that accumulates in CRCs and the associated lymph nodes is needed. Cellectar Biosciences has developed a phospholipid ether analog platform that is both diagnostic and therapeutic. CLR1502 is a near-infrared fluorescent molecule, whereas 124/131I-CLR1404 is under clinical investigation as a PET tracer/therapeutic agent imaged by SPECT. We investigated the use of CLR1502 for the detection of intestinal cancers in a murine model and 131I-CLR1404 in a patient with metastatic CRC. Mice that develop multiple intestinal tumors ranging from adenomas to locally advanced adenocarcinomas were utilized. After 96 hours post CLR1502 injection, the intestinal tumors were analyzed using a Spectrum IVIS (Perkin Elmer and a Fluobeam (Fluoptics. The intensity of the fluorescent signal was correlated with the histological characteristics for each tumor. Colon adenocarcinomas demonstrated increased accumulation of CLR1502 compared to non-invasive lesions (total radiant efficiency: 1.76×10(10 vs 3.27×10(9 respectively, p = 0.006. Metastatic mesenteric tumors and uninvolved lymph nodes were detected with CLR1502. In addition, SPECT imaging with 131I-CLR1404 was performed as part of a clinical trial in patients with advanced solid tumors. 131I-CLR1404 was shown to accumulate in metastatic tumors in a patient with colorectal adenocarcinoma. Together, these compounds might enhance our ability to properly resect CRCs through better localization of the primary tumor and improved lymph node identification as well as detect distant disease.

Establishment and characterization of models of chemotherapy resistance in colorectal cancer: Towards a predictive signature of chemoresistance

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Jensen, Niels F.; Stenvang, Jan; Beck, Mette Kristina

2015-01-01

Current standard treatments for metastatic colorectal cancer (CRC) are based on combination regimens with one of the two chemotherapeutic drugs, irinotecan or oxaliplatin. However, drug resistance frequently limits the clinical efficacy of these therapies. In order to gain new insights into mecha...

The prognostic value of the systemic inflammatory score in patients with unresectable metastatic colorectal cancer.

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Shibutani, Masatsune; Maeda, Kiyoshi; Nagahara, Hisashi; Fukuoka, Tatsunari; Matsutani, Shinji; Kimura, Kenjiro; Amano, Ryosuke; Hirakawa, Kosei; Ohira, Masaichi

2018-07-01

Inflammation has been widely recognized as a contributor to cancer progression and several inflammatory markers have been reported as associated with the clinical outcomes in patients with various types of cancer. Recently, a novel inflammatory marker, the systemic inflammatory score (SIS), which is based on a combination of the lymphocyte-to-monocyte ratio (LMR) and the serum albumin concentration has been reported as a useful prognostic marker. The aim of the present study was to assess the prognostic value of the SIS in patients with unresectable metastatic colorectal cancer (mCRC). The retrospective cohort study included 160 patients who underwent combination chemotherapy for unresectable mCRC between January 2008 and December 2016. The SIS was used to classify the patients into three groups based on their LMR and the serum albumin concentration. Patients with high-LMR and high serum albumin level were given a score of 0; patients with low-LMR or low serum albumin level were given a score of 1; patients with low-LMR and low serum albumin level were given a score of 2. There were significant differences in the overall survival among the three SIS groups and the SIS was an independent prognostic factor for the overall survival. Although the SIS was significantly associated with the overall survival rate even when using the original cut-off values, the SIS according to the new cut-off values had a more accurate prognostic value. The present study determined that the SIS was a useful biomarker for predicting the survival outcomes in patients with unresectable mCRC, although the optimum cut-off value of the SIS according to the patients' background needs to be examined in further studies.

Does sex of the patient play a role in survival for MSI colorectal cancer?

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Adrian Tulin

2018-04-01

Full Text Available Microsatellite instability (MSI is a feature of colorectal tumors that develops as a result of inactivation of the DNA mismatch repair system. It is found in about 15% of all colorectal cancers and is an important prognostic molecular marker when assessing patients with colorectal cancer. It can influence prognosis and treatment decisions in both the advanced and early stages. Although in early stages this marker suggests a favorable prognosis and presents an important argument against adjuvant treatment in stage II disease, in metastatic stages it no longer associated with such an optimistic outcome. The present trial is a prospective, single-center study which included 122 colorectal cancer patients who were tested for MSI using immunohistochemistry. The trial included patients with stage II to IV colorectal cancer, treated in the Prof. Dr. Agrippa Ionescu Emergency Hospital, Bucharest, Romania. Follow-up data were collected during a 24-month period. The study attempted to determine whether differences exist in overall survival for MSI (microsatellite instability vs. MSS (microsatellite stable colorectal cancer and to ascertain whether sex of the patient influences prognosis in MSI patients, irrespective of stage or treatment. Results demonstrated no significant differences in survival for MSI vs MSS colorectal patients, and patients’ gender proved not to influence the outcome in MSI patients.

Predictive value of pretreatment metabolic activity measured by fluorodeoxyglucose positron emission tomography in patients with metastatic advanced gastric cancer: the maximal SUV of the stomach is a prognostic factor

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Park, Jun Chul; Cheoi, Kungseok; Chung, Hyunsoo; Lee, Hyuk; Shin, Sung Kwan; Lee, Sang Kil; Lee, Yong Chan [Yonsei University College of Medicine, Department of Internal Medicine and Institute of Gastroenterology, Seoul (Korea, Republic of); Lee, Jae-Hoon; Yun, Mi Jin [Yonsei University College of Medicine, Department of Nuclear Medicine, Seoul (Korea, Republic of)

2012-07-15

Few studies have evaluated metabolic activity by {sup 18}F-FDG PET as a prognostic factor in advanced gastric cancer (AGC). We investigated its prognostic role in metastatic AGC. We enrolled 82 patients with metastatic AGC, who were treatment-naive and underwent pretreatment {sup 18}F-FDG PET/CT scanning. In each patient, the maximal standardized uptake value (SUVmax) was measured in each target lesion. Stomach{sub SUVmax} was defined as SUVmax in the stomach, while Total{sub SUVmax} was defined as the highest SUVmax among all the target lesions. The stomach was the organ most frequently displaying the highest SUVmax among all the target lesions (in 67.1 % of patients). A Total{sub SUVmax} value of 11.5 was the value with the maximum sum of sensitivity and specificity from receiver-operating characteristic curves for progression-free survival (PFS). PFS was significantly longer in patients with a Total{sub SUVmax} value <11.5 than in those with a Total{sub SUVmax} value {>=}11.5 (P = 0.023); however, overall survival (OS) was not (P = 0.055). A Stomach{sub SUVmax} value of 6.0 was derived by similar methods. PFS and OS were significantly longer in those with a Stomach{sub SUVmax} value <6.0 than in those with a Stomach{sub SUVmax} value {>=}6.0 (P = 0.001 and P = 0.006, respectively). Furthermore, those with a low Total{sub SUVmax} and those with a low Stomach{sub SUVmax} showed better chemotherapeutic responses (P = 0.016 and P = 0.034, respectively). Among patients with histologically undifferentiated carcinomas, those with lower Total{sub SUVmax} and those with lower Stomach{sub SUVmax} showed longer median PFS (P = 0.027 and P = 0.005, respectively) and OS (P = 0.009 and P <0.001, respectively). Multivariate analysis demonstrated Stomach{sub SUVmax} as an independent predictor of PFS (P = 0.002) and OS (P = 0.038). Pretreatment metabolic activity may be a useful prognostic marker in patients with metastatic AGC undergoing palliative chemotherapy. Notably

Real-life treatment of metastatic colorectal cancer with regorafenib: a single-centre review.

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Gotfrit, J; Vickers, M; Sud, S; Asmis, T; Cripps, C; Goel, R; Hsu, T; Jonker, D; Goodwin, R

2017-08-01

Various tyrosine kinase signalling pathways affect the development and progression of colorectal cancer (crc). In clinical trials, regorafenib has been associated with a survival benefit in metastatic crc (mcrc). We assessed the safety and efficacy of regorafenib in real-world patients. In a retrospective review of patients with mcrc treated with regorafenib at our institution from 2013 to 2015, patient demographics, treatment, and survival data were collected. Progression-free survival (pfs) and overall survival (os) were estimated using the Kaplan-Meier method. In total, 48 patients were offered regorafenib, and 35 (73%) started treatment. Of the patients who started regorafenib, 57% were men. Median age in the cohort was 61 years, and all patients had a performance status in the range 0-2. Time from diagnosis of mcrc to regorafenib treatment was more than 18 months in 71% of patients. Starting dose was 160 mg in 54% of the patients, 120 mg in 40%, and 80 mg in 6%. Dose reductions occurred in 34% of the patients, and interruptions, in 29%. Best response was progressive disease (60%) and stable disease (17%); response in the rest of the patients was unknown. The most common adverse events on regorafenib (any grade) were fatigue (57%), hyperbilirubinemia (43%), thrombocytopenia (37%), anorexia (31%), and hypertension (31%). The most common grade 3 or 4 adverse events were fatigue (29%), hypophosphatemia (17%), weight loss (11%), and hyperbilirubinemia (9%). Common reasons for discontinuing regorafenib included progressive disease (51%) and toxicity (26%). In patients treated with regorafenib, pfs was 2.4 months (95% confidence interval: 1.8 to 3.3 months) and os was 5.6 months (95% confidence interval: 3.7 to 8.9 months). No factors were associated with survival in univariate or multivariate analysis. In a real-world setting, regorafenib is associated with survival similar to that reported in the randomized controlled trials, but at the expense of toxicity leading

EGFR related mutational status and association to clinical outcome of third-line cetuximab-irinotecan in metastatic colorectal cancer

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Frifeldt Sanne K

2011-03-01

Full Text Available Abstract Background As supplement to KRAS mutational analysis, BRAF and PIK3CA mutations as well as expression of PTEN may account for additional non-responders to anti-EGFR-MoAbs treatment. The aim of the present study was to investigate the utility as biomarkers of these mutations in a uniform cohort of patients with metastatic colorectal cancer treated with third-line cetuximab/irinotecan. Methods One-hundred-and-seven patients were prospectively included in the study. Mutational analyses of KRAS, BRAF and PIK3CA were performed on DNA from confirmed malignant tissue using commercially available kits. Loss of PTEN and EGFR was assessed by immunohistochemistry. Results DNA was available in 94 patients. The frequency of KRAS, BRAF and PIK3CA mutations were 44%, 3% and 14%, respectively. All were non-responders. EGF receptor status by IHC and loss of PTEN failed to show any clinical importance. KRAS and BRAF were mutually exclusive. Supplementing KRAS analysis with BRAF and PIK3CA indentified additional 11% of non-responders. Patient with any mutation had a high risk of early progression, whereas triple-negative status implied a response rate (RR of 41% (p Conclusion Triple-negative status implied a clear benefit from treatment, and we suggest that patient selection for third-line combination therapy with cetuximab/irinotecan could be based on triple mutational testing.

Treatment with Antiangiogenic Drugs in Multiple Lines in Patients with Metastatic Colorectal Cancer: Meta-Analysis of Randomized Trials

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R.-D. Hofheinz

2016-01-01

Full Text Available Background. In metastatic colorectal cancer (mCRC, continuing antiangiogenic drugs beyond progression might provide clinical benefit. We synthesized the available evidence in a meta-analysis. Patients and Methods. We conducted a meta-analysis of studies investigating the use of antiangiogenic drugs beyond progression. Eligible studies were randomized phase II/III trials. Primary endpoints were overall survival (OS and progression-free survival (PFS. Secondary endpoints were the impact of continuing antiangiogenic drugs (i in subgroups, (ii in different types of compounds targeting the VEGF-axis (monoclonal antibodies versus tyrosine kinase inhibitors, and (iii on remission rates and prevention of progression. Results. Eight studies (3,668 patients were included. Continuing antiangiogenic treatment beyond progression significantly improved PFS (HR 0.64; 95%-CI, 0.55–0.75 and OS (HR 0.83; 95%-CI, 0.76–0.89. PFS was significantly improved in all subgroups with comparable HR. OS was improved in all subgroups stratified by age, gender, and ECOG status. The rate of patients achieving at least stable disease was improved with an OR of 2.25 (95%-CI, 1.41–3.58. Conclusions. This analysis shows a significant PFS and OS benefit as well as a benefit regarding disease stabilization when using antiangiogenic drugs beyond progression in mCRC. Future studies should focus on the optimal sequence of administering antiangiogenic drugs.

Combination Chemotherapy of Azacitidine and Cetuximab for Therapy-Related Acute Myeloid Leukemia following Oxaliplatin for Metastatic Colorectal Cancer

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Akari Hashimoto

2014-05-01

Full Text Available Therapy-related leukemia (TRL has been reported to occur after treatment with alkylating agents and/or topoisomerase II inhibitors. Oxaliplatin (OXP is used as a key drug for the treatment of colorectal cancer (CRC. Cisplatin and carboplatin have been linked with TRL, but the involvement of OXP is questionable. A 74-year-old male was diagnosed with peritoneal metastasis from CRC in July 2011. The patient received nine cycles of 5-fluorouracil (5-FU, leucovorin (LV, and OXP (mFOLFOX-6 regimen and three cycles of 5-FU and LV only, resulting in a clinical complete response. However, recurrence of CRC was detected by CT within 3 months after the last course of chemotherapy. In April 2013, laboratory tests showed pancytopenia and 15% blast cells. A bone marrow examination revealed multilineage dysplasia and 20.4% myeloblasts. Cytogenetic analysis indicated a complex karyotype that included chromosome 5 and 7 abnormalities. The patient was diagnosed with TRL and treated with a combination of azacitidine (AZA and cetuximab (Cmab for both cancers. AZA might be useful in TRL when a patient needs to be treated simultaneously for more than one primary cancer because of its low toxicity. Moreover, Cmab is an effective therapeutic tool in TRL patients with metastatic CRC with the wild-type K-ras gene.

Cetuximab Plus Oxaliplatin May Not Be Effective Primary Treatment for Metastatic Colorectal Cancer

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In a randomized phase III trial, the addition of the targeted therapy cetuximab to oxaliplatin and fluoropyrimidine chemotherapy did not prolong survival or time to disease progression of patients with advanced colorectal cancer.

A phase I/II study of biweekly capecitabine and irinotecan plus bevacizumab as second-line chemotherapy in patients with metastatic colorectal cancer

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Suenaga M

2015-03-01

Full Text Available Mitsukuni Suenaga,1 Nobuyuki Mizunuma,1 Satoshi Matsusaka,1 Eiji Shinozaki,1 Masato Ozaka,1 Mariko Ogura,1 Keisho Chin,1 Toshiharu Yamaguchi2 1Department of Gastroenterology, 2Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Ariake, Koto-ku, Tokyo, Japan Background: Triweekly capecitabine plus irinotecan (XELIRI is not completely regarded as a valid substitute for fluorouracil, leucovorin, and irinotecan (FOLFIRI in metastatic colorectal cancer (mCRC because of the potential for greater toxicity. We conducted a phase I/II study to assess the efficacy and safety of biweekly XELIRI plus bevacizumab (BV as second-line chemotherapy for mCRC.Methods: Patients with mCRC who had received prior chemotherapy including oxaliplatin and BV and had a UGT1A1 genotype of wild-type or heterozygous for UGT1A1*6 or *28 were eligible for this study. Treatment comprised capecitabine 1,000 mg/m2 twice daily from the evening of day 1 to the morning of day 8, intravenous irinotecan on day 1, and BV 5 mg/kg on day 1 every 2 weeks. The phase I study consisted of two steps (irinotecan 150 and 180 mg/m2, and dose-limiting toxicity was assessed during the first treatment cycle. The primary endpoint of the phase II study was progression-free survival (PFS.  Results: The recommended dose of irinotecan was determined to be 180 mg/m2 in the phase I study. Between November 2010 and August 2013, 44 patients were enrolled in phase II. The patients’ characteristics were as follows (N=44: median age, 60 years (range 32–80; male/female, 21/23; and UGT1A1 wild-type/heterozygous, 29/15. The median PFS was 6.8 months (95% confidence interval, 5.3–8.2 months, and the primary endpoint was met. Median overall survival was 18.3 months. The response rate was 22.7%. There was no significant difference in PFS or overall survival according to UGT1A1 status. Grade 3 or higher adverse events were mainly neutropenia in six

Potential role of pemetrexed in metastatic breast cancer patients pre-treated with anthracycline or taxane

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Li-Yan Zhou

2015-03-01

Full Text Available Objectives: This article reviews pharmacology, pharmacokinetic properties, clinical efficacy, and safety in metastatic breast cancer patients, as well as the predictive biomarkers for outcome of treatment with pemetrexed-based regimens. Methods: PubMed, Embase, OVID, and the Cochrane Library databases were searched from the beginning of each database without any limitations to the date of publication. Search terms were ‘‘pemetrexed’’ or ‘‘LY231514’’ or “Alimta”, “metastatic breast cancer”, and “advanced breast cancer”. Results: There were 15 studies (n = 1002 meeting our criteria for evaluation. Eight single-agent trials (n = 551 and seven using combinations with other agents (n = 451 were identified that evaluated pemetrexed for use in patients with metastatic breast cancer. Response rates to pemetrexed as a single agent varied from 8% to 31%, and with combination therapy have been reported to be between 15.8% and 55.7%. With routine supplementation of patients with folic acid, dexamethasone, and vitamin B12, the toxicity profile of these patients was mild, including dose-limiting neutropenia and thrombocytopenia, as well as lower grades of reversible hepatotoxicity and gastrointestinal toxicity. Expression of thymidylate synthase (TS and other biomarkers are associated with the prognosis and sensitivity for pemetrexed in breast cancer. Conclusion: Pemetrexed has shown remarkable activity with acceptable toxicities for treatment of metastatic breast cancer patients. Translational research on pemetrexed in breast cancer identified biomarkers as well as additional genes important to its clinical activity and toxicity. Further research is needed to clarify the role of pemetrexed in breast cancer treatment in order to guide oncologists. Keywords: Metastatic breast cancer, Chemotherapy, Pemetrexed, Anthracycline, Taxane

The source of pretreatment serum prostate-specific antigen in clinically localized prostate cancer--T, N, or M?

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Zagars, Gunar K.; Kavadi, Vivek S.; Pollack, Alan; Eschenbach, Andrew C. von; Sands, M. Elizabeth

1995-01-01

Purpose: Prostate-specific antigen (PSA) is an important marker for prostate cancer and has been shown to be secreted from the primary tumor and from metastases. However, the relative contribution of the primary and micrometastatic disease to the serum level of PSA in patients with clinically localized disease has not been delineated. This study addresses the source of pretreatment serum PSA in patients with clinically localized disease. Methods and Materials: The fall in serum PSA level following radical prostatectomy (280 patients; 105 T1, 165 T2, 10 T3) or definitive radiotherapy (427 patients; 122 T1, 147 T2, 158 T3/T4) was analyzed with the assumption that any fall in PSA following local treatment reflects the fraction of PSA produced in the prostate and its primary tumor. Results: Serum PSA level became undetectable in 277 of the 280 (99%) patients within 6 months of radical prostatectomy. The three patients who did not achieve undetectable levels had postsurgical values ≤ 0.9 ng/ml. Following definitive radiotherapy, nadir serum PSA values were between ≤ 0.3 and 20.3 ng/ml, with mean and median values of 1.9 and 1.2 ng/ml, respectively. Nadir PSA was undetectable in 52 patients (12%). Four patients' PSA did not fall, but rose from the start, and each developed metastatic disease within 9 months, and in each metastases appeared to contribute to pretreatment serum PSA. In the remaining patients, the maximal factor by which PSA fell to its nadir was higher the higher the pretreatment PSA level. We present arguments that this is most consistent with the hypothesis that virtually all detectable pretreatment serum PSA derives from the primary tumor. Confirmatory evidence that little of the pretreatment serum PSA came from metastases was obtained by extrapolating the rising PSA profile in 97 patients back to pretreatment time. Back-extrapolated PSA contributed a mean of 7% and a median of 5% to the pretreatment serum value. Because such back-extrapolated values

Radiolabeled antibody imaging in the management of colorectal cancer. Results of a multicenter clinical study

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Doerr, R.J.; Abdel-Nabi, H.; Krag, D.; Mitchell, E.

1991-01-01

Presurgical colorectal cancer patients (n = 116) received single intravenous infusions of 1 mg of CYT-103 (OncoScint CR103), an immunoconjugate of monoclonal antibody B72.3, radiolabeled with 111In. Following gamma camera imaging, 103 patients underwent an operative procedure: 92 had primary or recurrent colorectal carcinoma, 1 patient evaluated for recurrence of colorectal cancer had a second primary malignancy (small cell lung), and 10 patients had no demonstrable evidence of malignancy. 111In-CYT-103 immunoscintigraphic findings were consistent with the pathologic diagnoses for 70% of patients with colorectal cancer and 90% of disease-free patients. Antibody imaging contributed to surgical decision making through the detection of occult disease (12% of patients) and the confirmation of localized, potentially resectable disease without regional or metastatic spread. Seven patients (6%) experienced adverse effects, primarily fevers and itching, and 33% of patients developed antibodies to murine immunoglobulin after administration of 111In-CYT-103. The results of this study suggest that 111In-CYT-103 is a useful diagnostic tool for the presurgical evaluation of colorectal cancer patients

Towards a molecular classification of colorectal cancer: The role of BRAF

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Alexandra eThiel

2013-11-01

Full Text Available Different genetic aberrations of BRAF have been reported in various malignancies. BRAF is member of the RAS/RAF/MEK/ERK pathway and constitutive activity of this pathway can lead to increased cellular growth, invasion, and metastasis. The most common activating BRAF mutation in colorectal cancer is the V600E mutation, which is present in 5-15% of all tumors, and up to 80% of tumors with high microsatellite instability harbor this mutation. BRAF mutation is associated with proximal location, higher age, female gender, MSI-H, high grade, and mucinous histology, and is a marker of poor prognosis in colorectal cancer. The role of BRAF mutation as a predictive marker in respect of EGFR targeted treatments is controversial. BRAF V600 selective inhibitors have been approved for the treatment of V600 mutation positive metastatic melanoma, but the response rates in colorectal cancer are poor. This might be due to innate resistance mechanisms of colorectal cancers against the treatment solely targeting BRAF. To overcome resistance the combination of treatments, simultaneous inhibition of BRAF and MEK or PI3K/mTOR, might emerge as a successful therapeutic concept.

Prospective noninterventional study on the use of panitumumab monotherapy in patients with recurrent or progressive colorectal cancer: the VECTIS study

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Lakomy, Radek; Rogowski, Wojciech; Piko, Bela; Mihaylova, Zh; Pritzova, Eva; Kvocekova, Lucia

2015-01-01

Epidermal growth factor receptor-targeted monoclonal antibodies are active as monotherapy beyond second-line treatment. Skin toxicities (STs) are common during treatment, and a positive association between ST severity and patient outcome has been reported. This study collected information on panitumumab monotherapy use in patients with KRAS exon 2 wild-type metastatic colorectal cancer in clinical practice. This open-label, prospective, observational, noninterventional study included adult patients who had failed prior chemotherapy with 5-fluorouracil, oxaliplatin, and irinotecan. Patients received panitumumab monotherapy (6 mg/kg every 2 weeks) for ≤18 cycles. Effectiveness was assessed as disease control rate (DCR), tumor response, and freedom from progression. The incidence of ST and other adverse drug reactions (ADRs) was recorded, as were Eastern Cooperative Oncology Group performance status (ECOG PS) and quality of life. The KRAS analysis process was also evaluated. The full analysis set included 632 patients (64.6% male; mean age, 62.3 years), who completed a mean of 9.6 panitumumab cycles. ST, mainly grade 1/2, occurred in 84.3% of patients, 82.7% of whom required treatment. Nonskin ADRs occurred in 3.5% of patients. By the end of treatment, the DCR was 58.9% overall, and was 53.8% and 62.7%, respectively in patients with ST grade 0/1 and grade 2/3. Significant associations were observed between maximum ST grade and best response (P=0.0009), DCR (P=0.0046), tumor response (P=0.0002), and freedom from progression (P=0.0084). At the end of the study, 67.4% of the patients had an ECOG PS of 0/1. Quality of life was rated as “very good” or “good” in 70.3% of patients. Mean time to obtain KRAS results was 18.2 days; satisfaction with different aspects of KRAS testing was “very good” or “good” in 80%–97% of patients. Panitumumab monotherapy showed adequate effectiveness and safety in patients with heavily pretreated KRAS exon 2 wild

Addition of bevacizumab to first-line chemotherapy in advanced colorectal cancer: a systematic review and meta-analysis, with emphasis on chemotherapy subgroups

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Macedo Ligia

2012-03-01

Full Text Available Abstract Background Bevacizumab has an important role in first-line treatment of metastatic colorectal cancer. However, clinical trials studying its effect have involved distinct chemotherapy regimens with divergent results. The aim of this meta-analysis is to gather current data and evaluate not only the efficacy of bevacizumab, but also the impact of divergent backbone regimens. Methods A wide search of randomized clinical trials using bevacizumab in first-line metastatic colorectal cancer was performed in Embase, MEDLINE, LILACS and Cochrane databases. Meeting presentations and abstracts were also investigated. The resulting data were examined and included in the meta-analysis according to the type of regimen. Results Six trials, totaling 3060 patients, were analyzed. There was an advantage to using bevacizumab for overall survival (OS and progression-free survival (PFS (HR = 0.84; CI: 0.77-0.91; P Conclusions Bevacizumab has efficacy in first-line treatment of advanced colorectal cancer, but the current data are insufficient to support efficacy in all regimens, especially infusional fluorouracil regimens, like FOLFIRI and FOLFOX.

Prospective noninterventional study on the use of panitumumab monotherapy in patients with recurrent or progressive colorectal cancer: the VECTIS study

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Lakomy R

2015-10-01

0/1 and grade 2/3. Significant associations were observed between maximum ST grade and best response (P=0.0009, DCR (P=0.0046, tumor response (P=0.0002, and freedom from progression (P=0.0084. At the end of the study, 67.4% of the patients had an ECOG PS of 0/1. Quality of life was rated as “very good” or “good” in 70.3% of patients. Mean time to obtain KRAS results was 18.2 days; satisfaction with different aspects of KRAS testing was "very good" or “good” in 80%–97% of patients.Conclusion: Panitumumab monotherapy showed adequate effectiveness and safety in patients with heavily pretreated KRAS exon 2 wild-type metastatic colorectal cancer. The most common ADR was grade 1/2 ST. Keywords: observational study, panitumumab, metastatic colorectal cancer, skin toxicity, KRAS

Role of β1-Integrin in Colorectal Cancer: Case-Control Study

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Oh, Bo-Young; Kim, Kwang Ho; Chung, Soon Sup; Hong, Kyoung Sook

2014-01-01

Purpose In the metastatic process, interactions between circulating tumor cells (CTCs) and the extracellular matrix or surrounding cells are required. β1-Integrin may mediate these interactions. The aim of this study was to investigate whether β1-integrin is associated with the detection of CTCs in colorectal cancer. Methods We enrolled 30 patients with colorectal cancer (experimental group) and 30 patients with benign diseases (control group). Blood samples were obtained from each group, carcinoembryonic antigen (CEA) mRNA for CTCs marker and β1-integrin mRNA levels were estimated by using reverse transcription-polymerase chain reaction, and the results were compared between the two groups. In the experimental group, preoperative results were compared with postoperative results for each marker. In addition, we analyzed the correlation between the expressions of β1-integrin and CEA. Results CEA mRNA was detected more frequently in colorectal cancer patients than in control patients (P = 0.008). CEA mRNA was significantly reduced after surgery in the colorectal cancer patients (P = 0.032). β1-Integrin mRNA was detected more in colorectal cancer patients than in the patients with benign diseases (P < 0.001). In colorectal cancer patients, expression of β1-integrin mRNA was detected more for advanced-stage cancer than for early-stage cancer (P = 0.033) and was significantly decreased after surgery (P < 0.001). In addition, expression of β1-integrin mRNA was significantly associated with that of CEA mRNA in colorectal cancer patients (P = 0.001). Conclusion In conclusion, β1-integrin is a potential factor for forming a prognosis following surgical resection in colorectal cancer patients. β1-Integrin may be a candidate for use as a marker for early detection of micrometastatic tumor cells and for monitoring the therapeutic response in colorectal cancer patients. PMID:24851215

Digital PCR quantification of MGMT methylation refines prediction of clinical benefit from alkylating agents in glioblastoma and metastatic colorectal cancer.

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Barault, L; Amatu, A; Bleeker, F E; Moutinho, C; Falcomatà, C; Fiano, V; Cassingena, A; Siravegna, G; Milione, M; Cassoni, P; De Braud, F; Rudà, R; Soffietti, R; Venesio, T; Bardelli, A; Wesseling, P; de Witt Hamer, P; Pietrantonio, F; Siena, S; Esteller, M; Sartore-Bianchi, A; Di Nicolantonio, F

2015-09-01

O(6)-methyl-guanine-methyl-transferase (MGMT) silencing by promoter methylation may identify cancer patients responding to the alkylating agents dacarbazine or temozolomide. We evaluated the prognostic and predictive value of MGMT methylation testing both in tumor and cell-free circulating DNA (cfDNA) from plasma samples using an ultra-sensitive two-step digital PCR technique (methyl-BEAMing). Results were compared with two established techniques, methylation-specific PCR (MSP) and Bs-pyrosequencing. Thresholds for MGMT methylated status for each technique were established in a training set of 98 glioblastoma (GBM) patients. The prognostic and the predictive value of MGMT methylated status was validated in a second cohort of 66 GBM patients treated with temozolomide in which methyl-BEAMing displayed a better specificity than the other techniques. Cutoff values of MGMT methylation specific for metastatic colorectal cancer (mCRC) tissue samples were established in a cohort of 60 patients treated with dacarbazine. In mCRC, both quantitative assays methyl-BEAMing and Bs-pyrosequencing outperformed MSP, providing better prediction of treatment response and improvement in progression-free survival (PFS) (P alkylating agents. © The Author 2015. 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.

Pulmonary sclerosing hemangioma in a 21-year-old male with metastatic hereditary non-polyposis colorectal cancer: Report of a case

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Angele Martin K

2011-06-01

Full Text Available Abstract Background Pulmonary sclerosing hemangioma (SH is a rare tumor of the lung predominantly affecting Asian women in their fifth decade of life. SH is thought to evolve from primitive respiratory epithelium and mostly shows benign biological behavior; however, cases of lymph node metastases, local recurrence and multiple lesions have been described. Case Presentation We report the case of a 21-year-old Caucasian male with a history of locally advanced and metastatic rectal carcinoma (UICC IV; pT4, pN1, M1(hep that was eventually identified as having hereditary non-polyposis colorectal cancer (HNPCC, Lynch syndrome. After neoadjuvant chemotherapy followed by low anterior resection, adjuvant chemotherapy and metachronous partial hepatectomy, he was admitted for treatment of newly diagnosed bilateral pulmonary metastases. Thoracic computed tomography showed a homogenous, sharply marked nodule in the left lower lobe. We decided in favor of atypical resection followed by systematic lymphadenectomy. Histopathological analysis revealed the diagnosis of SH. Conclusions Cases have been published with familial adenomatous polyposis (FAP and simultaneous SH. FAP, Gardner syndrome and Li-Fraumeni syndrome, however, had been ruled out in the present case. To the best of our knowledge, this is the first report describing SH associated with Lynch syndrome.

Colorectal cancer: what's new in 1992

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Rivoire, M.

1992-01-01

Five studies presented at the 1992 ASCO meeting are analysed. Kligerman's study was designed to determine if pre-treatment with WR-2721 could p rotect normal tissues from the toxicities induced by radiation therapy (in 100 patients with an advanced rectal cancer). This pre-treatment resulted in a 13% reduction of moderate and severe acute toxicity. No WR-2721 patient experienced moderate or severe late toxicities compared to five in the group without pre-treatment. Minski studied the acute toxicity (during treatment and two weeks after) of combined pelvic radiation therapy, 5-FU and leucovorin when delivered pre-operatively (16 patients) versus post-operatively (25 patients) in patients with rectal cancer. The final report of the inter group study of 5-FU plus levamisole as adjuvant therapy for stage C colon cancer was made by Moertel. With a median follow-up time of 5.5 years, the 5-FU plus levamisole treatment has reduced the recurrence rate by 39%, the cancer related death rate by 32% and the overall death rate by 31%. Most of the recurrences occurred during the first two years. There was a decrease in the liver, great omentum, peritoneum and lung metastases, but there was no modification in loco-regional recurrence rate. Welt presented a phase I/II study of radio-immunotherapy with I 131 monoclonal antibody A33 in patients with advanced colorectal carcinoma. Results were characterized by major hematologic toxicity and minor tumor response rate. Heiss undertook a prospective study to evaluate the influence of homologous blood transfusion on recurrence rate after colorectal cancer surgery. Fifty-eight patients receiving autologous blood transfusion were compared with sixty-two patients receiving homologous transfusion. With a median follow-up of 21 months a higher recurrence rate was found in the homologous group (29.4% versus 16.7%)

High BRAF Mutation Frequency and Marked Survival Differences in Subgroups According to KRAS/BRAF Mutation Status and Tumor Tissue Availability in a Prospective Population-Based Metastatic Colorectal Cancer Cohort

DEFF Research Database (Denmark)

Sorbye, Halfdan; Dragomir, Anca; Sundström, Magnus

2015-01-01

were analyzed in a prospectively collected unselected population-based cohort of 798 non-resectable mCRC patients. The cohort contained many patients with poor performance status (39% PS 2-4) and elderly (37% age>75), groups usually not included in clinical trials. Patients without available tissue...... patients. Median survival in this cohort varied from 1 month in BRAF mutated patients not given chemotherapy to 26 months in wildtype KRAS/BRAF patients availability, BRAF mutation and KRAS mutation were all independent prognostic factors for survival. The observed 21% BRAF......CRC patients. Survival in unselected metastatic colorectal cancer patients is extremely variable and subgroups have an extremely short survival compared to trial patients. Patients without available TMA had worse prognostic factors and shorter survival, which questions the total generalizability of present TMA...

SATB2 is a Promising Biomarker for Identifying a Colorectal Origin for Liver Metastatic Adenocarcinomas

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Yi-Jun Zhang

2018-02-01

Full Text Available SATB2 (Special AT-rich sequence-binding protein 2 has recently been shown to be a specific biomarker of colorectal cancer (CRC. The aim of this study was to investigate the diagnostic potential of SATB2 as a means of detecting a CRC origin for liver metastases. SATB2 expression was examined in a resection cohort of 101 CRC and 273 non-CRC adenocarcinoma samples using immunohistochemistry (IHC. The diagnostic accuracy of CRC origins of liver metastases based on SATB2 and a three marker panel of SATB2, CK20 and CDX2 was evaluated using an independent cohort of 192 liver biopsies. IHC showed 97 of the 101 (96.0% primary CRC samples were SATB2 positive, compared to only 6 of the 273 (2.1% samples of other cancer types. The sensitivity, specificity and AUC values of SATB2 expression in resection samples were 97%, 97.1% and 0.977, respectively. Meanwhile, for the liver biopsy samples, the sensitivity, specificity and AUC values of a CRC liver metastases was 92.2%, 97.8% and 0.948 for SATB2, 95.1%, 91.0% and 0.959 for CK20, and 100%, 85.4% and 0.976 for CDX2, respectively. Further analysis demonstrated that all three-marker positivity was detected in 92/103 (89.3% CRC and 2/89 (2.2% non-CRC liver metastases sampled by biopsy. Our findings suggest that SATB2, as measured by IHC, could serve as a promising diagnostic biomarker of CRC metastases. Combining evaluation of SATB2 with CK20 and CDX2 to form a three marker panel further improved the detection of metastatic CRCs in liver biopsy tissues.

The development of a value based pricing index for new drugs in metastatic colorectal cancer.

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Dranitsaris, George; Truter, Ilse; Lubbe, Martie S

2011-06-01

Worldwide, prices for cancer drugs have been under downward pressure where several governments have mandated price cuts of branded products. A better alternative to government mandated price cuts would be to estimate a final price based on drug performance, cost effectiveness and a country's ability to pay. We developed a global pricing index for new cancer drugs in patients with metastatic colorectal cancer (mCRC) that encompasses all of these attributes. A pharmacoeconomic model was developed to simulate mCRC patients receiving chemotherapy plus a 'new drug' that improves survival by 1.4, 3 and 6months, respectively. Cost and utility data were obtained from cancer centres and oncology nurses (n=112) in Canada, Spain, India, South Africa and Malaysia. Multivariable analysis was then used to develop the pricing index, which considers survival benefit, per capita GDP and income dispersion (as measured by the Gini coefficient) as predictor variables. Higher survival benefits were associated with elevated drug prices, especially in higher income countries such as Canada. For Argentina with a per capita GDP of $15,000 and a Gini coefficient of 51, the index estimated that for a drug which provides a 4month survival benefit in mCRC, the value based price would be $US 630 per dose. In contrast, the same drug in a wealthier country like Norway (per capita GDP=$50,000) could command a price of $US 2,775 per dose. The application of this index to estimate a price based on cost effectiveness and the wealth of a nation would be important for opening dialogue between the key stakeholders and a better alternative to government mandated price cuts. Copyright © 2011 Elsevier Ltd. All rights reserved.

PTEN status in advanced colorectal cancer treated with cetuximab

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Negri, F V; Bozzetti, C; Lagrasta, C A; Crafa, P; Bonasoni, M P; Camisa, R; Pedrazzi, G; Ardizzoni, A

2009-01-01

Background: Loss of phosphatase and tensin homologue deleted in chromosome 10 (PTEN) function in advanced colorectal cancer (CRC) may represent one of the resistance mechanisms to cetuximab by interfering with the epidermal growth factor receptor signal transduction pathway. Methods: PTEN expression tested by indirect immunofluorescence was evaluated both on primary (n=43) and on metastatic (n=24) sites in CRC patients treated with cetuximab. Results: The loss of PTEN expression tested on metastatic sites was negatively associated with response (100% progressive disease (PD) in PTEN-negative cases vs 30% PD in PTEN-positive cases; P<0.05), PFS (0.8 vs 8.2 months; P<0.001) and OS (2.9 vs 14.2 months; P<0.001). Conclusion: A potential role of PTEN in the anti-tumour activity of cetuximab could be hypothesised. PMID:19953097

Natural history of hepatic metastases from colorectal cancer--pathobiological pathways with clinical significance.

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Paschos, Konstantinos A; Majeed, Ali W; Bird, Nigel C

2014-04-14

Colorectal cancer hepatic metastases represent the final stage of a multi-step biological process. This process starts with a series of mutations in colonic epithelial cells, continues with their detachment from the large intestine, dissemination through the blood and/or lymphatic circulation, attachment to the hepatic sinusoids and interactions with the sinusoidal cells, such as sinusoidal endothelial cells, Kupffer cells, stellate cells and pit cells. The metastatic sequence terminates with colorectal cancer cell invasion, adaptation and colonisation of the hepatic parenchyma. All these events, termed the colorectal cancer invasion-metastasis cascade, include multiple molecular pathways, intercellular interactions and expression of a plethora of chemokines and growth factors, and adhesion molecules, such as the selectins, the integrins or the cadherins, as well as enzymes including matrix metalloproteinases. This review aims to present recent advances that provide insights into these cell-biological events and emphasizes those that may be amenable to therapeutic targeting.

Bio markers and Anti-EGFR therapies for Krads wild-type tumors in metastatic colorectal cancer patients

International Nuclear Information System (INIS)

Diaz Rubio Garcia, E.

2009-01-01

The natural history of metastasis colorectal cancer has being clearly modified in terms of response rate, time to progression and overall survival, once the antiEGFR monoclonal antibodies (cetuximab and panitumumab) have emerged in combination with the standard cytotoxic chemotherapy (FOLFOX and FOLFIRI). However, the benefit from cetuximab and panitumumab is only confined to KRAS-wild type (KRAS-wt) colorectal tumors, while KRAS mutated tumors do not respond to these drugs. The 65 % of colorectal tumors are KRAS-wt tumors, but efficacy of antiEGFR therapies is detected only in 60-70 % of these KRAS-wt tumors. Other biomarkers and molecular pathways must be involved in the response of the antiEGFR therapies for the KRAS-wt colorectal tumors, such as the EGFR ligands, the EGFR-phosphorilated levels, the number of EGFR copies, the status of the KRAS effected B-RAF and the alternative intracellular signaling pathways PIK3CA/PTEN/AKT and JAK/STAT. A battery of these biomarkers is needed to select the most sensitive patients to the antiEGFR therapies. This pattern may represent a novel favorable cost-effectiveness tool to develop tailored treatments. A review of these biomarkers and molecular pathways, involved in the antiEGFR therapies response, is performed. (Author) 68 refs.

Clinical value of circulating endothelial cell levels in metastatic colorectal cancer patients treated with first-line chemotherapy and bevacizumab.

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Malka, D; Boige, V; Jacques, N; Vimond, N; Adenis, A; Boucher, E; Pierga, J Y; Conroy, T; Chauffert, B; François, E; Guichard, P; Galais, M P; Cvitkovic, F; Ducreux, M; Farace, F

2012-04-01

We investigated whether circulating endothelial cells (CECs) predict clinical outcome of first-line chemotherapy and bevacizumab in metastatic colorectal cancer (mCRC) patients. In a substudy of the randomized phase II FNCLCC ACCORD 13/0503 trial, CECs (CD45- CD31+ CD146+ 7-amino-actinomycin- cells) were enumerated in 99 patients by four-color flow cytometry at baseline and after one cycle of treatment. We correlated CEC levels with objective response rate (ORR), 6-month progression-free survival (PFS) rate (primary end point of the trial), PFS, and overall survival (OS). Multivariate analyses of potential prognostic factors, including CEC counts and Köhne score, were carried out. By multivariate analysis, high baseline CEC levels were the only independent prognostic factor for 6-month PFS rate (P < 0.01) and were independently associated with worse PFS (P = 0.02). High CEC levels after one cycle were the only independent prognostic factor for ORR (P = 0.03). High CEC levels at both time points independently predicted worse ORR (P = 0.025), 6-month PFS rate (P = 0.007), and PFS (P = 0.02). Köhne score was the only variable associated with OS. CEC levels at baseline and after one treatment cycle may independently predict ORR and PFS in mCRC patients starting first-line bevacizumab and chemotherapy.

Exploratory biomarker analysis for treatment response in KRAS wild type metastatic colorectal cancer patients who received cetuximab plus irinotecan

International Nuclear Information System (INIS)

Kim, Seung Tae; Ahn, Tae Jin; Lee, Eunjin; Do, In-Gu; Lee, Su Jin; Park, Se Hoon; Park, Joon Oh; Park, Young Suk; Lim, Ho Yeong; Kang, Won Ki; Kim, Suk Hyeong; Lee, Jeeyun; Kim, Hee Cheol

2015-01-01

More than half of the patients selected based on KRAS mutation status fail to respond to the treatment with cetuximab in metastatic colorectal cancer (mCRC). We designed a study to identify additional biomarkers that could act as indicators for cetuximab treatment in mCRC. We investigated 58 tumor samples from wild type KRAS CRC patients treated with cetuximab plus irinotecan (CI). We conducted the genotyping for mutations in either BRAF or PIK3CA and profiled comprehensively the expression of 522 kinase genes. BRAF mutation was detected in 5.1 % (3/58) of patients. All 50 patients showed wild type PIK3CA. Gene expression patterns that categorized patients with or without the disease control to CI were compared by supervised classification analysis. PSKH1, TLK2 and PHKG2 were overexpressed significantly in patients with the disease control to IC. The higher expression value of PSKH1 (r = 0.462, p < 0.001) and TLK2 (r = 0.361, p = 0.005) had the significant correlation to prolonged PFS. The result of this work demonstrated that expression nature of kinase genes such as PSKH1, TLK2 and PHKG2 may be informative to predict the efficacy of CI in wild type KRAS CRC. Mutations in either BRAF or PIK3CA were rare subsets in wild type KRAS CRC

High RBM3 expression is associated with an improved survival and oxaliplatin response in patients with metastatic colorectal cancer.

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Christina Siesing

Full Text Available High expression of the RNA-binding motif protein 3 (RBM3 has been shown to correlate, with prolonged survival in several malignant diseases and with the benefit of platinum-based chemotherapy in ovarian cancer. The aim of this study was to evaluate RBM3 in metastatic colorectal cancer (mCRC as a prognostic factor for overall survival and in relation to benefit of first-line chemotherapy.Immunohistochemical staining was conducted and evaluated in tumours from 455 mCRC patients. Kaplan-Meier analysis and Cox regression proportional hazards models were used to access the impact of RBM3 expression on overall survival (OS and progression-free survival (PFS.High RBM3 expression, both nuclear and cytoplasmic, was an independent prognostic factor for prolonged OS (hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.50-0.90 and HR 0.66, 95% CI 0.48-0.91, respectively. PFS was significantly longer in patients with high RBM3 expression who had received first-line oxaliplatin based treatment, compared to those who had received irinotecan based treatment, both regarding nuclear and cytoplasmic expression (p-value 0.020 and 0.022 respectively.High RBM3 expression is an independent predictor of prolonged survival in mCRC patients, in particular in patients treated with first-line oxaliplatin based chemotherapy.

Evaluation of immunological escape mechanisms in a mouse model of colorectal liver metastases

International Nuclear Information System (INIS)

Grimm, Martin; Thalheimer, Andreas; Gasser, Martin; Bueter, Marco; Strehl, Johanna; Wang, Johann; Nichiporuk, Ekaterina; Meyer, Detlef; Germer, Christoph T; Waaga-Gasser, Ana M

2010-01-01

The local and systemic activation and regulation of the immune system by malignant cells during carcinogenesis is highly complex with involvement of the innate and acquired immune system. Despite the fact that malignant cells do have antigenic properties their immunogenic effects are minor suggesting tumor induced mechanisms to circumvent cancer immunosurveillance. The aim of this study is the analysis of tumor immune escape mechanisms in a colorectal liver metastases mouse model at different points in time during tumor growth. CT26.WT murine colon carcinoma cells were injected intraportally in Balb/c mice after median laparotomy using a standardized injection technique. Metastatic tumor growth in the liver was examined by standard histological procedures at defined points in time during metastatic growth. Liver tissue with metastases was additionally analyzed for cytokines, T cell markers and Fas/Fas-L expression using immunohistochemistry, immunofluorescence and RT-PCR. Comparisons were performed by analysis of variance or paired and unpaired t test when appropriate. Intraportal injection of colon carcinoma cells resulted in a gradual and time dependent metastatic growth. T cells of regulatory phenotype (CD4+CD25+Foxp3+) which might play a role in protumoral immune response were found to infiltrate peritumoral tissue increasingly during carcinogenesis. Expression of cytokines IL-10, TGF-β and TNF-α were increased during tumor growth whereas IFN-γ showed a decrease of the expression from day 10 on following an initial increase. Moreover, liver metastases of murine colon carcinoma show an up-regulation of FAS-L on tumor cell surface with a decreased expression of FAS from day 10 on. CD8+ T cells express FAS and show an increased rate of apoptosis at perimetastatic location. This study describes cellular and macromolecular changes contributing to immunological escape mechanisms during metastatic growth in a colorectal liver metastases mouse model simulating the

Evaluation of prognostic factors in liver-limited metastatic colorectal cancer: a preplanned analysis of the FIRE-1 trial

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Giessen, C; Fischer von Weikersthal, L; Laubender, R P; Stintzing, S; Modest, D P; Schalhorn, A; Schulz, C; Heinemann, V

2013-01-01

Background: Liver-limited disease (LLD) denotes a specific subgroup of metastatic colorectal cancer (mCRC) patients. Patients and Methods: A total of 479 patients with unresectable mCRC from an irinotecan-based randomised phase III trial were evaluated. Patients with LLD and non-LLD and hepatic resection were differentiated. Based on baseline patient characteristic, prognostic factors for hepatic resection were evaluated. Furthermore, prognostic factors for median overall survival (OS) were estimated via Cox regression in LLD patients. Results: Secondary liver resection was performed in 38 out of 479 patients (resection rate: 7.9%). Prognostic factors for hepatic resection were LLD, lactate dehydrogenase (LDH), node-negative primary, alkaline phosphatase (AP) and Karnofsky performance status (PS). Median OS was significantly increased after hepatic resection (48 months), whereas OS in LLD (17 months) and non-LLD (19 months) was comparable in non-resected patients. With the inapplicability of Koehne's risk classification in LLD patients, a new score based on only the independent prognostic factors LDH and white blood cell (WBC) provided markedly improved information on the outcome. Conclusion: Patients undergoing hepatic resection showed favourable long-term survival, whereas non-resected LLD patients and non-LLD patients did not differ with regard to progression-free survival and OS. The LDH levels and WBC count were confirmed as prognostic factors and provide a useful and simple score for OS-related risk stratification also in LLD. PMID:23963138

A Novel Computational Tool for Mining Real-Life Data: Application in the Metastatic Colorectal Cancer Care Setting.

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Siegelmann-Danieli, Nava; Farkash, Ariel; Katzir, Itzhak; Vesterman Landes, Janet; Rotem Rabinovich, Hadas; Lomnicky, Yossef; Carmeli, Boaz; Parush-Shear-Yashuv, Naama

2016-01-01

Randomized clinical trials constitute the gold-standard for evaluating new anti-cancer therapies; however, real-life data are key in complementing clinically useful information. We developed a computational tool for real-life data analysis and applied it to the metastatic colorectal cancer (mCRC) setting. This tool addressed the impact of oncology/non-oncology parameters on treatment patterns and clinical outcomes. The developed tool enables extraction of any computerized information including comorbidities and use of drugs (oncological/non-oncological) per individual HMO member. The study in which we evaluated this tool was a retrospective cohort study that included Maccabi Healthcare Services members with mCRC receiving bevacizumab with fluoropyrimidines (FP), FP plus oxaliplatin (FP-O), or FP plus irinotecan (FP-I) in the first-line between 9/2006 and 12/2013. The analysis included 753 patients of whom 15.4% underwent subsequent metastasectomy (the Surgery group). For the entire cohort, median overall survival (OS) was 20.5 months; in the Surgery group, median duration of bevacizumab-containing therapy (DOT) pre-surgery was 6.1 months; median OS was not reached. In the Non-surgery group, median OS and DOT were 18.7 and 11.4 months, respectively; no significant OS differences were noted between FP-O and FP-I, whereas FP use was associated with shorter OS (12.3 month; p controlling for age and gender) identified several non-oncology parameters associated with poorer clinical outcomes including concurrent use of diuretics and proton-pump inhibitors. Our tool provided insights that confirmed/complemented information gained from randomized-clinical trials. Prospective tool implementation is warranted.

The clinical value of circulating tumour cells (CTCs) in patients undergoing pulmonary metastasectomy for metastatic colorectal cancer.

Science.gov (United States)

Hashimoto, Masaki; Tanaka, Fumihiro; Yoneda, Kazue; Takuwa, Teruhisa; Kuroda, Ayumi; Matsumoto, Seiji; Okumura, Yoshitomo; Kondo, Nobuyuki; Tsujimura, Tohru; Nakano, Takashi; Hasegawa, Seiki

2018-03-01

Circulating tumour cells (CTCs) are a potential surrogate for distant metastasis and are considered a useful clinical prognostic marker for metastatic colorectal cancer (mCRC). This prospective study evaluated the preoperative CTC count as a prognostic factor for pulmonary metastasectomy in mCRC patients. Seventy-nine mCRC patients who underwent curative-intent pulmonary metastasectomy were included. Preoperatively, 7.5 mL of peripheral blood from each patient was quantitatively evaluated for CTCs with the CellSearch ® system. The clinical significance of CTC count was evaluated according to Kaplan-Meier analyses and log-rank test. Multivariate analyses of the perioperative variables were performed. The distribution of CTC counts were as follows; 0 in 66 patients (83.5%), 1 in eight patients (10.1%), 2 in three patients (3.8%), and 3 and 6 in one patient (1.3%). The patients with multiple CTCs (CTC count ≥2) had significant shorter disease-free survival (DFS) (P=0.005, median DFS; 19.8 vs . 8.6 months) and overall survival (OS) (P=0.035, median DFS; not reached vs. 37.8 months), respectively. Multivariate analysis showed the patients with multiple CTCs had elevated risk of recurrence [hazard ratio (HR), 3.28; 95% confidence interval (CI), 1.24-8.67; P=0.017]. The detected rate of CTCs was quite low in mCRC patients who underwent pulmonary metastasectomy. The patient with multiple CTCs had shorter DFS in this study. The larger prospective clinical study is needed to establish the meaning of CTC in mCRC candidate for pulmonary metastasectomy.

Therapeutic efficacy and toxicity of bolus application of chemotherapy protocol in the treatment of metastatic colorectal cancer.

Science.gov (United States)

Šišić, Ibrahim; Pojskić, Belma; Mekić Abazović, Alma; Kovčin, Vladimir

2015-08-01

To compare efficacy and toxicity of bolus application of chemotherapy protocol, oxaliplatin, fluorouracil (bolus), leucovorin (folfox) between two groups of patients in the therapy of metastatic colorectal carcinoma (mCRC). A total of 63 patients were treated for mCRC in the period January 2009 - January 2010 at the Department of Oncology of the Cantonal Hospital Zenica, Bosnia and Herzegovina (first group, 30 patients) and at the Department of Oncology of the Clinical Hospital Centre Bežanijska kosa in Belgrade, Serbia, in the period January 2005 - January 2006 (second group, 33 patients). The patients were treated according the same protocol, i.v. bolus infusion, but in different day intervals (D), 1, 8, 15/28 days or D1-D5/28 days, respectively. In all patients the following factors were analyzed: tumor response, overall survival (OS), progression free survival, hematological and non-hematological toxicity . Colon was the primary localization in almost two thirds of patients. There was no statistically significant difference between the groups according to the age, hematological and non-hematological toxicity, as well as in achieved OS. Progression free survival expressed in months was in average 5 months though with a large range between minimal and maximal survival time. Both groups have shown equivalent efficacy to applied chemotherapy protocols. Overall survival in the two groups matched data from the literature. Further research should confirm success of the combination of chemotherapy protocols and their combination with the biological therapy. Copyright© by the Medical Assotiation of Zenica-Doboj Canton.

Therapeutic efficacy and toxicity of bolus application of chemotherapy protocol in the treatment of metastatic colorectal cancer

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Ibrahim Šišić

2015-08-01

Full Text Available Aim To compare efficacy and toxicity of bolus application of chemotherapy protocol, oxaliplatin, fluorouracil (bolus, leucovorin (folfox between two groups of patients in the therapy of metastatic colorectal carcinoma (mCRC. Methods A total of 63 patients were treated for mCRC in the period January 2009 – January 2010 at the Department of Oncology of the Cantonal Hospital Zenica, Bosnia and Herzegovina (first group, 30 patients and at the Department of Oncology of the Clinical Hospital Centre Bežanijska kosa in Belgrade, Serbia, in the period January 2005 – January 2006 (second group, 33 patients. The patients were treated according the same protocol, i.v. bolus infusion, but in different day intervals (D, 1, 8, 15/28 days or D1-D5/28 days, respectively. In all patients the following factors were analyzed: tumor response, overall survival (OS, progression free survival, hematological and non-hematological toxicity. Results Colon was the primary localization in almost two thirds of patients. There was no statistically significant difference between the groups according to the age, hematological and non-hematological toxicity, as well as in achieved OS. Progression free survival expressed in months was in average 5 months though with a large range between minimal and maximal survival time. Conclusion Both groups have shown equivalent efficacy to applied chemotherapy protocols. Overall survival in the two groups matched data from the literature. Further research should confirm success of the combination of chemotherapy protocols and their combination with the biological therapy.

Tissue detection of natural killer cells in colorectal adenocarcinoma

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Patsouris Efstratios S

2004-09-01

Full Text Available Abstract Background Natural killer (NK cells represent a first line of defence against a developing cancer; however, their exact role in colorectal cancer remains undetermined. The aim of the present study was to evaluate the expression of CD16 and CD57 [immunohistochemical markers of natural NK cells] in colorectal adenocarcinoma. Methods Presence of NK cells was investigated in 82 colorectal adenocarcinomas. Immunohistochemical analysis was performed, using 2 monoclonal antibodies (anti-Fc Gamma Receptor II, CD16 and an equivalent to Leu-7, specific for CD-57. The number of immunopositive cells (% was evaluated by image analysis. The cases were characterized according to: patient gender and age, tumor location, size, grade, bowel wall invasion, lymph node metastases and Dukes' stage. Results NK cells were detected in 79/82 cases at the primary tumor site, 27/33 metastatic lymph nodes and 3/4 hepatic metastases; they were detected in levels similar to those reported in the literature, but their presence was not correlated to the clinical or pathological characteristics of the series, except for a negative association with the patients' age (p = 0.031. Conclusions Our data do not support an association of NK cell tissue presence with clinical or pathological variables of colorectal adenocarcinoma, except for a negative association with the patients' age; this might possibly be attributed to decreased adhesion molecule expression in older ages.

Clinicopathological analysis of recurrence patterns and prognostic factors for survival after hepatectomy for colorectal liver metastasis

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Okuda Junji

2010-09-01

Full Text Available Abstract Background Hepatectomy is recommended as the most effective therapy for liver metastasis from colorectal cancer (CRCLM. It is crucial to elucidate the prognostic clinicopathological factors. Methods Eighty-three patients undergoing initial hepatectomy for CRCLM were retrospectively analyzed with respect to characteristics of primary colorectal and metastatic hepatic tumors, operation details and prognosis. Results The overall 5-year survival rate after initial hepatectomy for CRCLM was 57.5%, and the median survival time was 25 months. Univariate analysis clarified that the significant prognostic factors for poor survival were depth of primary colorectal cancer (≥ serosal invasion, hepatic resection margin ( Conclusions Optimal surgical strategies in conjunction with effective chemotherapeutic regimens need to be established in patients with risk factors for recurrence and poor outcomes as listed above.

Lysyl oxidase enzymatic function increases stiffness to drive colorectal cancer progression through FAK

DEFF Research Database (Denmark)

Baker, A-M; Bird, D; Lang, G

2013-01-01

The extracellular, matrix-modifying enzyme lysyl oxidase (LOX) has recently been linked to colorectal cancer (CRC) progression, in particular to the stages of invasion and metastasis. In this report, we use cell lines expressing a catalytically inactive mutant form of LOX to show that catalytic a...... for patients with metastatic CRC.Oncogene advance online publication, 28 May 2012; doi:10.1038/onc.2012.202....

HER2 activating mutations are targets for colorectal cancer treatment.

Science.gov (United States)

Kavuri, Shyam M; Jain, Naveen; Galimi, Francesco; Cottino, Francesca; Leto, Simonetta M; Migliardi, Giorgia; Searleman, Adam C; Shen, Wei; Monsey, John; Trusolino, Livio; Jacobs, Samuel A; Bertotti, Andrea; Bose, Ron

2015-08-01

The Cancer Genome Atlas project identified HER2 somatic mutations and gene amplification in 7% of patients with colorectal cancer. Introduction of the HER2 mutations S310F, L755S, V777L, V842I, and L866M into colon epithelial cells increased signaling pathways and anchorage-independent cell growth, indicating that they are activating mutations. Introduction of these HER2 activating mutations into colorectal cancer cell lines produced resistance to cetuximab and panitumumab by sustaining MAPK phosphorylation. HER2 mutants are potently inhibited by low nanomolar doses of the irreversible tyrosine kinase inhibitors neratinib and afatinib. HER2 gene sequencing of 48 cetuximab-resistant, quadruple (KRAS, NRAS, BRAF, and PIK3CA) wild-type (WT) colorectal cancer patient-derived xenografts (PDX) identified 4 PDXs with HER2 mutations. HER2-targeted therapies were tested on two PDXs. Treatment with a single HER2-targeted drug (trastuzumab, neratinib, or lapatinib) delayed tumor growth, but dual HER2-targeted therapy with trastuzumab plus tyrosine kinase inhibitors produced regression of these HER2-mutated PDXs. HER2 activating mutations cause EGFR antibody resistance in colorectal cell lines, and PDXs with HER2 mutations show durable tumor regression when treated with dual HER2-targeted therapy. These data provide a strong preclinical rationale for clinical trials targeting HER2 activating mutations in metastatic colorectal cancer. ©2015 American Association for Cancer Research.

Usefulness of analytical CEA doubling time and half-life time for overlooked synchronous metastases in colorectal carcinoma.

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Ito, Katsuki; Hibi, Kenji; Ando, Hideyuki; Hidemura, Kazuhiko; Yamazaki, Taiji; Akiyama, Seiji; Nakao, Akimasa

2002-02-01

Measurement of carcinoembryonic antigen (CEA) has been widely applied to detect recurrence, especially of colorectal carcinoma. The validity however, is still controversial. We investigated serial changes in CEA values to calculate whether the CEA doubling time and half-life time could predict metastatic progression or prognosis in colorectal carcinoma. Pre- and post-operative serial serum CEA contents were determined in 22 cases of colorectal cancer with or without metastasis. CEA values were determined by enzyme immunoassay (EIA). Patients were assigned depending upon survival time (within vs. more than 18 months after primary resection) for assessment of CEA doubling time. From the gradient of the semi-logarithmic CEA graph, the preoperative doubling time was calculated and the postoperative half-life time was estimated according to the diagnosis of metastases within 2 years after primary resection [metastasis (+) or (-)]. In spite of the effect of curative re-operation of metastatic lesions or of postoperative adjuvant chemotherapy, the CEA doubling time of the groups showed a relation with prognosis (p = 0.045, Student's t-test) when the patients were divided into >18 and time. The CEA half-life time of the groups without overlooked metastases was statistically longer than those with (mean +/- SD 8.01 +/- 2.07 and 4.33 +/- 1.11, respectively, p Clearance (k) showed a significant difference between the groups (p time appeared to be a less independent prognostic factor, whereas prolongation of the CEA half-life time might potentially suggest the existence of overlooked synchronous metastases from colorectal carcinoma.

Potential role of pemetrexed in metastatic breast cancer patients pre-treated with anthracycline or taxane

Institute of Scientific and Technical Information of China (English)

Li-Yan Zhou; Ye-Hui Shi; Yong-Sheng Jia; Zhong-Sheng Tong

2015-01-01

Objectives: This article reviews pharmacology, pharmacokinetic properties, clinical efficacy, and safety in metastatic breast cancer patients, as well as the predictive biomarkers for outcome of treatment with pemetrexed-based regimens. Methods: PubMed, Embase, OVID, and the Cochrane Library databases were searched from the beginning of each database without any limitations to the date of publication. Search terms were‘‘pemetrexed’’ or‘‘LY231514’’ or“Alimta”,“metastatic breast cancer”, and“advanced breast cancer”. Results: There were 15 studies (n ¼ 1002) meeting our criteria for evaluation. Eight single-agent trials (n ¼ 551) and seven using combinations with other agents (n ¼ 451) were identified that evaluated pemetrexed for use in patients with metastatic breast cancer. Response rates to pemetrexed as a single agent varied from 8%to 31%, and with combination therapy have been reported to be between 15.8% and 55.7%. With routine supplementation of patients with folic acid, dexamethasone, and vitamin B12, the toxicity profile of these patients was mild, including dose-limiting neutropenia and thrombocytopenia, as well as lower grades of reversible hepatotoxicity and gastrointestinal toxicity. Expression of thymidylate synthase (TS) and other biomarkers are associated with the prognosis and sensitivity for pemetrexed in breast cancer. Conclusion: Pemetrexed has shown remarkable activity with acceptable toxicities for treatment of metastatic breast cancer patients. Translational research on pemetrexed in breast cancer identified biomarkers as well as additional genes important to its clinical activity and toxicity. Further research is needed to clarify the role of pemetrexed in breast cancer treatment in order to guide oncologists. Copyright © 2015, Chinese Medical Association Production. Production and hosting by Elsevier B.V. on behalf of KeAi Com-munications Co., Ltd. This is an open access article under the CC BY-NC-ND license

Assessment of metastatic colorectal cancer with hybrid imaging: comparison of reading performance using different combinations of anatomical and functional imaging techniques in PET/MRI and PET/CT in a short case series

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Brendle, C.; Schwenzer, N.F.; Rempp, H.; Schmidt, H.; Pfannenberg, C.; Nikolaou, K.; Schraml, C. [Eberhard Karls University, Diagnostic and Interventional Radiology, Department of Radiology, Tuebingen (Germany); La Fougere, C. [Eberhard Karls University, Nuclear Medicine, Department of Radiology, Tuebingen (Germany)

2016-01-15

The purpose was to investigate the diagnostic performance of different combinations of anatomical and functional imaging techniques in PET/MRI and PET/CT for the evaluation of metastatic colorectal cancer lesions. Image data of 15 colorectal cancer patients (FDG-PET/CT and subsequent FDG-PET/MRI) were retrospectively evaluated by two readers in five reading sessions: MRI (morphology) alone, MRI/diffusion-weighted MRI (DWI), MRI/PET, MRI/DWI/PET; and PET/CT. Diagnostic performance of lesion detection with each combination was assessed in general and organ-based. The reference standard was given by histology and/or follow-up imaging. Separate analysis of mucinous tumours was performed. One hundred and eighty lesions (110 malignant) were evaluated (intestine n = 6, liver n = 37, lymph nodes n = 55, lung n = 4, and peritoneal n = 74). The overall lesion-based diagnostic accuracy was 0.46 for MRI, 0.47 for MRI/DWI, 0.57 for MRI/PET, 0.69 for MRI/DWI/PET and 0.66 for PET/CT. In the organ-based assessment, MRI/DWI/PET showed the highest accuracy for liver metastases (0.74), a comparable accuracy to PET/CT in peritoneal lesions (0.55), and in lymph node metastases (0.84). The accuracy in mucinous tumour lesions was limited in all modalities (MRI/DWI/PET = 0.52). PET/MRI including DWI is comparable to PET/CT in the evaluation of colorectal cancer metastases, with a markedly higher accuracy when using combined imaging data than the modalities separately. Further improvement is needed in the imaging of peritoneal carcinomatosis and mucinous tumours. (orig.)

Colorectal Cancer Genetic Heterogeneity Delineated by Multi-Region Sequencing.

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You-Wang Lu

Full Text Available Intratumor heterogeneity (ITH leads to an underestimation of the mutational landscape portrayed by a single needle biopsy and consequently affects treatment precision. The extent of colorectal cancer (CRC genetic ITH is not well understood in Chinese patients. Thus, we conducted deep sequencing by using the OncoGxOne™ Plus panel, targeting 333 cancer-specific genes in multi-region biopsies of primary and liver metastatic tumors from three Chinese CRC patients. We determined that the extent of ITH varied among the three cases. On average, 65% of all the mutations detected were common within individual tumors. KMT2C aberrations and the NCOR1 mutation were the only ubiquitous events. Subsequent phylogenetic analysis showed that the tumors evolved in a branched manner. Comparison of the primary and metastatic tumors revealed that PPP2R1A (E370X, SETD2 (I1608V, SMAD4 (G382T, and AR splicing site mutations may be specific to liver metastatic cancer. These mutations might contribute to the initiation and progression of distant metastasis. Collectively, our analysis identified a substantial level of genetic ITH in CRC, which should be considered for personalized therapeutic strategies.

The Genome-Wide Analysis of Carcinoembryonic Antigen Signaling by Colorectal Cancer Cells Using RNA Sequencing.

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Olga Bajenova

Full Text Available Сarcinoembryonic antigen (CEA, CEACAM5, CD66 is a promoter of metastasis in epithelial cancers that is widely used as a prognostic clinical marker of metastasis. The aim of this study is to identify the network of genes that are associated with CEA-induced colorectal cancer liver metastasis. We compared the genome-wide transcriptomic profiles of CEA positive (MIP101 clone 8 and CEA negative (MIP 101 colorectal cancer cell lines with different metastatic potential in vivo. The CEA-producing cells displayed quantitative changes in the level of expression for 100 genes (over-expressed or down-regulated. They were confirmed by quantitative RT-PCR. The KEGG pathway analysis identified 4 significantly enriched pathways: cytokine-cytokine receptor interaction, MAPK signaling pathway, TGF-beta signaling pathway and pyrimidine metabolism. Our results suggest that CEA production by colorectal cancer cells triggers colorectal cancer progression by inducing the epithelial- mesenchymal transition, increasing tumor cell invasiveness into the surrounding tissues and suppressing stress and apoptotic signaling. The novel gene expression distinctions establish the relationships between the existing cancer markers and implicate new potential biomarkers for colorectal cancer hepatic metastasis.

Higher Quality of Molecular Testing, an Unfulfilled Priority: Results from External Quality Assessment for KRAS Mutation Testing in Colorectal Cancer

NARCIS (Netherlands)

Tembuyser, L.; Ligtenberg, M.J.L.; Normanno, N.; Delen, S.; Krieken, J.H.J.M. van; Dequeker, E.M.

2014-01-01

Precision medicine is now a key element in clinical oncology. RAS mutational status is a crucial predictor of responsiveness to anti-epidermal growth factor receptor agents in metastatic colorectal cancer. In an effort to guarantee high-quality testing services in molecular pathology, the European

Carcinoembryonic antigen promotes colorectal cancer progression by targeting adherens junction complexes

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Bajenova, Olga, E-mail: o.bazhenova@spbu.ru [Theodosius Dobzhansky Center for Genome Bioinformatics, St. Petersburg State University, St. Petersburg 199034 (Russian Federation); Department of Genetics and Biotechnology, St. Petersburg State University, St. Petersburg 199034 (Russian Federation); Department of Surgery and Biomedical Sciences, Creighton University, Omaha, NE 68178 (United States); Chaika, Nina [Department of Surgery and Biomedical Sciences, Creighton University, Omaha, NE 68178 (United States); Tolkunova, Elena; Davydov-Sinitsyn, Alexander [Institute of Cytology, Russian Academy of Sciences, St. Petersburg 194064 (Russian Federation); Gapon, Svetlana [Boston Children' s Hospital, Boston, MA 02115 (United States); Thomas, Peter [Department of Surgery and Biomedical Sciences, Creighton University, Omaha, NE 68178 (United States); O’Brien, Stephen [Theodosius Dobzhansky Center for Genome Bioinformatics, St. Petersburg State University, St. Petersburg 199034 (Russian Federation)

2014-06-10

Oncomarkers play important roles in the detection and management of human malignancies. Carcinoembryonic antigen (CEA, CEACAM5) and epithelial cadherin (E-cadherin) are considered as independent tumor markers in monitoring metastatic colorectal cancer. They are both expressed by cancer cells and can be detected in the blood serum. We investigated the effect of CEA production by MIP101 colorectal carcinoma cell lines on E-cadherin adherens junction (AJ) protein complexes. No direct interaction between E-cadherin and CEA was detected; however, the functional relationships between E-cadherin and its AJ partners: α-, β- and p120 catenins were impaired. We discovered a novel interaction between CEA and beta-catenin protein in the CEA producing cells. It is shown in the current study that CEA overexpression alters the splicing of p120 catenin and triggers the release of soluble E-cadherin. The influence of CEA production by colorectal cancer cells on the function of E-cadherin junction complexes may explain the link between the elevated levels of CEA and the increase in soluble E-cadherin during the progression of colorectal cancer. - Highlights: • Elevated level of CEA increases the release of soluble E-cadherin during the progression of colorectal cancer. • CEA over-expression alters the binding preferences between E-cadherin and its partners: α-, β- and p120 catenins in adherens junction complexes. • CEA produced by colorectal cancer cells interacts with beta-catenin protein. • CEA over-expression triggers the increase in nuclear beta-catenin. • CEA over-expression alters the splicing of p120 catenin protein.

Carcinoembryonic antigen promotes colorectal cancer progression by targeting adherens junction complexes

International Nuclear Information System (INIS)

Bajenova, Olga; Chaika, Nina; Tolkunova, Elena; Davydov-Sinitsyn, Alexander; Gapon, Svetlana; Thomas, Peter; O’Brien, Stephen

2014-01-01

Oncomarkers play important roles in the detection and management of human malignancies. Carcinoembryonic antigen (CEA, CEACAM5) and epithelial cadherin (E-cadherin) are considered as independent tumor markers in monitoring metastatic colorectal cancer. They are both expressed by cancer cells and can be detected in the blood serum. We investigated the effect of CEA production by MIP101 colorectal carcinoma cell lines on E-cadherin adherens junction (AJ) protein complexes. No direct interaction between E-cadherin and CEA was detected; however, the functional relationships between E-cadherin and its AJ partners: α-, β- and p120 catenins were impaired. We discovered a novel interaction between CEA and beta-catenin protein in the CEA producing cells. It is shown in the current study that CEA overexpression alters the splicing of p120 catenin and triggers the release of soluble E-cadherin. The influence of CEA production by colorectal cancer cells on the function of E-cadherin junction complexes may explain the link between the elevated levels of CEA and the increase in soluble E-cadherin during the progression of colorectal cancer. - Highlights: • Elevated level of CEA increases the release of soluble E-cadherin during the progression of colorectal cancer. • CEA over-expression alters the binding preferences between E-cadherin and its partners: α-, β- and p120 catenins in adherens junction complexes. • CEA produced by colorectal cancer cells interacts with beta-catenin protein. • CEA over-expression triggers the increase in nuclear beta-catenin. • CEA over-expression alters the splicing of p120 catenin protein

EGFR signaling in colorectal cancer: a clinical perspective

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Saletti P

2015-01-01

Full Text Available Piercarlo Saletti,1 Francesca Molinari,2 Sara De Dosso,1 Milo Frattini2 1Oncology Institute of Southern Switzerland, Bellinzona, 2Laboratory of Molecular Pathology, Institute of Pathology, Locarno, Switzerland Abstract: Colorectal cancer (CRC remains a formidable health burden worldwide, with up to 50% of patients developing metastases during the course of their disease. This group of CRC patients, characterized by the worst prognosis, has been extensively investigated to improve their life expectancy. Main efforts, focused on the epidermal growth-factor receptor (EGFR, which plays a pivotal role in CRC pathogenesis, have led to the development and introduction in clinical practice of specific targeted therapies (ie, monoclonal antibodies. Subsequently, the scientific community has tried to identify molecular predictors of the efficacy of such therapies. However, it has become clear that EGFR alterations occurring in CRC are difficult to investigate, and therefore their predictive role is unclear. In contrast, the clinical role of two downstream members (KRAS and NRAS has been clearly demonstrated. Currently, EGFR-targeted therapies can be administered only to patients with wild-type KRAS and NRAS genes. Our review addresses the medical management of metastatic CRC. Specifically, we describe in detail the molecular biology of metastatic CRC, focusing on the EGFR signaling pathway, and we discuss the role of current and emerging related biomarkers and therapies in this field. We also summarize the clinical evidence regarding anti-EGFR monoclonal antibodies and examine potential future perspectives. Keywords: colorectal cancer, EGFR, gene mutations, cetuximab, panitumumab

Review of the Clinical Evidence for the Use of DEBIRI in the Treatment of Colorectal Metastatic Disease

Energy Technology Data Exchange (ETDEWEB)

Young, Shamar, E-mail: youn1862@umn.edu; D’Souza, Donna; Flanagan, Siobhan; Golzarian, Jafar [University of Minnesota, Department of Radiology, Division of Interventional Radiology (United States)

2017-04-15

Colorectal cancer is a common malignancy that most commonly metastasizes to the liver. There has been considerable effort in developing new treatment options for these patients. One method that has been developed for the treatment of colorectal metastases to the liver is irinotecan-loaded drug-eluting bead (DEBIRI) embolization. This article reviews the current literature on DEBIRI and discusses the state of current knowledge and possible areas of future investigation.

Total lesion glycolysis (TLG) as an imaging biomarker in metastatic colorectal cancer patients treated with regorafenib

International Nuclear Information System (INIS)

Lim, Yoojoo; Lee, Kyung-Hun; Bang, Ji-In; Paeng, Jin Chul; Han, Sae-Won; Kim, Jee Hyun; Kang, Gyeong Hoon; Jeong, Seung-Yong; Park, Kyu Joo; Kim, Tae-You

2017-01-01

This study was performed to evaluate whether fluorine-18 fluorodeoxyglucose positron-emission tomography/computed tomography (FDG PET/CT) could predict treatment outcome of regorafenib in metastatic colorectal cancer (mCRC). Previously treated refractory mCRC patients were enrolled into a prospective biomarker study of regorafenib. For this sub-study, the results of FDG PET/CT scans at baseline and after two cycles of treatment were analyzed. Various metabolic parameters obtained from PET images were analyzed in relation to treatment outcome. A total of 40 patients were evaluable for PET image analysis. Among various PET parameters, total lesion glycolysis (TLG) measured in the same target lesions for RECIST 1.1 analysis were the most significant in predicting prognosis, with the lowest p-value observed in TLG calculated using the margin threshold of 40 % (TLG 40 % ). Further analysis using TLG 40 % showed significantly longer overall survival (OS) in patients with lower baseline TLG 40 % (<151.8) (p = 0.003, median 14.2 vs. 9.1 months in <151.8 and ≥151.8, respectively). Patients showing higher decrease in TLG 40 % after treatment showed significantly longer progression-free survival (PFS) (p = 0.001, median 8.0 vs. 2.4 months in % ΔTLG 40 % < -9.6 % and ≥ -9.6 %, respectively) and OS (p = 0.002, median 16.4 vs. 9.1 months in % ΔTLG 40 % < -9.6 % and ≥ -9.6 %, respectively). The same cutoff could discriminate patients with longer survival among the patients who were under the stable disease category according to RECIST 1.1 (median PFS 8.4 vs. 6.8 months, p = 0.020; median OS 18.3 vs. 11.5 months, p = 0.049). Measurement of TLG can predict treatment outcome of regorafenib in mCRC. (orig.)

Angiogenesis-related protein expression in bevacizumab-treated metastatic colorectal cancer: NOTCH1 detrimental to overall survival

International Nuclear Information System (INIS)

Paiva, Tadeu Ferreira Jr.; Jesus, Victor Hugo Fonseca de; Marques, Raul Amorim; Costa, Alexandre André Balieiro Anastácio da; Macedo, Mariana Petaccia de; Peresi, Patricia Maria; Damascena, Aline; Rossi, Benedito Mauro; Begnami, Maria Dirlei; Lima, Vladmir Cláudio Cordeiro de

2015-01-01

The development of targeted therapies has undoubtedly broadened therapeutic options for patients with colorectal cancer (CRC). The use of bevacizumab to reduce angiogenesis has been associated with improved clinical outcomes. However, an urgent need for prognostic/predictive biomarkers for anti-angiogenic therapies still exists. Clinical data of 105 CRC patients treated with bevacizumab in conjunction with chemotherapy were analyzed. The expression of vascular endothelial growth factor (VEGF) receptors, NOTCH1 receptor and its ligand DLL4 were determined by immunohistochemistry. Tumor samples were arranged on a tissue microarray. The association between protein expression and clinicopathological characteristics and outcomes was determined. Bevacizumab was administered as a first-line of treatment in 70.5 % of our cases. The median progression-free survival (PFS) was 10.2 months. The median overall survival (OS) of the total cohort was 24.4 months. Bevacizumab, as the first-line of treatment, and the presence of liver metastasis were independently associated with objective response rate. Membrane VEGFR1 and VEGFR3 expressions were associated with the presence of lung metastasis; interestingly, VEGFR3 was associated with less liver metastasis. NOTCH1 expression was associated with lymph node metastasis. There was a trend toward association between improved PFS and lower NOTCH1 expression (p = 0.06). Improved OS was significantly associated with lower NOTCH1 expression (p = 0.01). In a multivariate analysis, ECOG (Eastern Cooperative Oncology Group) performance status, liver metastasis, histological grade, and NOTCH1 expression were independently associated with OS. Our findings illustrated the expression profile of angiogenesis-related proteins and their association with clinicopathological characteristics and outcomes. NOTCH1 expression is a detrimental prognostic factor in metastatic CRC patients treated with chemotherapy plus bevacizumab. The online version of

Total lesion glycolysis (TLG) as an imaging biomarker in metastatic colorectal cancer patients treated with regorafenib

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Lim, Yoojoo; Lee, Kyung-Hun [Seoul National University Hospital, Department of Internal Medicine, 101 Daehang-ro, Jongno-gu, Seoul (Korea, Republic of); Bang, Ji-In; Paeng, Jin Chul [Seoul National University Hospital, Department of Nuclear Medicine, 101 Daehang-ro, Jongno-gu, Seoul (Korea, Republic of); Han, Sae-Won [Seoul National University Hospital, Department of Internal Medicine, 101 Daehang-ro, Jongno-gu, Seoul (Korea, Republic of); Seoul National University College of Medicine, Cancer Research Institute, Seoul (Korea, Republic of); Kim, Jee Hyun [Seoul National University Bundang Hospital, Department of Internal Medicine, Geyonggi-do (Korea, Republic of); Kang, Gyeong Hoon [Seoul National University Hospital, Department of Pathology, Seoul (Korea, Republic of); Jeong, Seung-Yong; Park, Kyu Joo [Seoul National University Hospital, Department of Surgery, Seoul (Korea, Republic of); Kim, Tae-You [Seoul National University Hospital, Department of Internal Medicine, 101 Daehang-ro, Jongno-gu, Seoul (Korea, Republic of); Seoul National University College of Medicine, Cancer Research Institute, Seoul (Korea, Republic of); Seoul National University, Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul (Korea, Republic of)

2017-05-15

This study was performed to evaluate whether fluorine-18 fluorodeoxyglucose positron-emission tomography/computed tomography (FDG PET/CT) could predict treatment outcome of regorafenib in metastatic colorectal cancer (mCRC). Previously treated refractory mCRC patients were enrolled into a prospective biomarker study of regorafenib. For this sub-study, the results of FDG PET/CT scans at baseline and after two cycles of treatment were analyzed. Various metabolic parameters obtained from PET images were analyzed in relation to treatment outcome. A total of 40 patients were evaluable for PET image analysis. Among various PET parameters, total lesion glycolysis (TLG) measured in the same target lesions for RECIST 1.1 analysis were the most significant in predicting prognosis, with the lowest p-value observed in TLG calculated using the margin threshold of 40 % (TLG{sub 40} {sub %}). Further analysis using TLG{sub 40} {sub %} showed significantly longer overall survival (OS) in patients with lower baseline TLG{sub 40} {sub %} (<151.8) (p = 0.003, median 14.2 vs. 9.1 months in <151.8 and ≥151.8, respectively). Patients showing higher decrease in TLG{sub 40} {sub %} after treatment showed significantly longer progression-free survival (PFS) (p = 0.001, median 8.0 vs. 2.4 months in % ΔTLG{sub 40} {sub %} < -9.6 % and ≥ -9.6 %, respectively) and OS (p = 0.002, median 16.4 vs. 9.1 months in % ΔTLG{sub 40} {sub %} < -9.6 % and ≥ -9.6 %, respectively). The same cutoff could discriminate patients with longer survival among the patients who were under the stable disease category according to RECIST 1.1 (median PFS 8.4 vs. 6.8 months, p = 0.020; median OS 18.3 vs. 11.5 months, p = 0.049). Measurement of TLG can predict treatment outcome of regorafenib in mCRC. (orig.)

Prognostic factors and a survival score for patients with metastatic spinal cord compression from colorectal cancer

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Rades, D.; Douglas, S.; Huttenlocher, S. [Luebeck Univ. (Germany). Dept. of Radiation Oncology; Veninga, T. [Dr. Bernard Verbeeten Institute, Tilburg (Netherlands). Dept. of Radiation Oncology; Bajrovic, A. [University Medical Center Eppendorf, Hamburg (Germany). Dept. of Radiation Oncology; Rudat, V. [Saad Specialist Hospital Al-Khobar (Saudi Arabia). Dept. of Radiation Oncology; Schild, S.E. [Mayo Clinic, Scottsdale, AZ (United States). Dept. of Radiation Oncology

2012-12-15

Background: This study aimed to identify independent prognostic factors and to create a survival score for patients with metastatic spinal cord compression (MSCC) from colorectal cancer (CRC). Patients and methods: Data from 121 patients irradiated for MSCC from CRC were retrospectively analyzed. Eleven potential prognostic factors were investigated including tumor type, age, gender, Eastern Cooperative Oncology Group performance status score (ECOG-PS), number of involved vertebrae, ambulatory status prior to radiotherapy (RT), other bone metastases, visceral metastases, interval from cancer diagnosis to RT of MSCC, time of developing motor deficits prior to RT, and the RT schedule. Results: On multivariate analysis, improved motor function was significantly associated with an ECOG-PS of 1-2 (p = 0.011) and a slower development of motor deficits (p < 0.001). Improved local control was significantly associated with absence of visceral metastases (p = 0.043) and longer-course RT (p = 0.008). Improved survival was significantly associated with an ECOG-PS of 1-2 (p < 0.001), ambulatory status (p < 0.001), absence of visceral metastases (p < 0.001), and a slower development of motor deficits (p = 0.047). These four prognostic factors were included in a survival score. The score for each factor was determined by dividing the 6-month survival rate by 10. The prognostic score represented the sum of the factor scores. Four prognostic groups were designed; the 6-month survival rates were 0% for 8-12 points, 26% for 13-18 points, 62% for 20-23 points, and 100% for 24-27 points (p < 0.001). Conclusion: This study identified several independent prognostic factors for treatment outcomes in patients irradiated for MSCC from CRC. The survival prognosis of these patients can be estimated with a new score. (orig.)

The impact of surgical resection of the primary tumor on the development of synchronous colorectal liver metastasis: a systematic review.

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Pinson, H; Cosyns, S; Ceelen, Wim P

2018-05-22

In recent years different therapeutic strategies for synchronously liver metastasized colorectal cancer were described. Apart from the classical staged surgical approach, simultaneous and liver-first strategies are now commonly used. One theoretical drawback of the classical approach is, however, the stimulatory effect on liver metastases growth that may result from resection of the primary tumour. This systematic review, therefore, aims to investigate the current insights on the stimulatory effects of colorectal surgery on the growth of synchronous colorectal liver metastases in humans. The systematic review was conducted according to the PRISMA statement. A literature search was performed using PubMed and Embase. Articles investigating the effects of colorectal surgery on synchronous colorectal liver metastases were included. Primary endpoints were metastatic tumor volume, metabolic and proliferative activity and tumour vascularization. Four articles meeting the selection criteria were found involving 200 patients. These studies investigate the effects of resection of the primary tumour on synchronous liver metastases using histological and radiological techniques. These papers support a possible stimulatory effect of resection of the primary tumor. Some limited evidence supports the hypothesis that colorectal surgery might stimulate the growth and development of synchronous colorectal liver metastases.

Single-Agent Panitumumab in Frail Elderly Patients With Advanced RAS and BRAF Wild-Type Colorectal Cancer: Challenging Drug Label to Light Up New Hope

Science.gov (United States)

Cremolini, Chiara; Aprile, Giuseppe; Lonardi, Sara; Orlandi, Armando; Mennitto, Alessia; Berenato, Rosa; Antoniotti, Carlotta; Casagrande, Mariaelena; Marsico, Valentina; Marmorino, Federica; Cardellino, Giovanni Gerardo; Bergamo, Francesca; Tomasello, Gianluca; Formica, Vincenzo; Longarini, Raffaella; Giommoni, Elisa; Caporale, Marta; Di Bartolomeo, Maria; Loupakis, Fotios; de Braud, Filippo

2015-01-01

Background. No prospective trials have specifically addressed the efficacy and safety of panitumumab in elderly patients with metastatic colorectal cancer (CRC). We aimed at assessing the efficacy and safety of single agent panitumumab in “frail” elderly patients diagnosed with metastatic RAS and BRAF wild-type CRC. Materials and Methods. Forty elderly patients (aged ≥75 years) with metastatic RAS-BRAF wild-type CRC received off-label prescriptions of single-agent panitumumab at seven Italian institutions. Treatment was administered as first line in patients with absolute contraindication to any chemotherapy or as second-line treatment after failure of a fluoropyrimidine-based treatment, in the presence of contraindication to irinotecan. The outcome measures included objective response rate (ORR), as well as progression-free survival (PFS), disease control rate (DCR), overall survival (OS), and safety. Results. The median PFS and OS were 6.4 months (95% confidence interval [CI]: 4.9–8 months) and 14.3 months (95% CI: 10.9–17.7 months), respectively. ORR was 32.5%, and DCR was 72.5%. Dose reductions related to adverse events (AEs) were reported in 9 (23%) patients, but no permanent treatment discontinuation caused by was reported. The most frequent grade 3 AE was skin rash, with an incidence of 20%. Conclusion. Panitumumab is effective and well-tolerated in frail elderly patients with RAS-BRAF wild-type metastatic CRC and deemed unfit for chemotherapy. A randomized study is needed to confirm these data. Implications for Practice: Treatment of elderly patients with metastatic colorectal cancer represents a difficult challenge in clinical practice. A significant proportion of frail elderly patients do not receive treatment, reflecting ongoing uncertainty of clinical benefit and toxicity of chemotherapy. Unfit condition in this cohort of patients further limits antineoplastic prescription and consequently patient survival. RAS and BRAF wild-type status could

Cost-effectiveness analysis of aflibercept in combination with FOLFIRI in the treatment of patients with metastatic colorectal cancer

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M.ª Echave

2014-07-01

Full Text Available Objectives: To estimate the incremental cost per life-year gained (LYG of aflibercept in combination with FOLFIRI as second-line treatment in metastatic colorectal cancer (mCRC patients previously treated with oxaliplatin. Methods: Based on clinical trial VELOUR results, a three-state Markov model (stable disease, progression and death with 2-week cycle duration was designed. Transition to health state «progression» implied the interruption of second-line treatment and administration of a third-line treatment (post-second line chemotherapy. Cost estimation included disease management cost (pharmaceutical, adverse event management, administration costs, etc.. Both cost and outcomes were discounted (3% annually. Sensitivity analyses (SA were performed to test model robustness. Results: Administration of aflibercept + FOLFIRI as second-line treatment provided 1.78 LYG (21 life-months gained. With FOLFIRI 1.43 LYG (17 months were obtained. The cost of the clinical management of aflibercept + FOLFIRI implied an additional investment of 13,564 compared with FOLFIRI for a lifetime horizon, being total costs for aflibercept + FOLFIRI of 38,346, compared to 24,782 with FOLFIRI. In the cost-effectiveness analysis 38,931/LYG was obtained with aflibercept in combination with FOLFIRI versus FOLFIRI. Conclusion: Aflibercept in combination with FOLFIRI increased overall survival versus FOLFIRI, so it is an effective strategy in the treatment of patients with mCRC. Aflibercept in combination with FOLFIRI is an efficient strategy for second-line mCRC treatment from the National Health System perspective.

DCLK1 immunoreactivity in colorectal neoplasia

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Bellows CF

2012-04-01

Full Text Available Giuseppe Gagliardi1, Monica Goswami1, Roberto Passera2, Charles F Bellows11Department of Surgery and Pathology, Tulane University, New Orleans, LA, USA; 2Division of Nuclear Medicine Azienda Ospedaliero-Universitaria San Giovanni Battista, Turin, ItalyIntroduction: Microtubule-associated doublecortin and CaM kinase-like-1 (DCLK1 is a novel candidate marker for intestinal stem cells. The aim of our study was to assess DCLK1 immunoreactivity in colorectal carcinogenesis and its correlation with prognosis.Methods: DCLK1 immunostaining was performed in colorectal tissue from 71 patients, including 18 adenomatous polyps, 40 primary adenocarcinomas, and 14 metastatic lesions. Each case was evaluated by a combined scoring method based on the intensity of staining (score 0–3 and the percentage of tissue staining positive (score 0–3. Immunoexpression for DCLK1 was considered as positive when the combined score was 2–6 and negative with a score of 0–1.Results: Overall, 14/18 (78% of polyps, 30/40 (75% of primary adenocarcinomas, and 7/14 (50% of distant metastases were positive for DCLK1. In adenomatous polyps and primary cancer there was no association between DCLK1 staining score and tumor pathology. However, after curative colorectal cancer resection, patients whose tumor had a high (≥5 combined staining score had increased cancer-specific mortality compared to patients with low (0–4 staining score (hazard ratio 5.89; 95% confidence interval: 1.22–28.47; P = 0.027.Conclusion: We found that DCLK1 is frequently expressed in colorectal neoplasia and may be associated with poor prognosis. Further studies are necessary to validate the use of DCLK1 as a prognostic marker.Keywords: DCLK1, DCAMKL-1, gastrointestinal stem cell, cancer stem cell, adenomatous polyps, liver metastasis, immunohistochemistry

Low Expression of DYRK2 (Dual Specificity Tyrosine Phosphorylation Regulated Kinase 2 Correlates with Poor Prognosis in Colorectal Cancer.

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Haiyan Yan

Full Text Available Dual-specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2 is a member of dual-specificity kinase family, which could phosphorylate both Ser/Thr and Tyr substrates. The role of DYRK2 in human cancer remains controversial. For example, overexpression of DYRK2 predicts a better survival in human non-small cell lung cancer. In contrast, amplification of DYRK2 gene occurs in esophageal/lung adenocarcinoma, implying the role of DYRK2 as a potential oncogene. However, its clinical role in colorectal cancer (CRC has not been explored. In this study, we analyzed the expression of DYRK2 from Oncomine database and found that DYRK2 level is lower in primary or metastatic CRC compared to adjacent normal colon tissue or non-metastatic CRC, respectively, in 6 colorectal carcinoma data sets. The correlation between DYRK2 expression and clinical outcome in 181 CRC patients was also investigated by real-time PCR and IHC. DYRK2 expression was significantly down-regulated in colorectal cancer tissues compared with adjacent non-tumorous tissues. Functional studies confirmed that DYRK2 inhibited cell invasion and migration in both HCT116 and SW480 cells and functioned as a tumor suppressor in CRC cells. Furthermore, the lower DYRK2 levels were correlated with tumor sites (P = 0.023, advanced clinical stages (P = 0.006 and shorter survival in the advanced clinical stages. Univariate and multivariate analyses indicated that DYRK2 expression was an independent prognostic factor (P < 0.001. Taking all, we concluded that DYRK2 a novel prognostic biomarker of human colorectal cancer.

Preclinical Efficacy of [V4Q5]dDAVP, a Second Generation Vasopressin Analog, on Metastatic Spread and Tumor-Associated Angiogenesis in Colorectal Cancer.

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Garona, Juan; Sobol, Natasha T; Pifano, Marina; Segatori, Valeria I; Gomez, Daniel E; Ripoll, Giselle V; Alonso, Daniel F

2018-06-01

Control of metastatic spread of colorectal cancer (CRC) remains as a major therapeutic challenge. [V4Q5]dDAVP is a vasopressin peptide analog with previously reported anticancer activity against carcinoma tumors. By acting as a selective agonist of AVPR2 present in endothelial and tumor cells, [V4Q5]dDAVP is able to impair tumor aggressiveness and distant spread. Our aim was to evaluate the potential therapeutic benefits of [V4Q5]dDAVP on highly aggressive CRC disease using experimental models with translational relevance. Murine CT-26 and human Colo-205 AVPR2-expressing CRC cell lines were used to test the preclinical efficacy of [V4Q5]dDAVP, both in vitro and in vivo. In syngeneic mice surgically implanted with CT-26 cells in the spleen, sustained i.v. treatment with [V4Q5]dDAVP (0.3 µg/kg) dramatically impaired metastatic progression to liver without overt signs of toxicity, and also reduced experimental lung colonization. The compound inhibited in vivo angiogenesis driven by Colo-205 cells in athymic mice, as well as in vitro endothelial cell migration and capillary tube formation. [V4Q5]dDAVP exerted AVPR2-dependent cytostatic activity in vitro (IC50 1.08 µM) and addition to 5-FU resulted in synergistic antiproliferative effects both in CT-26 and Colo-205 cells. The present preclinical study establishes for the first time the efficacy of [V4Q5]dDAVP on CRC. These encouraging results suggest that the novel second generation vasopressin analog could be used for the management of aggressive CRC as an adjuvant agent during surgery or to complement standard chemotherapy, limiting tumor angiogenesis and metastasis and thus protecting the patient from CRC recurrence.

Enhancement of P53-Mutant Human Colorectal Cancer Cells Radiosensitivity by Flavonoid Fisetin

International Nuclear Information System (INIS)

Chen Wenshu; Lee Yijang; Yu Yichu; Hsaio Chinghui

2010-01-01

Purpose: The aim of this study was to investigate whether fisetin is a potential radiosensitizer for human colorectal cancer cells, which are relatively resistant to radiotherapy. Methods and Materials: Cell survival was examined by clonogenic survival assay, and DNA fragmentation was assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay. The effects of treatments on cell cycle distribution and apoptosis were examined by flow cytometry. Western blot analysis was performed to ascertain the protein levels of γ-H2AX, phospho-Chk2, active caspase-3, PARP cleavage, phospho-p38, phospho-AKT, and phospho-ERK1/2. Results: Fisetin pretreatment enhanced the radiosensitivity of p53-mutant HT-29 human colorectal cancer cells but not human keratocyte HaCaT cells; it also prolonged radiation-induced G 2 /M arrest, enhanced radiation-induced cell growth arrest in HT-29 cells, and suppressed radiation-induced phospho-H2AX (Ser-139) and phospho-Chk2 (Thr-68) in p53-mutant HT-29 cells. Pretreatment with fisetin enhanced radiation-induced caspase-dependent apoptosis in HT-29 cells. Fisetin pretreatment augmented radiation-induced phosphorylation of p38 mitogen-activated protein kinase, which is involved in caspase-mediated apoptosis, and SB202190 significantly reduced apoptosis and radiosensitivity in fisetin-pretreated HT-29 cells. By contrast, both phospho-AKT and phospho-ERK1/2, which are involved in cell proliferation and antiapoptotic pathways, were suppressed after irradiation combined with fisetin pretreatment. Conclusions: To our knowledge, this study is the first to provide evidence that fisetin exerts a radiosensitizing effect in p53-mutant HT-29 cells. Fisetin could potentially be developed as a novel radiosensitizer against radioresistant human cancer cells.

Systematic review and economic evaluation of bevacizumab and cetuximab for the treatment of metastatic colorectal cancer.

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Tappenden, P; Jones, R; Paisley, S; Carroll, C

2007-03-01

To assess the clinical effectiveness and cost-effectiveness of bevacizumab and cetuximab in the treatment of individuals with metastatic colorectal cancer (CRC). Searches of main electronic databases were conducted in April and May 2005. For the assessment of bevacizumab, trials were included if they recruited participants with untreated metastatic CRC for first-line treatment. Only trials comparing bevacizumab in combination with irinotecan and/or established fluorouracil (5-FU)-containing or releasing regimens given as first-line therapy were included. For the assessment of cetuximab, trials were included if they recruited participants with epidermal growth-factor receptor-expressing metastatic CRC who had previously failed irinotecan-including therapy. Independent cost-effectiveness models of bevacizumab and cetuximab were developed using survival modelling methods. Adding bevacizumab to irinotecan in combination with 5-FU/folic acid (FA) plus irinotecan resulted in a statistically significant increase in median overall survival (OS) of 4.7 months. Adding bevacizumab to 5-FU/FA resulted in a non-significant increase in median OS of 3.7 months within one study and 7.7 months in another. Adding bevacizumab to irinotecan, fluorouracil and leucovorin (IFL) resulted in a statistically significant increase in median progression-free survival (PFS) of 4.4 months. Adding bevacizumab to 5-FU/FA resulted in a statistically significant increase in median PFS of 3.7 months, and a statistically significant increase in time to disease progression of 3.8 months compared to FU/FA alone. An overall tumour response rate of 44.8% was reported for bevacizumab plus IFL compared to 34.8% for IFL plus placebo. This addition was statistically significant. The addition of bevacizumab to 5-FU/FA resulted in a significant difference in tumour response rate within one study, but not another. Bevacizumab in combination with IFL or 5-FU/FA was observed to result in an increase of grade 3

The high affinity selectin glycan ligand C2-O-sLex and mRNA transcripts of the core 2 β-1,6-N-acetylglusaminyltransferase (C2GnT1) gene are highly expressed in human colorectal adenocarcinomas

International Nuclear Information System (INIS)

St Hill, Catherine A; Farooqui, Mariya; Mitcheltree, Gregory; Gulbahce, H Evin; Jessurun, Jose; Cao, Qing; Walcheck, Bruce

2009-01-01

The metastasis of cancer cells and leukocyte extravasation into inflamed tissues share common features. Specialized carbohydrates modified with sialyl Lewis x (sLe x ) antigens on leukocyte membranes are ligands for selectin adhesion molecules on activated vascular endothelial cells at inflammatory sites. The activity of the enzyme core 2 β1,6 N-acetylglucosaminyltransferase (C2GnT1) in leukocytes greatly increases their ability to bind to endothelial selectins. C2GnT1 is essential for the synthesis of core 2-branched O-linked carbohydrates terminated with sLe x (C2-O-sLe x ). Our goal was to determine the expression profiles of C2-O-sLe x in the malignant progression and metastasis of colorectal adenocarcinomas. The well characterized CHO-131 monoclonal antibody (mAb) specifically recognizes C2-O-sLe x present in human leukocytes and carcinoma cells. Using CHO-131 mAb, we investigated whether C2-O-sLe x was present in 113 human primary colorectal adenocarcinomas, 10 colorectal adenomas, 46 metastatic liver tumors, 28 normal colorectal tissues, and 5 normal liver tissues by immunohistochemistry. We also examined mRNA levels of the enzyme core 2 β1,6-N-acetylglucosaminyltransferase (C2GnT1) in 20 well, 15 moderately, and 2 poorly differentiated colorectal adenocarcinomas, and in 5 normal colorectal tissues by using quantitative real-time polymerase chain reactions (RT-PCR). We observed high reactivity with CHO-131 mAb in approximately 70% of colorectal carcinomas and 87% of metastatic liver tumors but a lack of reactivity in colorectal adenomas and normal colonic and liver tissues. Positive reactivity with CHO-131 mAb was very prominent in neoplastic colorectal glands of well to moderately differentiated adenocarcinomas. The most intense staining with CHO-131 mAb was observed at the advancing edge of tumors with the deepest invasive components. Finally, we analyzed C2GnT1 mRNA levels in 37 colorectal adenocarcinomas and 5 normal colorectal tissues by RT

BRAFV600E mutation analysis in patients with metastatic colorectal cancer (mCRC in daily clinical practice: correlations with clinical characteristics, and its impact on patients' outcome.

Directory of Open Access Journals (Sweden)

Zacharenia Saridaki

Full Text Available To prospectively evaluate the usefulness of the BRAFV600E mutation detection in daily clinical practice in patients with metastatic Colorectal Cancer (mCRC.504 mCRC patients treated with systemic chemotherapy ± biologics were analyzed.A statistically significant higher incidence of the BRAF mutation was observed in patients with ECOG-PS 2 (p=0.001, multiple metastatic sites (p=0.002,> 65 years old (p=0.004, primary tumors located in the colon (p<0.001, high-grade tumors (p=0.001 and in those with mucinous features (p=0.037. Patients with BRAFV600E mutated tumors had a statistically significantly reduced progression-free survival (PFS compared to wild-type (wt ones (4.1 and 11.6 months, respectively; p<0.001 and overall survival (OS (14.0 vs. 34.6 months, respectively; p<0.001. In the multivariate analysis the BRAFV600E mutation emerged as an independent factor associated with reduced PFS (HR: 4.1, 95% CI 2.7-6.2; p<0.001 and OS (HR: 5.9, 95% CI 3.7-9.5; p<0.001. Among the 273 patients treated with salvage cetuximab or panitumumab, the BRAFV600E mutation was correlated with reduced PFS (2.2 vs. 6.0 months; p<0.0001 and OS (4.3 vs. 17.4 months; p<0.0001.The presence of BRAFV600E-mutation in mCRC characterizes a subgroup of patients with distinct biologic, clinical and pathological features and is associated with very poor patients' prognosis.

Topoisomerase 1(TOP1) gene copy number in stage III colorectal cancer patients and its relation to prognosis

DEFF Research Database (Denmark)

Rømer, Maria Unni Koefoed; Nygård, Sune Boris; Christensen, Ib Jarle

2013-01-01

A Topoisomerase 1 (Top1) poison is frequently included in the treatment regimens for metastatic colorectal cancer (mCRC). However, no predictive biomarkers for Top1 poisons are available. We here report a study on the TOP1 gene copy number in CRC patients and its association with patient prognosis...

Long survival in a patient with metastatic colorrectal carcinoma: reality or utopia?

Science.gov (United States)

Illán, Andrea; Aires, Jonathan; Quintana, Laura

2017-09-01

We report the case of a 42-year-old male patient with mucinous-type metastatic colorectal carcinoma of eight years of evolution. He has received multiple lines of cytostatic treatment with acceptable tolerance and without significant impairment in his quality of life. At present, it is estimated that the overall survival of metastatic colon cancer in cytostatic treatment is around 24 months. However, a small subset of patients may present prolonged survivals of 5 to 10 years after diagnosis, revealing heterogeneity of tumor behavior and response to treatment. Our clinical case represents a long survivor patient despite the advanced stage of his oncological mucinous-colorrectal disease, endorsed in the scientific literature as having worse rates of objective response and less survival. There are different therapeutic approaches that can achieve a significant overall survival. It is essential in clinical practice to use all drugs available to achieve increase of progression-free survival and overall survival, with maintenance of an adequate quality of life.

Danish Colorectal Cancer Group Database.

Science.gov (United States)

Ingeholm, Peter; Gögenur, Ismail; Iversen, Lene H

2016-01-01

The aim of the database, which has existed for registration of all patients with colorectal cancer in Denmark since 2001, is to improve the prognosis for this patient group. All Danish patients with newly diagnosed colorectal cancer who are either diagnosed or treated in a surgical department of a public Danish hospital. The database comprises an array of surgical, radiological, oncological, and pathological variables. The surgeons record data such as diagnostics performed, including type and results of radiological examinations, lifestyle factors, comorbidity and performance, treatment including the surgical procedure, urgency of surgery, and intra- and postoperative complications within 30 days after surgery. The pathologists record data such as tumor type, number of lymph nodes and metastatic lymph nodes, surgical margin status, and other pathological risk factors. The database has had >95% completeness in including patients with colorectal adenocarcinoma with >54,000 patients registered so far with approximately one-third rectal cancers and two-third colon cancers and an overrepresentation of men among rectal cancer patients. The stage distribution has been more or less constant until 2014 with a tendency toward a lower rate of stage IV and higher rate of stage I after introduction of the national screening program in 2014. The 30-day mortality rate after elective surgery has been reduced from >7% in 2001-2003 to database is a national population-based clinical database with high patient and data completeness for the perioperative period. The resolution of data is high for description of the patient at the time of diagnosis, including comorbidities, and for characterizing diagnosis, surgical interventions, and short-term outcomes. The database does not have high-resolution oncological data and does not register recurrences after primary surgery. The Danish Colorectal Cancer Group provides high-quality data and has been documenting an increase in short- and long

The Prognostic and Predictive Value of Soluble Type IV Collagen in Colorectal Cancer

DEFF Research Database (Denmark)

Rolff, Hans Christian; Christensen, Ib Jarle; Vainer, Ben

2016-01-01

PURPOSE: To investigate the prognostic and predictive biomarker value of type IV collagen in colorectal cancer. EXPERIMENTAL DESIGN: Retrospective evaluation of two independent cohorts of patients with colorectal cancer included prospectively in 2004-2005 (training set) and 2006-2008 (validation....... RESULTS: High levels of type IV collagen showed independent prognostic significance in both cohorts with hazard ratios (HRs; for a one-unit change on the log base 2 scale) of 2.25 [95% confidence intervals (CIs), 1.78-2.84; P ... and validation set, respectively. The prognostic impact was present both in patients with metastatic and nonmetastatic disease. The predictive value of the marker was investigated in stage II and III patients. In the training set, type IV collagen was prognostic both in the subsets of patients receiving...

Diffusion-weighted magnetic resonance imaging predicts survival in patients with liver-predominant metastatic colorectal cancer shortly after selective internal radiation therapy

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Schmeel, Frederic Carsten; Simon, Birgit; Luetkens, Julian Alexander; Traeber, Frank; Schmeel, Leonard Christopher; Schild, Hans Heinz; Hadizadeh, Dariusch Reza [University Hospital Bonn, Rheinische-Friedrich-Wilhelms-Universitaet Bonn, Department of Radiology, Bonn (Germany); Sabet, Amir [University Hospital Bonn, Rheinische-Friedrich-Wilhelms-Universitaet Bonn, Department of Nuclear Medicine, Bonn (Germany); University Hospital Essen, Universitaet Duisburg-Essen, Department of Nuclear Medicine, Essen (Germany); Ezziddin, Samer [University Hospital Bonn, Rheinische-Friedrich-Wilhelms-Universitaet Bonn, Department of Nuclear Medicine, Bonn (Germany); University Hospital Saarland, Universitaet des Saarlandes, Department of Nuclear Medicine, Homburg (Germany)

2017-03-15

To investigate whether quantifications of apparent diffusion coefficient (ADC) on diffusion-weighted imaging (DWI) can predict overall survival (OS) in patients with liver-predominant metastatic colorectal cancer (CRC) following selective internal radiation therapy with {sup 90}Yttrium-microspheres (SIRT). Forty-four patients underwent DWI 19 ± 16 days before and 36 ± 10 days after SIRT. Tumour-size and intratumoral minimal ADC (minADC) values were measured for 132 liver metastases on baseline and follow-up DWI. Optimal functional imaging response to treatment was determined by receiver operating characteristics and defined as ≥22 % increase in post-therapeutic minADC. Survival analysis was performed with the Kaplan-Meier method and Cox-regression comparing various variables with potential impact on OS. Median OS was 8 months. The following parameters were significantly associated with median OS: optimal functional imaging response (18 vs. 5 months; p < 0.001), hepatic tumour burden <50 % (8 vs. 5 months; p = 0.018), Eastern Cooperative Oncology Group performance scale <1 (10 vs. 4 months; p = 0.012) and progressive disease according to Response and Evaluation Criteria in Solid Tumours (8 vs. 3 months; p = 0.001). On multivariate analysis, optimal functional imaging response and hepatic tumour burden remained independent predictors of OS. Functional imaging response assessment using minADC changes on DWI may predict survival in CRC shortly after SIRT. (orig.)

Raltitrexed (Tomudex administration in patients with relapsed metastatic colorectal cancer after weekly irinotecan/5-Fluorouracil/Leucovorin chemotherapy

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Vadiaka Maria

2002-01-01

Full Text Available Abstract Purpose The present study aimed at evaluating the efficacy of Raltitrexed, a specific thymidilate synthase inhibitor, in patients with advanced colorectal cancer (ACC in relapse (>8 weeks after a prior response or disease stabilization to first-line chemotherapy combination with lrinotecan+5-Fluorouracil (5-FU+Leucovorin (LV. Methods Twenty-five patients with metastatic ACC entered; 17 males/8 females, median age 61 (range: 47–70, median Karnovsky PS: 80 (70–90, and sites of metastases; liver: 21, lung: 4, lymph nodes: 7, peritoneal: 5 and a life expectancy of at least 3 months, were entered in the present pilot study. All patients had progressed after prior chemotherapy with lrinotecan+5-FU+LV. Raltitrexed was administered at a dose of 3 mg/m2 i.v. every 21 days. Results Three patients (12% achieved a partial response (PR, 8 (32% had stable disease (SD, and the remaining 14 (56% developed progressive disease (PD. Median time-to-progression (TTP was 5.5 months (range, 2–8.5, and median overall survival (OS 8 months (range, 4.0–12.5. Toxicity was generally mild; it consisted mainly of myelosuppression; neutropenia grade 1–2: 52%-grade 3: 28%, and anemia grade 1–2 only: 36%. Mild mucositis grade 1–2 occured in 13.5% of patients and was the principal non-hematologic toxicity. Conclusion Response to treatment with Raltitrexed is limited in patients with ACC failing after an initial response or non-progression to the weekly lrinotecan+5-FU+LV combination. However, it appears that a limited number of patients with PR/SD may derive clinical benefit, but final proof would require a randomized study.

Metastatic Malignancy to the Colon and Rectum: A Report of 14 Cases from One Single Institute.

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Lin, Chi-Chun; Lin, Chun-Chi; Chen, Wei-Shone; Lin, Tzu-Chen; Lin, Jen-Kou; Jiang, Jeng-Kai

2017-10-31

Metastatic malignancy occurs rarely in the colon or rectum. We presented 14 patients with colorectal metastasis (CRM). A retrospective review was conducted on a computerized colorectal tumor database at the Taipei Veterans General Hospital from January 2000 to June 2013. The incidence of CRM was 0.19% (14 in 7,524 patients). There were 6 males and 8 females with a mean age of 66.9 ± 13.6 years. Origins of the CRM included lung cancers (n = 3), prostate cancers (n = 2), and others (n = 1, respectively). Clinical presentations were not specific and colonoscopic pictures were indistinguishable from primary colorectal cancers; 5 of the 9 biopsies identified metastasis. Eight patients had extracolonic metastasis and 6 patients had CRM only. Significantly better survival was observed in the CRM-only group (p = 0.037). The mean interval from the treatment of primary tumor to the diagnosis of CRM was 30.2 ± 49.0 months. The mean survival time after CRM was 24.9 ± 30.8 months. Clinical features and colonoscopic findings of CRM were indistinguishable from primary colorectal cancer. Histopathological review of the biopsy could be helpful in identifying the primary lesion. Surgical resection with curative intent provided longer survival in CRM-only patients. © 2017 S. Karger AG, Basel.

KRAS and BRAF Mutation Detection: Is Immunohistochemistry a Possible Alternative to Molecular Biology in Colorectal Cancer?

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Nicolas Piton

2015-01-01

Full Text Available KRAS genotyping is mandatory in metastatic colorectal cancer treatment prior to undertaking antiepidermal growth factor receptor (EGFR monoclonal antibody therapy. BRAF V600E mutation is often present in colorectal carcinoma with CpG island methylator phenotype and microsatellite instability. Currently, KRAS and BRAF evaluation is based on molecular biology techniques such as SNaPshot or Sanger sequencing. As molecular testing is performed on formalin-fixed paraffin-embedded (FFPE samples, immunodetection would appear to be an attractive alternative for detecting mutations. Thus, our objective was to assess the validity of KRAS and BRAF immunodetection of mutations compared with the genotyping reference method in colorectal adenocarcinoma. KRAS and BRAF genotyping was assessed by SNaPshot. A rabbit anti-human KRAS polyclonal antibody was tested on 33 FFPE colorectal tumor samples with known KRAS status. Additionally, a mouse anti-human BRAF monoclonal antibody was tested on 30 FFPE tumor samples with known BRAF status. KRAS immunostaining demonstrated both poor sensitivity (27% and specificity (64% in detecting KRAS mutation. Conversely, BRAF immunohistochemistry showed perfect sensitivity (100% and specificity (100% in detecting V600E mutation. Although molecular biology remains the reference method for detecting KRAS mutation, immunohistochemistry could be an attractive method for detecting BRAF V600E mutation in colorectal cancer.

KRAS and BRAF Mutation Detection: Is Immunohistochemistry a Possible Alternative to Molecular Biology in Colorectal Cancer?

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Borrini, Francesco; Bolognese, Antonio; Lamy, Aude; Sabourin, Jean-Christophe

2015-01-01

KRAS genotyping is mandatory in metastatic colorectal cancer treatment prior to undertaking antiepidermal growth factor receptor (EGFR) monoclonal antibody therapy. BRAF V600E mutation is often present in colorectal carcinoma with CpG island methylator phenotype and microsatellite instability. Currently, KRAS and BRAF evaluation is based on molecular biology techniques such as SNaPshot or Sanger sequencing. As molecular testing is performed on formalin-fixed paraffin-embedded (FFPE) samples, immunodetection would appear to be an attractive alternative for detecting mutations. Thus, our objective was to assess the validity of KRAS and BRAF immunodetection of mutations compared with the genotyping reference method in colorectal adenocarcinoma. KRAS and BRAF genotyping was assessed by SNaPshot. A rabbit anti-human KRAS polyclonal antibody was tested on 33 FFPE colorectal tumor samples with known KRAS status. Additionally, a mouse anti-human BRAF monoclonal antibody was tested on 30 FFPE tumor samples with known BRAF status. KRAS immunostaining demonstrated both poor sensitivity (27%) and specificity (64%) in detecting KRAS mutation. Conversely, BRAF immunohistochemistry showed perfect sensitivity (100%) and specificity (100%) in detecting V600E mutation. Although molecular biology remains the reference method for detecting KRAS mutation, immunohistochemistry could be an attractive method for detecting BRAF V600E mutation in colorectal cancer. PMID:25983749

Phase I clinical and pharmacokinetic study of S-1 plus oral leucovorin in patients with metastatic colorectal cancer.

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Yoshino, Takayuki; Hyodo, Ichinosuke; Nishina, Tomohiro; Narahara, Hiroyuki; Sugimoto, Naotoshi; Yoshisue, Kunihiro; Boku, Narikazu

2017-01-01

S-1 has shown a response rate of 35% in chemonaïve patients with metastatic colorectal cancer (mCRC). Leucovorin enhances the antitumor activity of 5-fluorouracil, and concurrent oral administration of S-1 and leucovorin may represent a more active treatment option for mCRC. S-1 (35 mg/m 2 ) and leucovorin (25 mg/body) were orally administered twice daily to chemonaïve patients with mCRC. Predefined dose (schedule)-limiting toxicities (DLTs) during the first course and treatment continuity during the first two courses were evaluated during three periods of treatment with S-1 plus leucovorin (level 0, 2 weeks; level 1, 3 weeks; and level 2, 4 weeks), each followed by a 2-week rest. The pharmacokinetics (PK) of S-1 and leucovorin were studied on days 1 and 14 of the first course. Fifteen patients were enrolled. All three patients had DLTs at level 2, and this level was considered the maximum tolerated schedule. Level 0 was designated as the recommended schedule based on the incidences of DLTs and treatment continuity. The main toxic effects were gastrointestinal, such as diarrhea and stomatitis. There was no grade 4 adverse event or treatment-related death. The overall response rate was 67% (95% confidence interval, 38-88%). The PK profiles of S-1 plus leucovorin were similar to those in previous studies. The recommended schedule was 2 weeks of S-1 plus leucovorin followed by a 2-week rest. The increased response and gastrointestinal toxicities of S-1 plus leucovorin as compared with S-1 monotherapy suggest that co-administration of leucovorin enhanced the activity of S-1.

Synthesis and expression of CDw75 antigen in human colorectal cancer

International Nuclear Information System (INIS)

Costa-Nogueira, Clotilde; Villar-Portela, Susana; Cuevas, Elisa; Gil-Martín, Emilio; Fernández-Briera, Almudena

2009-01-01

Increased ST6Gal I activity has been associated with the α(2,6)sialylation enhancement of membrane glycoconjugates observed in metastatic colorectal carcinomas (CRC). Siaα(2,6)Galβ(1,4)GlcNAc sequence, known as CDw75, is a sialylated carbohydrate determinant generated by the ST6Gal I. This epitope has been reported to be associated with the progression of gastric and colorectal tumours, hence there are only a few conclusive studies to date. By radioisotopic techniques we evaluated the ST6Gal I activity in healthy, transitional and tumour tissues from 43 patients with CRC. By immunohistochemistry we assessed the CDw75 expression in 25 colorectal adenomas, 43 tumours, 13 transitional and 28 healthy tissues of CRC patients. ST6Gal I activity was likewise found to be statistically higher in tumour tissue respect to healthy tissue from CRC patients. CDw75 expression was positive in 20% of colorectal adenomas. Furthermore, 70% of tumour specimens and 8.3% of transitional specimens were positive for CDw75 expression, whereas none of the healthy ones showed the presence of the epitope. The major contribution of this study is the inclusion of data from transitional tissue and the analysis of CDw75 antigen expression in CRC and in colorectal adenomas, little known so far. ST6Gal I activity and CDw75 antigen expression were increased in CRC. Although their comparison did not reach the statistical significance, a great extent of patients showed both, an enhanced tumour ST6Gal I activity and an increased CDw75 expression in the tumour tissue. So, these two variables may play a role in malignant transformation. The expression of CDw75 in colorectal adenomas suggests that this antigen may be a tumour marker in CRC

Epidermal growth factor receptor gene copy number in 101 advanced colorectal cancer patients treated with chemotherapy plus cetuximab

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Zeuli Massimo

2010-04-01

Full Text Available Abstract Background Responsiveness to Cetuximab alone can be mediated by an increase of Epidermal Growth factor Receptor (EGFR Gene Copy Number (GCN. Aim of this study was to assess the role of EGFR-GCN in advanced colorectal cancer (CRC patients receiving chemotherapy plus Cetuximab. Methods One hundred and one advanced CRC patients (43 untreated- and 58 pre-treated were retrospectively studied by fluorescence in situ hybridization (FISH to assess EGFR-GCN and by immunohistochemistry (IHC to determine EGFR expression. Sixty-one out of 101 patients were evaluated also for k-ras status by direct sequencing. Clinical end-points were response rate (RR, progression-free survival (PFS and overall survival (OS. Results Increased EGFR-GCN was found in 60/101 (59% tumor samples. There was no correlation between intensity of EGFR-IHC and EGFR-GCN (p = 0.43. Patients receiving chemotherapy plus Cetuximab as first line treatment had a RR of 70% (30/43 while it was 18% (10/56 in the group with previous lines of therapy (p Conclusion In metastatic CRC patients treated with chemotherapy plus Cetuximab number of chemotherapy lines and increased EGFR-GCN were significantly associated with a better clinical outcome, independent of k-ras status.

[A case of metastatic gastric cancer originating from transverse colon cancer].

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Nushijima, Youichirou; Nakano, Katsutoshi; Sugimoto, Keishi; Nakaguchi, Kazunori; Kan, Kazuomi; Maruyama, Hirohide; Doi, Sadayuki; Okamura, Shu; Murata, Kohei

2014-11-01

Metastatic gastric cancer is uncommon, and metastasis of colorectal cancer to the stomach is extremely rare. We report a case of metastatic gastric cancer that originated from transverse colon cancer. A 52-year-old woman underwent a left hemicolectomy and D3 lymph node dissection based on a diagnosis of transverse colon cancer. The pathology results were as follows: mucinous adenocarcinoma, type 2, 6 × 11 cm, ss, ly1 v1, pm (-), dm (-), n1 (+), P0, H0, M0, Stage IIIa. The patient received XELOX as postoperative adjuvant therapy for 6 months. One year and 3 months after the left hemicolectomy, gastroscopy revealed a submucosal tumor in the lower body of the stomach and an incipient cancer in the cardia of the stomach, and a colonoscopy revealed an incipient cancer in the transverse colon. An endoscopic ultrasonography fine needle aspiration biopsy of the submucosal tumor in the lower body of the stomach was performed. Histology showed that this tumor was a mucinous adenocarcinoma similar to the primary transverse colon cancer, which led to a diagnosis of metastatic gastric cancer originating from transverse colon cancer. Distant metastasis was not detected. Endoscopic submucosal dissection of the incipient gastric cancer was performed, as were distal gastrectomy and partial colectomy. Peritoneal dissemination and para-aortic lymph node recurrence were detected 7 months after the second surgery.

Comparison of 1H-MRS-detected metabolic characteristics in single metastatic brain tumors of different origin

International Nuclear Information System (INIS)

Chernov, M.F.; Ono, Yuko; Kubo, Osami; Hori, Tomokatsu

2006-01-01

Various types of intracranial metastases exhibit different growth patterns, which can be reflected in their metabolic characteristics and investigated noninvasively by proton magnetic resonance spectroscopy ( 1 H-MRS). The objective of the present study was comparison of the 1 H-MRS-detected metabolic parameters in brain metastases of different origin. Twenty-five patients (15 men and 10 women; mean age, 62.0 years) with single, previously nontreated metastatic brain tumors were investigated by long-echo single-voxel volume-selected 1 H-MRS. The primary cancer was located in the lungs (10 cases), colon and rectum (8 cases), breast (3 cases), kidney (2 cases), prostate (1 case), and cardiac muscle (1 case). Comparison of clinical and radiological variables, including type of tumor contrast enhancement and extension of peritumoral edema, did not disclose statistically significant differences in metastatic brain tumors of different origin. At the same time, comparison of 1 H-MRS-detected metabolic characteristics revealed that metastases of colorectal carcinoma have greater content of mobile lipids (Lip) compared to other neoplasms. In conclusion, high Lip content in the viable brain metastases of colorectal carcinoma can be used as an additional diagnostic clue for noninvasive identification of these tumors and should be taken into consideration in cases of 1 H-MRS-based differentiation of their recurrence and radiation-induced necrosis after radiosurgical or radiotherapeutic treatment. (author)

Caffeic acid phenethyl ester preferentially sensitizes CT26 colorectal adenocarcinoma to ionizing radiation without affecting bone marrow radioresponse

International Nuclear Information System (INIS)

Chen, Y.-J.; Liao, H.-F.; Tsai, T.-H.; Wang, S.-Y.; Shiao, M.-S.

2005-01-01

Purpose: Caffeic acid phenethyl ester (CAPE), a component of propolis, was reported capable of depleting glutathione (GSH). We subsequently examined the radiosensitizing effect of CAPE and its toxicity. Methods and Materials: The effects of CAPE on GSH level, GSH metabolism enzyme activities, NF-κB activity, and radiosensitivity in mouse CT26 colorectal adenocarcinoma cells were determined. BALB/c mouse with CT26 cells implantation was used as a syngeneic in vivo model for evaluation of treatment and toxicity end points. Results: CAPE entered CT26 cells rapidly and depleted intracellular GSH in CT26 cells, but not in bone marrow cells. Pretreatment with nontoxic doses of CAPE significantly enhanced cell killing by ionizing radiation (IR) with sensitizer enhancement ratios up to 2.2. Pretreatment of CT26 cells with N-acetyl-L-cysteine reversed the GSH depletion activity and partially blocked the radiosensitizing effect of CAPE. CAPE treatment in CT26 cells increased glutathione peroxidase, decreased glutathione reductase, and did not affect glutathione S-transferase or γ-glutamyl transpeptidase activity. Radiation activated NF-κB was reversed by CAPE pretreatment. In vivo study revealed that pretreatment with CAPE before IR resulted in greater inhibition of tumor growth and prolongation of survival in comparison with IR alone. Pretreatment with CAPE neither affected body weights nor produced hepatic, renal, or hematopoietic toxicity. Conclusions: CAPE sensitizes CT26 colorectal adenocarcinoma to IR, which may be via depleting GSH and inhibiting NF-κB activity, without toxicity to bone marrow, liver, and kidney

Radioimmunoscintigraphy with 99mTc-labelled anti-CEA monoclonal antibodies in colorectal carcinoma patients

International Nuclear Information System (INIS)

Sergieva, S.; Baychev, G.; Tzingilev, D.; Delijski, T.; Kirova, G.; Kirilova, B.; Nenovska, M.

1998-01-01

Sixteen patients (2 female and 14 male, aged 42-75) were given intravenous injections with 99m Tc (555-740 MBq)-labelled anti-CEA MAb (CEA-Scan, Mallinckrodt Medical and M-CEATEC, Sorin Biomedica). Five of them were with duly established or established or suspected primary colorectal carcinoma, and eleven were studied postoperatively after recording an increase CEA levels in serum. The patients were scanned within 4-24 h of infusion using planar and tomographic imaging in rotation gamma-camera DIACAM (Siemens). At all 16 patients 27 true positive results were obtained: in 7 primary colorectal carcinomas, 5 locally recurrent tumors, 7 liver metastases, 6 lymphogeneous lesions and two - in the ureteral region. True negative results were established at three patients, false positive - in one patient with chronic inflammation, and false negative results - in 3 cases with liver metastases foci < 8 mm. Having 90 % sensitivity, 75 % specificity and 82.3 % accuracy, radioimmunoscintigraphy is a highly informative and sensitive imaging method for diagnosing and following up of primary, recurrent and metastatic foci in colorectal carcinoma patients. (author)

Takotsubo cardiomyopathy in two men receiving bevacizumab for metastatic cancer

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Thérèse H Franco

2008-10-01

Full Text Available Thérèse H Franco, Ahmed Khan, Vishal Joshi, Beje ThomasDepartment of Internal Medicine, University of Connecticut, Farmington, CT, USAAbstract: Bevacizumab is a monoclonal antibody that inhibits vascular endothelial growth factor (VEGF. It is a novel chemotherapeutic agent currently approved as part of combination chemotherapy for metastatic colorectal cancer, non-small cell lung cancer, and breast cancer (Hurwitz et al 2004; Sandler et al 2006; Traina et al 2007. Arterial thrombosis, including cerebral infarction, transient ischemic attacks, myocardial infarction, and angina are common, occurring in 4.4% of patients whose regimen includes bevacizumab (versus 1.9% on regimen without bevacizumab (Genetech, Inc. 2008. This series will review two cases of patients exposed to bevacizumab who subsequently developed ST elevations on electrocardiogram (ECG and elevated cardiac biomarkers. Both patients underwent cardiac catheterization, which demonstrated apical ballooning and akinesis in a distribution discordant with the observed (noncritical atherosclerotic lesions. Both patients had recovery of left ventricular function within 30 days. The clinical presentation, including ECGs and findings on catheterization as well as the rapid recovery of ventricular function, is consistent with the diagnosis of takotsubo cardiomyopathy. Takotsubo cardiomyopathy was first described in 1991, but the pathophysiology and exact mechanism of injury remain largely unknown. These two cases are notable for their occurrence in men and the association with treatment of metastatic cancer including bevacizumab.Keywords: vascular endothelial growth factor, bevacizumab, metastatic cancer, chemotherapy, takotsubo, cardiomyopathy

Laparoscopic versus open 1-stage resection of synchronous liver metastases and primary colorectal cancer.

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Gorgun, Emre; Yazici, Pinar; Onder, Akin; Benlice, Cigdem; Yigitbas, Hakan; Kahramangil, Bora; Tasci, Yunus; Aksoy, Erol; Aucejo, Federico; Quintini, Cristiano; Miller, Charles; Berber, Eren

2017-08-01

The aim of this study is to compare the perioperative and oncologic outcomes of open and laparoscopic approaches for concomitant resection of synchronous colorectal cancer and liver metastases. Between 2006 and 2015, all patients undergoing combined resection of primary colorectal cancer and liver metastases were included in the study (n=43). Laparoscopic and open groups were compared regarding clinical, perioperative and oncologic outcomes. There were 29 patients in the open group and 14 patients in the laparoscopic group. The groups were similar regarding demographics, comorbidities, histopathological characteristics of the primary tumor and liver metastases. Postoperative complication rate (44.8% vs . 7.1%, P=0.016) was higher, and hospital stay (10 vs . 6.4 days, P=0.001) longer in the open compared to the laparoscopic group. Overall survival (OS) was comparable between the groups (P=0.10); whereas, disease-free survival (DFS) was longer in laparoscopic group (P=0.02). According to the results, in patients, whose primary colorectal cancer and metastatic liver disease was amenable to a minimally invasive resection, a concomitant laparoscopic approach resulted in less morbidity without compromising oncologic outcomes. This suggests that a laparoscopic approach may be considered in appropriate patients by surgeons with experience in both advanced laparoscopic liver and colorectal techniques.

Clinical activity of pazopanib in metastatic extraosseous Ewing sarcoma

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Steven Attia

2015-05-01

Full Text Available We report a response to pazopanib in a 69-year-old man with heavily pre-treated metastatic extraosseous Ewing sarcoma in addition to molecular profiling of his tumor. To our knowledge, this case is the earliest to demonstrate activity of an oral multi-targeted kinase inhibitor in Ewing sarcoma. This case provides rationale for adding a Ewing sarcoma arm to SARC024, a phase II study of regorafenib, another multi-targeted kinase inhibitor, in patients with liposarcoma, osteosarcoma and Ewing and Ewing-like sarcomas (NCT02048371. This national multi-institutional study is ongoing.

Optimising the use of cetuximab in the continuum of care for patients with metastatic colorectal cancer.

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Goldberg, Richard M; Montagut, Clara; Wainberg, Zev A; Ronga, Philippe; Audhuy, François; Taieb, Julien; Stintzing, Sebastian; Siena, Salvatore; Santini, Daniele

2018-01-01

The anti-epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab in combination with chemotherapy is a standard of care in the first-line treatment of RAS wild-type (wt) metastatic colorectal cancer (mCRC) and has demonstrated efficacy in later lines. Progressive disease (PD) occurs when tumours develop resistance to a therapy, although controversy remains about whether PD on a combination of chemotherapy and targeted agents implies resistance to both components. Here, we propose that some patients may gain additional clinical benefit from the reuse of cetuximab after having PD on regimens including cetuximab in an earlier treatment line. We conducted a non-systematic literature search in PubMed and reviewed published and ongoing clinical trials, focusing on later-line cetuximab reuse in patients with mCRC. Evidence from multiple studies suggests that cetuximab can be an efficacious and tolerable treatment when continued or when fit patients with mCRC are retreated with it after a break from anti-EGFR therapy. Furthermore, on the basis of available preclinical and clinical evidence, we propose that longitudinal monitoring of RAS status may identify patients suitable for such a strategy. Patients who experience progression on cetuximab plus chemotherapy but have maintained RAS wt tumour status may benefit from continuation of cetuximab with a chemotherapy backbone switch because they have probably developed resistance to the chemotherapeutic agents rather than the biologic component of the regimen. Conversely, patients whose disease progresses on cetuximab-based therapy due to drug-selected clonal expansion of RAS- mutant tumour cells may regain sensitivity to cetuximab following a defined break from anti-EGFR therapy. Looking to the future, we propose that RAS status determination at disease progression by liquid, needle or excisional biopsy may identify patients eligible for cetuximab continuation and rechallenge. With this approach, treatment

Bevacizumab plus FOLFIRI or FOLFOX in chemotherapy-refractory patients with metastatic colorectal cancer: a retrospective study

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Portales Fabienne

2009-09-01

Full Text Available Abstract Background The anti-VEGF antibody bevacizumab associated with an irinotecan or oxaliplatin-based chemotherapy was proved to be superior to the chemotherapy alone in first or second line treatment of metastatic colorectal cancer (mCRC. However, it was reported to have no efficacy in 3rd or later-line, alone or with 5FU. The aim of this study was to evaluate the activity of bevacizumab combined with FOLFIRI or FOLFOX in mCRC who have failed prior chemotherapy with fluoropyrimidine plus irinotecan and/or oxaliplatin. Methods Thirty one consecutive patients treated between May 2005 and October 2006 were included in this retrospective study. All of them have progressed under a chemotherapy with fluoropyrimidine plus irinotecan and/or oxaliplatin and received bevacizumab (5 mg/kg in combination with FOLFIRI or simplified FOLFOX4 every 14 days. Results Ten patients (32.2% had an objective response (1 CR, 9 PR and 12 (38.8% were stabilized. The response and disease control rates were 45.4% and 100% when bevacizumab was administered in 2nd or 3rd line and 25% and 55% in 4th or later line respectively (p = 0.024 and p = 0.008. Among the patients who had previously received the same chemotherapy than that associated with bevacizumab (n = 28 the overall response rate was 35.7% and 39.3% were stabilized. Median progression free survival (PFS and overall survival (OS were of 9.7 and 18.4 months respectively. Except a patient who presented a hypertension associated reversible posterior leukoencephalopathy syndrome, tolerance of bevacizumab was acceptable. A rectal bleeding occurred in one patient, an epistaxis in five. Grade 1/2 hypertension occurred in five patients. Conclusion This study suggests that bevacizumab combined with FOLFOX or FOLFIRI may have the possibility to be active in chemorefractory and selected mCRC patients who did not receive it previously.

Clinical significance of BRAF non-V600E mutations on the therapeutic effects of anti-EGFR monoclonal antibody treatment in patients with pretreated metastatic colorectal cancer: the Biomarker Research for anti-EGFR monoclonal Antibodies by Comprehensive Cancer genomics (BREAC) study.

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Shinozaki, Eiji; Yoshino, Takayuki; Yamazaki, Kentaro; Muro, Kei; Yamaguchi, Kensei; Nishina, Tomohiro; Yuki, Satoshi; Shitara, Kohei; Bando, Hideaki; Mimaki, Sachiyo; Nakai, Chikako; Matsushima, Koutatsu; Suzuki, Yutaka; Akagi, Kiwamu; Yamanaka, Takeharu; Nomura, Shogo; Fujii, Satoshi; Esumi, Hiroyasu; Sugiyama, Masaya; Nishida, Nao; Mizokami, Masashi; Koh, Yasuhiro; Abe, Yukiko; Ohtsu, Atsushi; Tsuchihara, Katsuya

2017-11-07

Patients with BRAF V600E -mutated metastatic colorectal cancer (mCRC) have a poorer prognosis as well as resistance to anti-EGFR antibodies. However, it is unclear whether BRAF mutations other than BRAF V600E (BRAF non-V600E mutations) contribute to anti-EGFR antibody resistance. This study was composed of exploratory and inference cohorts. Candidate biomarkers identified by whole exome sequencing from super-responders and nonresponders in the exploratory cohort were validated by targeted resequencing for patients who received anti-EGFR antibody in the inference cohort. In the exploratory cohort, 31 candidate biomarkers, including KRAS/NRAS/BRAF mutations, were identified. Targeted resequencing of 150 patients in the inference cohort revealed 40 patients with RAS (26.7%), 9 patients with BRAF V600E (6.0%), and 7 patients with BRAF non-V600E mutations (4.7%), respectively. The response rates in RAS, BRAF V600E , and BRAF non-V600E were lower than those in RAS/BRAF wild-type (2.5%, 0%, and 0% vs 31.9%). The median PFS in BRAF non-V600E mutations was 2.4 months, similar to that in RAS or BRAF V600E mutations (2.1 and 1.6 months) but significantly worse than that in wild-type RAS/BRAF (5.9 months). Although BRAF non-V600E mutations identified were a rare and unestablished molecular subtype, certain BRAF non-V600E mutations might contribute to a lesser benefit of anti-EGFR monoclonal antibody treatment.

Predicting Treatment Response of Colorectal Cancer Liver Metastases to Conventional Lipiodol-Based Transarterial Chemoembolization Using Diffusion-Weighted MR Imaging: Value of Pretreatment Apparent Diffusion Coefficients (ADC) and ADC Changes Under Therapy.

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Lahrsow, Maximilian; Albrecht, Moritz H; Bickford, Matthew W; Vogl, Thomas J

2017-06-01

To use absolute pretreatment apparent diffusion coefficients (ADC) derived from diffusion-weighted MR imaging (DWI) to predict response to repetitive cTACE for unresectable liver metastases of colorectal carcinoma (CRLM) at 1 and 3 months after start of treatment. Fifty-five metastases in 34 patients were examined with DWI prior to treatment and 1 month after initial cTACE. Treatment was performed in 4-week intervals. Response was evaluated at 1 and 3 months after start of therapy. Metastases showing a decrease of ≥30% in axial diameter were classified as responding lesions. One month after initial cTACE, seven lesions showed early response. There was no significant difference in absolute pretreatment ADC values between responding and non-responding lesions (p = 0.94). Three months after initial cTACE, 17 metastases showed response. There was a significant difference (p = 0.021) between absolute pretreatment ADC values of lesions showing response (median 1.08 × 10 -3  mm 2 /s) and no response (median 1.30 × 10 -3  mm 2 /s). Pretreatment ADC showed fair diagnostic value to predict response (AUC 0.7). Lesions showing response at 3 months also revealed a significant increase in ADC between measurements before treatment and at one month after initial cTACE (p < 0.001). Applying an increase in ADC of 12.17%, response at 3 months after initial cTACE could be predicted with a sensitivity and specificity of 77 and 74%, respectively (AUC 0.817). Furthermore, there was a strong and significant correlation (r = 0.651, p < 0.001) between percentage change in size after third cTACE and percentage change in ADC. In patients with CRLM, ADC measurements are potential biomarkers for assessing response to cTACE.

Molecular profiling in the treatment of colorectal cancer: focus on regorafenib

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Yan Y

2015-10-01

Full Text Available Yiyi Yan, Axel Grothey Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA Abstract: Metastatic colorectal cancer (mCRC is a highly heterogeneous disease. Its treatment outcome has been significantly improved over the last decade with the incorporation of biological targeted therapies, including anti-EGFR antibodies, cetuximab and panitumumab, and VEGF inhibitors, bevacizumab, ramucirumab, and aflibercept. The identification of predictive biomarkers has further improved the survival by accurately selecting patients who are most likely to benefit from these treatments, such as RAS mutation profiling for EGFR antibodies. Regorafenib is a multikinase inhibitor currently used as late line therapy for mCRC. The molecular and genetic markers associated with regorafenib treatment response are yet to be characterized. Here, we review currently available clinical evidence of mCRC molecular profiling, such as RAS, BRAF, and MMR testing, and its role in targeted therapies with special focus on regorafenib treatment. Keywords: metastatic colon cancer, targeted therapy, molecular profiling, regorafenib 

Assessment of perioperative stress in colorectal cancer by use of in vitro cell models: a systematic review

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Tove Kirkegaard

2017-11-01

Full Text Available Background The perioperative period is important for patient outcome. Colorectal cancer surgery can lead to metastatic disease due to release of disseminated tumor cells and the induction of surgical stress response. To explore the overall effects on surgically-induced changes in serum composition, in vitro model systems are useful. Methods A systematic search in PubMed and EMBASE was performed to identify studies describing in vitro models used to investigate cancer cell growth/proliferation, cell migration, cell invasion and cell death of serum taken pre- and postoperatively from patients undergoing colorectal tumor resection. Results Two authors (MG and TK independently reviewed 984 studies and identified five studies, which fulfilled the inclusion criteria. Disagreements were solved by discussion. All studies investigated cell proliferation and cell invasion, whereas three studies investigated cell migration, and only one study investigated cell death/apoptosis. One study investigated postoperative peritoneal infection due to anastomotic leak, one study investigated mode of anesthesia (general anesthesia with volatile or intravenous anesthetics, and one study investigated preoperative intervention with granulocyte macrophage colony stimulating factor (GMCSF. In all studies an increased proliferation, cell migration and invasion was demonstrated after surgery. Anesthetics with propofol and intervention with GMCSF significantly reduced postoperative cell proliferation, whereas peritoneal infection enhanced the invasive capability of tumor cells. Conclusion This study suggests that in vitro cell models are useful and reliable tools to explore the effect of surgery on colorectal cancer cell proliferation and metastatic ability. The models should therefore be considered as additional tests to investigate the effects of perioperative interventions.

Identification Of Inequalities In The Selection Of Liver Surgery For Colorectal Liver Metastases In Sweden.

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Norén, A; Sandström, P; Gunnarsdottir, K; Ardnor, B; Isaksson, B; Lindell, G; Rizell, M

2018-04-01

Liver resection for colorectal liver metastases offers a 5-year survival rate of 25%-58%. This study aimed to analyze whether patients with colorectal liver metastases undergo resection to an equal extent and whether selection factors play a role in the selection process. Data were retrieved from the Swedish Colorectal Cancer Registry (2007-2011) for colorectal cancer and colorectal liver metastases. The patients identified were linked to the Swedish Registry of Liver and Bile surgery and the National Patient Registry to identify whether liver surgery or ablative treatment was performed. Analyses for age, sex, type of primary tumor and treating hospital (university, county, or district), American Society of Anesthesiologists class, and radiology for detection of metastatic disease were performed. Of 28,355 patients with colorectal cancer, 21.6% (6127/28,355) presented with liver metastases. Of the patients with liver metastases, 18.5% (1134/6127) underwent liver resection or ablation. The cumulative proportion of liver resection/ablation was 4% (1134/28,355) of all colorectal cancer. If "not bowel resected" were excluded, the proportion slightly increased to 4.7% (1134/24,262). Around 15% of the patients with metastases were registered as referrals for liver surgery. In a multivariable analysis patients treated at a university hospital for primary tumor were more frequently surgically treated for liver metastases (p 70 years and those with American Society of Anesthesiologists class >2 underwent liver resection less frequently. Magnetic resonance imaging of the liver was more often used in diagnostic work-up in men. Patients with colorectal liver metastases are unequally treated in Sweden, as indicated by the low referral rate. The proximity to a hepatobiliary unit seems important to enhance the patient's chances of being offered liver surgery.

Prognostic Impact of Neutrophil/Lymphocyte Ratio, Platelet Count, CRP, and Albumin Levels in Metastatic Colorectal Cancer Patients Treated with FOLFIRI-Bevacizumab.

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Artaç, Mehmet; Uysal, Mükremin; Karaağaç, Mustafa; Korkmaz, Levent; Er, Zehra; Güler, Tunç; Börüban, Melih Cem; Bozcuk, Hakan

2017-06-01

Metastatic colorectal cancer (mCRC) is a lethal disease and fluorouracil-leucovorin-irinotecan (FOLFIRI) plus bevacizumab (bev) is a standard approach. Hence, there is a strong need for identifying new prognostic factors to show the efficacy of FOLFIRI-bev. This is a retrospective study including patients (n = 90) with mCRC from two centers in Turkey. Neutrophil/lymphocyte (N/L) ratio, platelet count, albumin, and C-reactive protein (CRP) were recorded before FOLFIRI-bev therapy. The efficacy of these factors on progression-free survival (PFS) was analyzed with Kaplan Meier and Cox regression analysis. And the cutoff value of N/L ratio was analyzed with ROC analysis. The median age was 56 years (range 21-80). Forty-seven percent of patients with N/L ratio >2.5 showed progressive disease versus 43 % in patients with N/L ratio ratio >2.5 versus 13.5 months for the patients with N/L ratio analysis, high baseline neutrophil count, LDH, N/L ratio, and CRP were all significantly associated with poor prognosis. At multivariate Cox regression analysis, CRP was confirmed to be a better independent prognostic factor. CRP variable was divided into above the upper limit of normal (ULN) and normal value. The median PFSs of the patients with normal and above ULN were 11.3 versus 5.8 months, respectively (p = 0.022). CRP and N/L ratio are potential predictors for advanced mCRC treated with FOLFIRI-bev.

MiRNA-21 Expression Decreases from Primary Tumors to Liver Metastases in Colorectal Carcinoma.

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Fabian Feiersinger

Full Text Available Metastasis is the major cause of death in colorectal cancer patients. Expression of certain miRNAs in the primary tumors has been shown to be associated with progression of colorectal cancer and the initiation of metastasis. In this study, we compared miRNA expression in primary colorectal cancer and corresponding liver metastases in order to get an idea of the oncogenic importance of the miRNAs in established metastases.We analyzed the expression of miRNA-21, miRNA-31 and miRNA-373 in corresponding formalin-fixed paraffin-embedded (FFPE tissue samples of primary colorectal cancer, liver metastasis and healthy tissues of 29 patients by quantitative real-time PCR.All three miRNAs were significantly up-regulated in the primary tumor tissues as compared to healthy colon mucosa of the respective patients (p < 0.01. MiRNA-21 and miRNA-31 were also higher expressed in liver metastases as compared to healthy liver tissues (p < 0.01. No significant difference of expression of miRNA-31 and miRNA-373 was observed between primary tumors and metastases. Of note, miRNA-21 expression was significantly reduced in liver metastases as compared to the primary colorectal tumors (p < 0.01.In the context of previous studies demonstrating increased miRNA-21 expression in metastatic primary tumors, our findings raise the question whether miRNA-21 might be involved in the initiation but not in the perpetuation and growth of metastases.

Scrotal metastases from colorectal carcinoma: a case report.

LENUS (Irish Health Repository)

McWeeney, Doireann M

2012-01-31

ABSTRACT: A 72-year-old man presented with a two month history of rectal bleeding. Colonoscopy demonstrated synchronous lesions at 3 cm and 40 cm with histological analysis confirming synchronous adenocarcinomata. He developed bilobar hepatic metastases while undergoing neoadjuvant chemoradiotherapy. Treatment was complicated by Fournier\\'s gangrene of the right hemiscrotum which required surgical debridement. Eight months later he re-presented with an ulcerating lesion on the right hemiscrotum. An en-bloc resection of the ulcerating scrotal lesion and underlying testis was performed. Immunohistological analysis revealed metastatic adenocarcinoma of large bowel origin. Colorectal metastasis to the urogenital tract is rare and here we report a case of rectal carcinoma metastasizing to scrotal skin.

Effect of Proton Beam on Cancer Progressive and Metastatic Enzymes

International Nuclear Information System (INIS)

Sohn, Y. H.; Nam, K. S.; Oh, Y. H.; Kim, M. K.; Kim, M. Y.; Jang, J. S.

2008-04-01

The purpose of this study was to investigate the effect of proton beam on enzymes for promotion/progression of carcinogenesis and metastasis of malignant tumor cells to clarify proton beam-specific biological effects. The changes of cancer chemopreventive enzymes in human colorectal adenocarcinoma HT-29 cells irradiated with proton beams were tested by measuring the activities of quinine reductase (QR), glutathione S-transferase (GST), and ornithine decarboxylase (ODC), glutathione (GSH) levels, and expression of cyclooxygenase-2 (COX-2). We also examined the effect of proton beam on the ODC activity and expression of COX-2 in human breast cancer cell. We then assessed the metastatic capabilities of HT-29 and MDA-MB-231 cells irradiated with proton beam by measuring the invasiveness of cells through Matrigel-coated membrane and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced MMP activity in MDA-MB-231 and HT-29 cells. QR activity of irradiated HT-29 cells was slightly increased. Proton irradiation at dose of 32 Gy in HT-29 cells increased GST activity by 1.23-fold. In addition GSH levels in HT-29 cells was significantly increased 1.23- (p<0.05), 1.32- (p<0.01) and 1.34-fold (p<0.01) with the proton irradiation at doses of 8, 16 and 32 Gy, respectively. These results suggest that colon cancer chemopreventive activity was increased with the proton irradiation by increasing QR and GST activities and GSH levels and inhibiting ODC activity. Proton ion irradiation decreased the invasiveness of TPA-treated HT-29 cells and MDA-MB-231 cells through Matrigel-coated membrane. Proton ion irradiation pretreatment decreased TPA-induced MMP activity in MDA-MB-231 and HT-29 cells. Further studies are necessary to investigate if these findings could be translated to in vivo situations

Five year colorectal cancer outcomes in a large negative CT colonography screening cohort

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Kim, David H.; Pooler, B.D.; Pickhardt, Perry J. [University of Wisconsin School of Medicine and Public Health, Department of Radiology, Madison, WI (United States); Weiss, Jennifer M. [University of Wisconsin School of Medicine and Public Health, Section of Gastroenterology, Department of Internal Medicine, Madison, WI (United States)

2012-07-15

To assess the 5-year incidence of clinically presenting colorectal cancers following a negative CT colonography (CTC) screening examination, as few patient outcome data regarding a negative CTC screening result exist. Negative CTC screening patients (n = 1,050) in the University of Wisconsin Health system over a 14-month period were included. An electronic medical record (EMR) review was undertaken, encompassing provider, colonoscopy, imaging and histopathology reports. Incident colorectal cancers and other important GI tumours were recorded. Of the 1,050 cohort (mean [{+-}SD] age 56.9 {+-} 7.4 years), 39 (3.7%) patients were excluded owing to lack of follow-up within our system beyond the initial screening CTC. The remaining 1,011 patients were followed for an average of 4.73 {+-} 1.15 years. One incident colorectal adenocarcinoma represented a crude cancer incidence of 0.2 cancers per 1,000 patient years. EMR revealed 14 additional patients with clinically important GI tumours including: advanced adenomas (n = 11), appendiceal goblet cell carcinoid (n = 1), appendiceal mucinous adenoma (n = 1) and metastatic ileocolonic carcinoid (n = 1). All positive patients including the incident carcinoma are alive at the time of review. Clinically presenting colorectal adenocarcinoma is rare in the 5 years following negative screening CTC, suggesting that current strategies, including non-reporting of diminutive lesions, are appropriate. (orig.)

Five year colorectal cancer outcomes in a large negative CT colonography screening cohort

International Nuclear Information System (INIS)

Kim, David H.; Pooler, B.D.; Pickhardt, Perry J.; Weiss, Jennifer M.

2012-01-01

To assess the 5-year incidence of clinically presenting colorectal cancers following a negative CT colonography (CTC) screening examination, as few patient outcome data regarding a negative CTC screening result exist. Negative CTC screening patients (n = 1,050) in the University of Wisconsin Health system over a 14-month period were included. An electronic medical record (EMR) review was undertaken, encompassing provider, colonoscopy, imaging and histopathology reports. Incident colorectal cancers and other important GI tumours were recorded. Of the 1,050 cohort (mean [±SD] age 56.9 ± 7.4 years), 39 (3.7%) patients were excluded owing to lack of follow-up within our system beyond the initial screening CTC. The remaining 1,011 patients were followed for an average of 4.73 ± 1.15 years. One incident colorectal adenocarcinoma represented a crude cancer incidence of 0.2 cancers per 1,000 patient years. EMR revealed 14 additional patients with clinically important GI tumours including: advanced adenomas (n = 11), appendiceal goblet cell carcinoid (n = 1), appendiceal mucinous adenoma (n = 1) and metastatic ileocolonic carcinoid (n = 1). All positive patients including the incident carcinoma are alive at the time of review. Clinically presenting colorectal adenocarcinoma is rare in the 5 years following negative screening CTC, suggesting that current strategies, including non-reporting of diminutive lesions, are appropriate. (orig.)

Cost-effectiveness of RAS screening before monoclonal antibodies therapy in metastatic colorectal cancer based on FIRE3 Study

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Wen, Feng; Yang, Yu; Zhang, Pengfei; Zhang, Jian; Zhou, Jing; Tang, Ruilei; Chen, Hongdou; Zheng, Hanrui; Fu, Ping; Li, Qiu

2015-01-01

The surprising results published by FIRE-3 revealed that the overall survival (OS) of RAS wild-type metastatic colorectal cancer (mCRC) patients treated with Cetuximab(Cmab) and FOLFIRI combination was prolonged to 33.1 months. The substantial increase in testing and treatment costs, however, impose a considerable health burden on patients and society. Hence the study was aimed to assess the cost-effectiveness of RAS screening before monoclonal antibodies (mAbs) therapy based on FIRE-3 study. Four groups were analyzed: group 1, patients with KRAS testing treated with Cmab and FOLFIRI; group 2, patients with RAS testing treated with Cmab and FOLFIRI; group 3, patients with KRAS testing treated with bevacizumab(Bmab) and FOLFIRI; group 4, patients with RAS testing treated with Bmab and FOLFIRI. A Markov model comprising 3 health states (progression-free survival, progressive disease and death) was built. The costs were calculated from a Chinese payer perspective, and survival was reported in quality-adjusted life-months (QALMs). Average total lifetime costs ranged from $104,682.44 (RAS-Bmab) to $136,867.44 (RAS-Cmab), while the survival gained varied from 16.88 QALMs in RAS-Bmab to 21.85 QALMs in RAS-Cmab. The cost per QALM was $6,263.86 for RAS-Cmab, $6,145.84 for KRAS-Bmab, $6,201.57 for RAS-Bmab and $6,960.70 for KRAS-Cmab respectively. The KRAS-Cmab strategy was dominated by the other 3 groups. The first-treatment cost of RAS-Cmab was the most influential one to the model. In all, the RAS screening prior to Cmab treatment in mCRC seems to be a cost-effective strategy in the time of monoclonal antibodies (mAbs) therapy with the most gained QALMs. PMID:26418570

STUDY DATA OF KRAS- AND RAS-UNMUTATED (WILD TYPE OF COLORECTAL CANCER

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V. A. Gorbunova

2015-01-01

Full Text Available  Analysis of latest trials, comparing treatment schemes including chemotherapy with anti-EGFR monoclonal antibodies or bevacizumab is presented in this article. The data in these trials is inconsistent, but detailed analysis of FIRE-3 trial allows to distinguish a wild-type RAS patient group that benefits most from chemotherapy with cetuximab or panitumumab as 1st line metastatic colorectal cancer treatment. A final analysis of this patient group in CALGB/SWOG 80 405 trial is pending. The RAS analysis is pivotal for choice of 1st line chemotherapy.

Genetic dissimilarity between primary colorectal carcinomas and their lymph node metastases: ploidy, p53, bcl-2, and c-myc expression--a pilot study.

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Zalata, Khaled Refaat; Elshal, Mohamed Farouk; Foda, Abd AlRahman Mohammad; Shoma, Ashraf

2015-08-01

The current paradigm of metastasis proposes that rare cells within primary tumors acquire metastatic capability via sequential mutations, suggesting that metastases are genetically dissimilar from their primary tumors. This study investigated the changes in the level of expression of a well-defined panel of cell proliferation, differentiation, and apoptosis markers between the primary colorectal cancer (CRC) and the corresponding synchronous lymph node (LN) metastasis from the same patients. DNA flow cytometry and immunostaining of p53, bcl-2, and c-myc were carried out on 36 cases of CRC radical resection specimens with their corresponding LN metastases. There was very low probability that the histological patterns of primary tumors and LN metastases are independent (p < 0.001). Metastatic tumors were significantly more diffusely positive for p53 than the primary tumors (p < 0.001). Conversely, primary tumors were significantly more diffusely positive for c-myc than metastatic tumors (p = 0.011). No significant difference was found between the LNs and the primary tumors in bcl-2 positivity (p = 0.538) and DNA aneuploidy (p = 0.35), with a tendency towards negative bcl-2 and less aneuploidy in LN metastases than primary tumors. In conclusion, LN metastatic colorectal carcinomas have a tendency of being less differentiated, with a higher incidence of diffuse p53 staining, lower incidence of bcl-2 staining, and less aneuploidy in comparison to their primary counterparts suggesting a more aggressive biological behavior, which could indicate the necessity for more aggressive adjuvant therapy.

Anti-CEA monoclonal antibody in the diagnosis of colorectal, lung and ovarian carcinoma

International Nuclear Information System (INIS)

Jiang, N.; Lu, B.; Lu, X.; Sha, X.; Yue, D.

2000-01-01

This study evaluated the diagnostic value of radioimmnoimaging (RII) with 99 Tc labeled monoclonal antibody C50, raised originally against carcinoembryonic antigen (anti-CEA) in various tumors. 152 pathologically confirmed patients with a tumor were imaged prior to surgery with an anti-CEA monoclonal antibody labeled with 99 Tc. There were 115 patients with ovarian carcinoma, 26 patients with colorectal carcinoma and 11 patients with lung carcinoma. Images were acquired at 3-6 h post injection and were analyzed by the double blind method. Images of patients with ovarian cancer were compared with B-ultrasound images. Immunohistochemical staining was performed on all cases of colorectal cancer. All RII images demonstrated excellent contrast, clear lesions, and no serious toxic or other side reactions occurred. Transient chills and fever were observed in 3 cases. This study showed a sensitivity=88.2%, specificity=83.2%, and an accuracy=4.0%. The smallest lesion size detected was 2 x 2 cm. The total combined lesion detection rate for primary, metastatic, and recurrence lesions was 84.4%. We conclude that 99 Tc labeled anti-CEA MoAb C50 can be used in the diagnosis of colorectal carcinoma, ovarian carcinoma, and lung carcinoma

Benefit of FOLFOX to unresectable liver metastases secondary from colorectal carcinoma in an oncologic emergency.

Science.gov (United States)

Sugimoto, Maki; Yasuda, Hideki; Koda, Keiji; Yamazaki, Masato; Tezuka, Tohru; Takenoue, Tomohiro; Kosugi, Chihiro; Higuchi, Ryota; Yamamoto, Shiho; Watayo, Yoshihisa; Yagawa, Yohsuke; Suzuki, Masato

2007-09-01

Liver metastasis is an important prognostic factor in colorectal cancer. The efficacy of resection of metastatic lesions in liver metastasis of colorectal cancer is also widely recognized. However, studies on treatment methods of unresectable cases have not been sufficient and obtaining complete remission (CR) for liver metastasis is rare with chemotherapy. Selection of reliable chemotherapy for unresectable liver metastasis is an urgent necessity. The usefulness of oxaliplatin, 5-flurouracil and leucovorin combination therapy (FOLFOX) has recently been reported, but CR of liver metastasis is rare. The current status and new therapeutic significance of FOLFOX therapy are discussed based on the literature of colorectal cancer chemotherapy to date, and the clinical experience in which we obtained CR for liver metastasis is reported. The patient had stage IV rectal cancer, perforative peritonitis, pelvic abscess and simultaneous multiple liver metastasis. The patient underwent an emergency operation using the Hartmann's procedure. Liver metastasis is considered to be a prognostic factor and FOLFOX was selected as the postoperative chemotherapy, CR of the liver metastasis was obtained. FOLFOX was suggested to have new clinical significance in oncologic emergencies against unresectable liver metastasis in colorectal cancer and should serve as adjuvant chemotherapy that will contribute to improvement of treatment results.

Gd-EOB-DTPA-Enhanced MRI for Detection of Liver Metastases from Colorectal Cancer: A Surgeon’s Perspective!

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Kelly J. Lafaro

2013-01-01

Full Text Available Colorectal cancer affects over one million people worldwide annually, with the liver being the most common site of metastatic spread. Adequate resection of hepatic metastases is the only chance for a cure in a subset of patients, and five-year survival increases to 35% with complete resection. Traditionally, computed tomographic imaging (CT was utilized for staging and to evaluate metastases in the liver. Recently, the introduction of hepatobiliary contrast-enhanced magnetic resonance imaging (MRI agents including gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Eovist in the United States, Primovist in Europe, or Gd-EOB-DTPA has proved to be a sensitive method for detection of hepatic metastases. Accurate detection of liver metastases is critical for staging of colorectal cancer as well as preoperative planning.

PET/CT diagnostic of colo-rectal cancers

International Nuclear Information System (INIS)

Straciuc, O.

2012-01-01

Full text: Objective: Presenting the advantages of Positron Emission Tomography/Computed Tomography (PET/ CT) examination, using the radiotracer fluorure 18-deoxyglucose (FDG) in colo-rectal cancer diagnostic. Basics of the method will be also presented. Introduction: FDG PET/CT is recognized as the most efficient diagnostic imaging weapon in colorectal cancer, enable too comprehend all the 3 targets needed for staging of colo-rectal cancers: 1)Detection and evaluation of primary tumor (T) and recurrence; 2) Lymphadenopathy (N); 3)Metastatic disease (M). Assessment of treatment response during and after therapy, follow up and radiotherapy planning are also indications for PET/CT. There are two essential advantages of the method: 1)The whole body examination; 2)The complementary morphological information offered by CT and functional information offered by PET. Material and methods: Study of a total of 394 patients diagnosed with colo-rectal cancer of the total of 4125 investigated by PET/CT in Diagnosztika Pozitron center of Oradea, between 01.06.2008 - 06.06.2012. All cases had documented preoperative or postoperative histopathologic evaluation. We used a Siemens Biograph 16 device and only FDG as radiotracer, injected intravenously at a dose of 0.1-0.15 mCi /kg. Standard protocol of examination was performed at 60 minutes after FDG injection. CT acquisition consists of 'low dose' from vertex to thighs, followed by PET acquisition in 7 to 8 beds. Results: We followed the performance of PET/CT diagnostic in staging and restaging of colorectal cancer compared with other imaging methods. 141 patients had negative examinations. 107 patients were diagnosed with locally recurrent lesions, lymphadenopathy and/ or metastases. Compared with the results of previous imaging new metabolically active lesions were detected in 87 patients by PET/CT and suspected lesions were denied in 48 patients. Significant clinically cases are presented. Conclusions: The data obtained by PET

Abiraterone acetate, exemestane or the combination in postmenopausal patients with estrogen receptor-positive metastatic breast cancer ?

OpenAIRE

O'Shaughnessy, J.; Campone, M.; Brain, E.; Neven, P.; Hayes, D.; Bondarenko, I.; Griffin, T. W.; Martin, J.; De Porre, P.; Kheoh, T.; Yu, M. K.; Peng, W.; Johnston, S.

2015-01-01

Background Androgen receptor (AR) signaling and incomplete inhibition of estrogen signaling may contribute to metastatic breast cancer (MBC) resistance to a nonsteroidal aromatase inhibitor (NSAI; letrozole or anastrozole). We assessed whether combined inhibition of androgen biosynthesis with abiraterone acetate plus prednisone and estradiol synthesis with exemestane (E) may be of clinical benefit to postmenopausal patients with NSAI-pretreated estrogen receptor-positive (ER+) MBC. Patients a...

Feasibility, safety, and efficacy of aerobic training in pretreated patients with metastatic breast cancer: A randomized controlled trial.

Science.gov (United States)

Scott, Jessica M; Iyengar, Neil M; Nilsen, Tormod S; Michalski, Meghan; Thomas, Samantha M; Herndon, James; Sasso, John; Yu, Anthony; Chandarlapaty, Sarat; Dang, Chau T; Comen, Elizabeth A; Dickler, Maura N; Peppercorn, Jeffrey M; Jones, Lee W

2018-04-06

The investigation of exercise training in metastatic breast cancer has received minimal attention. This study determined the feasibility and safety of aerobic training in metastatic breast cancer. Sixty-five women (age, 21-80 years) with metastatic (stage IV) breast cancer (57% were receiving chemotherapy, and >40% had ≥ 2 lines of prior therapy) were allocated to an aerobic training group (n = 33) or a stretching group (n = 32). Aerobic training consisted of 36 supervised treadmill walking sessions delivered thrice weekly between 55% and 80% of peak oxygen consumption (VO 2peak ) for 12 consecutive weeks. Stretching was matched to aerobic training with respect to location, frequency, duration, and intervention length. The primary endpoint was aerobic training feasibility, which was a priori defined as the lost to follow-up (LTF) rate (aerobic training was LTF, whereas the mean attendance rate was 63% ± 30%. The rates of permanent discontinuation and dose modification were 27% and 49%, respectively. Intention-to-treat analyses indicated improvements in PROs, which favored the attention control group (P values > .05). Per protocol analyses indicated that 14 of 33 patients (42%) receiving aerobic training had acceptable tolerability (relative dose intensity ≥ 70%), and this led to improvements in VO 2peak and functional capacity (P values Aerobic training at the dose and schedule tested is safe but not feasible for a significant proportion of patients with metastatic breast cancer. The acceptable feasibility and promising benefit for select patients warrant further evaluation in a dose-finding phase 1/2 study. Cancer 2018. © 2018 American Cancer Society. © 2018 American Cancer Society.

Cetuximab and irinotecan as third line therapy in patients with advanced colorectal cancer after failure of irinotecan, oxaliplatin and 5-fluorouracil

DEFF Research Database (Denmark)

Pfeiffer, Per; Nielsen, Dorte; Yilmaz, Mette

2007-01-01

Cetuximab (Erbitux) in combination with irinotecan is the most promising combination in heavily pretreated patients with advanced colorectal cancer. Efficacy of this combination was confirmed in the pivotal BOND I study. The aim of the present study was to evaluate efficacy and toxicity of a comb......Cetuximab (Erbitux) in combination with irinotecan is the most promising combination in heavily pretreated patients with advanced colorectal cancer. Efficacy of this combination was confirmed in the pivotal BOND I study. The aim of the present study was to evaluate efficacy and toxicity......) and irinotecan (each 2 or 3 weeks) at three university hospitals. Median age was 57 years (23-78), and median performance status was 1 (0-3). Response rate was 20%, median TTP was 5.5 months and median OS was 10.4 months. Response and survival was significantly correlated with severity of skin toxicity. Toxicity...... grade 3 was rare (skin toxicity 8%, diarrhoea 10%, nausea 3%, vomiting 3%, fatigue 8%). Salvage therapy with cetuximab and irinotecan is effective in patients pretreated with irinotecan, and oxaliplatin and in a general population the results from the BOND I study was confirmed...

Addition of sunitinib to cetuximab and irinotecan in patients with heavily pre-treated advanced colorectal cancer

DEFF Research Database (Denmark)

Qvortrup, Camilla; Jensen, Benny Vittrup; Jørgensen, Trine Lembrecht

2010-01-01

Results of continuous sunitinib, in combination with cetuximab and irinotecan every other week (SIC) for compassionate use in heavily pre-treated patients with mCRC are presented.......Results of continuous sunitinib, in combination with cetuximab and irinotecan every other week (SIC) for compassionate use in heavily pre-treated patients with mCRC are presented....

Na,K-ATPase isozymes in colorectal cancer and liver metastases

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Marc eBaker Bechmann

2016-01-01

Full Text Available The goal of this study was to define Na,K-ATPase α and β subunit isoform expression and isozyme composition in colorectal cancer cells and liver metastases. The α1, α3 and β1 isoforms were the most highly expressed in tumor cells and metastases; in the plasma membrane of non-neoplastic cells and mainly in a cytoplasmic location in tumor cells. α1β1 and α3β1 isozymes found in tumor and metastatic cells exhibit the highest and lowest Na+ affinity respectively and the highest K+ affinity. Mesenchymal cell isozymes possess an intermediate Na+ affinity and a low K+ affinity. In cancer, these ions are likely to favor optimal conditions for the function of nuclear enzymes involved in mitosis, especially a high intra-nuclear K+ concentration. A major and striking finding of this study was that in liver, metastasized CRC cells express the α3β1 isozyme. Thus, the α3β1 isozyme could potentially serve as a novel exploratory biomarker of CRC metastatic cells in liver.

The Clinical and Cost Effectiveness of Aflibercept in Combination with Irinotecan and Fluorouracil-Based Therapy (FOLFIRI) for the Treatment of Metastatic Colorectal Cancer Which has Progressed Following Prior Oxaliplatin-Based Chemotherapy: a Critique of the Evidence.

Science.gov (United States)

Wade, Ros; Duarte, Ana; Simmonds, Mark; Rodriguez-Lopez, Rocio; Duffy, Steven; Woolacott, Nerys; Spackman, Eldon

2015-05-01

The National Institute for Health and Care Excellence (NICE) invited the manufacturer of aflibercept (Sanofi) to submit clinical and cost-effectiveness evidence for aflibercept in combination with irinotecan and fluorouracil-based therapy [irinotecan/5-fluorouracil/folinic acid (FOLFIRI)] for the treatment of metastatic colorectal cancer which has progressed following prior oxaliplatin-based chemotherapy, as part of the Institute's Single Technology Appraisal process. The Centre for Reviews and Dissemination and Centre for Health Economics at the University of York were commissioned to act as the independent Evidence Review Group (ERG). This article provides a description of the company submission, the ERG review and the resulting NICE guidance TA307 issued in March 2014. The ERG critically reviewed the evidence presented in the manufacturer's submission and identified areas requiring clarification, for which the manufacturer provided additional evidence. The clinical effectiveness data were derived from one good-quality double-blind randomised controlled trial (RCT), the VELOUR trial, which compared aflibercept plus FOLFIRI with placebo plus FOLFIRI. This RCT found a small but statistically significant increase in overall survival (OS); the difference in median OS was 1.44 months (13.5 months in the aflibercept group and 12.06 months in the placebo group). There was also a statistically significant increase in progression-free survival (PFS) with aflibercept; the difference in median PFS was 2.23 months (6.9 months in the aflibercept group and 4.67 months in the placebo group). However, grade 3-4 adverse events were more frequent in the aflibercept group than the placebo group: 83.5% compared with 62.5%. Treatment-emergent adverse events led to permanent discontinuation of treatment in 26.8% of patients in the aflibercept group and 12.1% of patients in the placebo group. The manufacturer's submission included an estimation of mean OS benefit based on extrapolation

Translating clinical research of Molecular Biology into a personalized, multidisciplinary approach of colorectal cancer patients.

Science.gov (United States)

Strambu, V; Garofil, D; Pop, F; Radu, P; Bratucu, M; Popa, F

2014-03-15

Although multimodal treatment has brought important benefit, there is still great heterogeneity regarding the indication and response to chemotherapy in Stage II and III, and individual variations related to both overall survival and toxicity of new therapies in metastatic disease or tumor relapse. Recent research in molecular biology led to the development of a large scale of genetic biomarkers, but their clinical use is not concordant with the high expectations. The Aim of this review is to identify and discuss the molecular markers with proven clinical applicability as prognostic and/or predictive factors in CRC and also to establish a feasible algorithm of molecular testing, as routine practice, in the personalized, multidisciplinary approach of colorectal cancer patients in our country. Despite the revolution that occurred in the field of molecular marker research, only Serum CEA, Immunohistochemical analysis of mismatch repair proteins and PCR testing for KRAS and BRAF mutations have confirmed their clinical utility in the management of colorectal cancer. Their implementation in the current practice should partially resolve some of the controversies related to this heterogenic pathology, in matters of prognosis in different TNM stages, stage II patient risk stratification, diagnosis of hereditary CRC and likelihood of benefit from anti EGFR therapy in metastatic disease. The proposed algorithms of molecular testing are very useful but still imperfect and require further validation and constant optimization.

FGFR2 amplification is predictive of sensitivity to regorafenib in gastric and colorectal cancers in vitro.

Science.gov (United States)

Cha, Yongjun; Kim, Hwang-Phill; Lim, Yoojoo; Han, Sae-Won; Song, Sang-Hyun; Kim, Tae-You

2018-03-24

Although regorafenib has demonstrated survival benefits in patients with metastatic colorectal and gastrointestinal stromal tumors, no proven biomarker has been identified for predicting sensitivity to regorafenib. Here, we investigated preclinical activity of regorafenib in gastric and colorectal cancer cells to identify genetic alterations associated with sensitivity to regorafenib. Mutation profiles and copy number assays of regorafenib target molecules indicated that amplification of FGFR2 was the only genetic alteration associated with in vitro sensitivity to regorafenib. Regorafenib effectively inhibited phosphorylation of FGFR2 and its downstream signaling molecules in a dose-dependent manner and selectively in FGFR2 amplified cells. Regorafenib induced G1 arrest (SNU-16, KATO-III) and apoptosis (NCI-H716), however, no significant changes were seen in cell lines without FGFR2 amplification. In SNU-16 mice xenografts, regorafenib significantly inhibited tumor growth, proliferation, and FGFR signaling compared to treatment with control vehicle. Regorafenib effectively abrogates activated FGFR2 signaling in FGFR2 amplified gastric and colorectal cancer and therefore, might be considered for integration into treatment in patients with FGFR2 amplified gastric and colorectal cancers. This article is protected by copyright. All rights reserved. Molecular Oncology (2018) © 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

[Management of synchronous colorectal liver metastases].

Science.gov (United States)

Dupré, Aurélien; Gagnière, Johan; Chen, Yao; Rivoire, Michel

2013-04-01

At time of diagnosis, 10 to 25% of patients with colorectal cancer present synchronous liver metastases. The treatment of such patients remains controversial without any evidence based organization. Therapeutic sequences are discussed including chemotherapy, colorectal surgery, liver resection and even radio-chemotherapy for some rectal cancers. In case of resectable liver metastases, preoperative chemotherapy offers the advantage of earlier treatment of micro-metastases as well as evaluation of tumor responsiveness, which can help shape future therapy. In this setting, different surgical strategies can be chosen (classical staged procedures with colorectal surgery followed by liver surgery, simultaneous resections or liver first approach) depending on the importance of the primary and metastatic tumors. The literature remains limited, but the results of these strategies seem identical in term of postoperative morbidity and long-term survival. Staged procedures are preferred in case of major liver resection. Location of the primary tumor on the low or mid rectum will necessitate preoperative long course chemoradiotherapy and a more complex multidisciplinary organization. For patients with extensive liver metastases, non-resectability must be assessed by experienced surgeon and radiologist before treatment and during chemotherapy. In this group of patients, improved chemotherapy regimen associated with targeted therapies and new surgical strategies (portal vein embolization, ablation, staged hepatectomies…) have improved resection rate (15 to 30-40%) and long-term survival. Treatment organization for the primary tumor remains controversial. Resection of the primary to manage symptoms such as obstruction, perforation or bleeding is advocated. For patients with asymptomatic primary a non-surgical approach permits to begin rapidly chemotherapy and obtain a better control of the disease. On the other hand, initial resection of the primary may avoid complications and

TH and DCX mRNAs in peripheral blood and bone marrow predict outcome in metastatic neuroblastoma patients.

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Yáñez, Yania; Hervás, David; Grau, Elena; Oltra, Silvestre; Pérez, Gema; Palanca, Sarai; Bermúdez, Mar; Márquez, Catalina; Cañete, Adela; Castel, Victoria

2016-03-01

In metastatic neuroblastoma (NB) patients, accurate risk stratification and disease monitoring would reduce relapse probabilities. This study aims to evaluate the independent prognostic significance of detecting tyrosine hydroxylase (TH) and doublecortin (DCX) mRNAs by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) in peripheral blood (PB) and bone marrow (BM) samples from metastatic NB patients. RT-qPCR was performed on PB and BM samples from metastatic NB patients at diagnosis, post-induction therapy and at the end of treatment for TH and DCX mRNAs detection. High levels of TH and DCX mRNAs when detected in PB and BM at diagnosis independently predicted worse outcome in a cohort of 162 metastatic NB. In the subgroup of high-risk metastatic NB, TH mRNA detected in PB remained as independent predictor of EFS and OS at diagnosis. After the induction therapy, high levels of TH mRNA in PB and DCX mRNA in BM independently predicted poor EFS and OS. Furthermore TH mRNA when detected in BM predicted worse EFS. TH mRNA in PB samples at the end of treatment is an independent predictor of worse outcome. TH and DCX mRNAs levels in PB and BM assessed by RT-qPCR should be considered in new pre-treatment risk stratification strategies to reliable estimate outcome differences in metastatic NB patients. In those high-risk metastatic NB, TH and DCX mRNA quantification could be used for the assessment of response to treatment and for early detection of progressive disease or relapses.

Colorectal Cancer Screening

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... Genetics of Colorectal Cancer Colorectal Cancer Screening Research Colorectal Cancer Screening (PDQ®)–Patient Version What is screening? Go ... These are called diagnostic tests . General Information About Colorectal Cancer Key Points Colorectal cancer is a disease in ...

Colorectal Cancer Prevention

Science.gov (United States)

... Genetics of Colorectal Cancer Colorectal Cancer Screening Research Colorectal Cancer Prevention (PDQ®)–Patient Version What is prevention? Go ... to keep cancer from starting. General Information About Colorectal Cancer Key Points Colorectal cancer is a disease in ...

Significance of pretreatment cardiovascular morbidity as a risk factor during treatment with parenteral oestrogen or combined androgen deprivation of 915 patients with metastasized prostate cancer

DEFF Research Database (Denmark)

Johansson, Robert; Damber, Jan Erik; Hagerman, Inger

2011-01-01

This study aimed to evaluate prognostic risk factors for cardiovascular events during treatment of metastatic prostate cancer patients with high-dose parenteral polyoestradiol phosphate (PEP, Estradurin®) or combined androgen deprivation (CAD) with special emphasis on pretreatment cardiovascular...

Cost-effectiveness analysis of cetuximab in treatment of metastatic colorectal cancer in Iranian pharmaceutical market

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Majid Davari

2015-01-01

Conclusions: The FOLFOX regimen + cetuximab provides lower costs per additional life years gained (more cost-effective compared with its alternatives in the treatment of patients with unresectable metastatic CRC. However, according to the WHO indicator, none of the cetuximab regimens could be considered as cost effective for the Iranian health care market.

TH-E-BRF-08: Subpopulations of Similarly-Responding Lesions in Metastatic Prostate Cancer

International Nuclear Information System (INIS)

Lin, C; Harmon, S; Perk, T; Jeraj, R

2014-01-01

Purpose: In patients with multiple lesions, resistance to cancer treatments and subsequent disease recurrence may be due to heterogeneity of response across lesions. This study aims to identify subpopulations of similarly-responding metastatic prostate cancer lesions in bone using quantitative PET metrics. Methods: Seven metastatic prostate cancer patients treated with AR-directed therapy received pre-treatment and mid-treatment [F-18]NaF PET/CT scans. Images were registered using an articulated CT registration algorithm and transformations were applied to PET segmentations. Midtreatment response was calculated on PET-based texture features. Hierarchical agglomerative clustering was used to form groups of similarly-responding lesions, with the number of natural clusters (K) determined by the inconsistency coefficient. Lesion clustering was performed within each patient, and for the pooled population. The cophenetic coefficient (C) quantified how well the data was clustered. The Jaccard Index (JI) assessed similarity of cluster assignments from patient clustering and from population clustering. Results: 188 lesions in seven patients were identified for analysis (between 6 to 53 lesions per patient). Lesion response was defined as percent change relative to pre-treatment for 23 uncorrelated PET-based feature identifiers. . High response heterogeneity was found across all lesions (i.e. range ΔSUVmax =−95.98% to 775.00%). For intra-patient clustering, K ranged from 1–20. Population-based clustering resulted in 75 clusters, of 1-6 lesions each. Intra-patient clustering resulted in higher quality clusters than population clustering (mean C=0.95, range=0.89 to 1.00). For all patients, cluster assignments from population clustering showed good agreement to intra-patient clustering (mean JI=0.87, range=0.68 to 1.00). Conclusion: Subpopulations of similarly-responding lesions were identified in patients with multiple metastatic lesions. Good agreement was found between

Survival, safety, and prognostic factors for outcome with Regorafenib in patients with metastatic colorectal cancer refractory to standard therapies: results from a multicenter study (REBACCA) nested within a compassionate use program

International Nuclear Information System (INIS)

Adenis, Antoine; Fouchardiere, Christelle de la; Paule, Bernard; Burtin, Pascal; Tougeron, David; Wallet, Jennifer; Dourthe, Louis-Marie; Etienne, Pierre-Luc; Mineur, Laurent; Clisant, Stéphanie; Phelip, Jean-Marc; Kramar, Andrew; Andre, Thierry

2016-01-01

Randomized trials have shown a survival benefit for regorafenib over placebo in patients with metastatic colorectal cancer (mCRC) that progressed after standard therapies. We evaluated survival and safety outcomes in patients treated with regorafenib in a real-life setting. REBECCA is a cohort study nested within a compassionate use program designed to evaluate survival, safety, and potential prognostic factors for outcome associated with regorafenib in patients with mCRC refractory to standard therapies. Treatment effects according to various patient and tumour characteristics were evaluated using univariate and multivariate Cox proportional hazards regression models. Of 1178 patients in the compassionate use program, 654 were in the full analysis set. Median follow-up was 16.5 months. Median survival was 5.6 months. The 12-month survival rate was 22 %. Survival was independently and unfavourably affected by the following variables: poor performance status, short time from initial diagnosis of metastases to the start of regorafenib, low initial regorafenib dose, >3 metastatic sites, presence of liver metastases, and KRAS mutations. We identified prognostic groups of patients with low, intermediate, and high risk of death, with a median survival of 9.2, 5.2, and 2.5 months, respectively. Five-hundred-twenty-four patients (80 %) experienced at least one regorafenib-related adverse event, most commonly, fatigue, hand-foot skin reaction, diarrhea, anorexia, arterial hypertension, and mucositis. The safety and efficacy profile of regorafenib in REBECCA are similar to those in randomized trials. Our prognostic model identified subgroups of mCRC patients who derived a minimal and maximum benefit from regorafenib. Clinicaltrials.gov: NCT02310477

Early post-treatment FDG PET predicts survival after {sup 90}Y microsphere radioembolization in liver-dominant metastatic colorectal cancer

Energy Technology Data Exchange (ETDEWEB)

Sabet, Amir; Aouf, Anas; Sabet, Amin; Ghamari, Shahab; Biersack, Hans-Juergen [University Hospital, Department of Nuclear Medicine, Bonn (Germany); Meyer, Carsten; Pieper, Claus C. [University Hospital, Department of Radiology, Bonn (Germany); Mayer, Karin [University Hospital, Department of Medicine and Oncology, Bonn (Germany); Ezziddin, Samer [University Hospital, Department of Nuclear Medicine, Bonn (Germany); Saarland University, Department of Nuclear Medicine, Homburg (Germany)

2014-10-29

The aim of this study was to evaluate the predictive value of early metabolic response 4 weeks post-treatment using {sup 18}F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT in patients with unresectable hepatic metastases of colorectal cancer (CRC) undergoing radioembolization (RE) with {sup 90}Y-labelled microspheres. A total of 51 consecutive patients with liver-dominant metastases of CRC were treated with RE and underwent {sup 18}F-FDG PET/CT at baseline and 4 weeks after RE. In each patient, three hepatic metastases with the highest maximum standardized uptake value (SUV{sub max}) were selected as target lesions. Metabolic response was defined as >50 % reduction of tumour to liver ratios. Survival analyses using Kaplan-Meier and multivariate analyses were performed to identify prognostic factors for overall survival (OS). Investigated baseline characteristics included age (>60 years), performance status (Eastern Cooperative Oncology Group >1), bilirubin (>1.0 mg/dl), hepatic tumour burden (>25 %) and presence of extrahepatic disease. The median OS after RE was 7 months [95 % confidence interval (CI) 5-8]; early metabolic responders (n = 33) survived longer than non-responders (p < 0.001) with a median OS of 10 months (95 % CI 3-16) versus 4 months (95 % CI 2-6). Hepatic tumour burden also had significant impact on treatment outcome (p < 0.001) with a median OS of 5 months (95 % CI, 3-7) for patients with >25 % metastatic liver replacement vs 14 months (95 % CI 6-22) for the less advanced patients. Both factors (early metabolic response and low hepatic tumour burden) remained as independent predictors of improved survival on multivariate analysis. These are the first findings to show that molecular response assessment in CRC using {sup 18}F-FDG PET/CT appears feasible as early as 4 weeks post-RE, allowing risk stratification and potentially facilitating early response-adapted treatment strategies. (orig.)

Risk of second primary colorectal cancer among colorectal cancer cases: A population-based analysis

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Kavitha P Raj

2011-01-01

Full Text Available Background: Patients with history of colorectal cancer (CRC are at increased risk for developing a second primary colorectal cancer (SPCRC as compared to the general population. However, the degree of risk is uncertain. Here, we attempt to quantify the risk, using data from the large population-based California Cancer Registry (CCR. Materials and Methods: We analyzed the CCR data for cases with surgically-treated colon and rectal cancer diagnosed during the period 1990-2005 and followed through up to January 2008. We excluded those patients diagnosed with metastatic disease and those in whom SPCRC was diagnosed within 6 months of the diagnosis of the primary CRC. Standardized incidence ratios (SIR with 95% confidence intervals (CI were calculated to evaluate risk as compared to the underlying population after taking into account age, sex, ethnicity, and time at risk. Results: The study cohort consisted of 69809 cases with colon cancer and 34448 with rectal cancer. Among these patients there were 1443 cases of SPCRCs. The SIR for developing SPCRC was higher in colon cancer survivors (SIR=1.4; 95% CI: 1.3 to 1.5 as compared to the underlying population. The incidence of SPCRC was also higher in females (SIR=1.5; 95% CI: 1.3 to 1.6 and Hispanics (SIR=2.0; 95% CI: 1.7 to 2.4 with primary colon cancer. The SIR for developing an SPCRC was higher only among those whose initial tumor was located in the descending colon (SIR=1.6; 95% CI: 1.3 to 2.0 and proximal colon (SIR=1.4; 95% CI: 1.3 to 1.6. Conclusions: Our results confirm that CRC patients, especially females and Hispanics, are at a higher risk of developing SPCRC than the general population. Differential SPCRC risk by colorectal tumor subsite is dependent on gender and ethnicity, underscoring the heterogeneous nature of CRC.

Eligibility of real-world patients with chemo-refractory, K-RAS wild-type, metastatic colorectal cancer for palliative intent regorafenib monotherapy.

Science.gov (United States)

Angeles, Arkhjamil; Hung, Wayne; Cheung, Winson Y

2018-06-23

The CORRECT trial demonstrated survival benefits with regorafenib monotherapy in patients with treatment-refractory, metastatic colorectal cancer (mCRC). However, the trial's stringent eligibility criteria for regorafenib may limit its external validity. We aimed to examine treatment attrition rates and eligibility for regorafenib in routine practice. We identified patients at the British Columbia Cancer Agency diagnosed with mCRC who demonstrated disease progression or intolerable toxicity on 2 or more lines of systemic therapy. During the study timeframe, panitumumab and cetuximab were only used in the chemo-refractory setting. Data on clinicopathologic variables and patient outcomes were ascertained and analyzed. Eligibility was determined using the CORRECT trial criteria. A total of 391 patients were identified, among whom only 39% were eligible for regorafenib: 35% in the panitumumab group and 51% in the cetuximab group. The main reasons for ineligibility in all patients were Eastern Cooperative Oncology Group Performance Status (ECOG PS) > 1 (69%), an elevated total bilirubin (21%), and thromboembolic events in the past 6 months (10%). No difference in eligibility for regorafenib was observed between patients previously receiving panitumumab or cetuximab (P = 0.914; 95% CI 0.550-1.951). Kaplan-Meier analyses showed that regorafenib-eligible compared to regorafenib-ineligible patients had an increased median overall survival of 5.3 versus 2.1 months, respectively (P < 0.001). However, Cox proportional hazard analyses showed that only ECOG PS rather than trial eligibility was correlated with outcomes. The strict eligibility criteria disqualify most patients with treatment-refractory mCRC for regorafenib therapy. Future trials should broaden the eligibility criteria to improve external validity.

ABC-Transporter Expression Does Not Correlate with Response to Irinotecan in Patients with Metastatic Colorectal Cancer

NARCIS (Netherlands)

Trumpi, K.; Emmink, B. L.; Prins, A. M.; van Oijen, M. G. H.; van Diest, P. J.; Punt, C. J. A.; Koopman, M.; Kranenburg, O.; Borel Rinkes, I. H. M.

2015-01-01

Background: Active efflux of irinotecan by ATP-binding cassette (ABC)-transporters, in particular ABCB1 and ABCG2, is a well-established drug resistance mechanism in vitro and in pre-clinical mouse models, but its relevance in colorectal cancer (CRC) patients is unknown. Therefore, we assessed the

A randomized study comparing short-time infusion of oxaliplatin in combination with capecitabine XELOX(30) and chronomodulated XELOX(30) as first-line therapy in patients with advanced colorectal cancer

DEFF Research Database (Denmark)

Qvortrup, C; Jensen, Benny Vittrup; Fokstuen, T

2010-01-01

Chronotherapy is one of the several approaches to increase efficacy and reduce toxicity of chemotherapy. In a phase II study in the second-line in patients with metastatic colorectal cancer (mCRC), we found that chronomodulated XELOX (XELOX(30Chron)) was a well-tolerated regimen with potentially...

Can preoperative CEA and CA19-9 serum concentrations suggest metastatic disease in colorectal cancer patients?

Science.gov (United States)

Stojkovic Lalosevic, Milica; Stankovic, Sanja; Stojkovic, Mirjana; Markovic, Velimir; Dimitrijevic, Ivan; Lalosevic, Jovan; Petrovic, Jelena; Brankovic, Marija; Pavlovic Markovic, Aleksandra; Krivokapic, Zoran

2017-01-01

This study was designed to investigate the efficiency of preoperative serum carcinoembryonic antigen (CEA) and carbohydrate cancer antigen (CA19-9) levels for diagnosing synchronous liver metastases and lymph node in colorectal carcinoma (CRC) patients. A total of 300 patients with histologically diagnosed CRC were included in this study between May 2014 and March 2015. The data were obtained prospectively from patient's medical records: medical history, demographics, tumor location, differentiation (grade), depth of the tumor (T), lymph node metastases (N), distant metastases (M), lymphatics, venous and perineural invasion, and disease stage. Tumor markers were measured with an electrochemiluminescent assay and the reference value was 5ng/ml for CEA and for Ca19-9, 37u/ml. There was A high statistically significant difference in the levels of serum CEA and CA19-9 between different disease stages of CRC (PCEA (stage I 3.76±8.73; II 5.68±17.27, III 7.56±14.81, and IV 70.90±253.23) and CA 19-9 levels (stage I 9.65±11.03, II 9.83±11.09; III 19.58±36.91, and IV 228.9±985.38, respectively). The mean CEA and CA19-9 serum levels were significantly higher in patients with regional lymph nodes involvement (CEA 37.21±177.85 vs 4.79±9.90, CA19-9 119.51±687.71 VS 12.24±17.69, respectively, PCEA 86.56±277.65 vs. 5.98±12.98, and CA19-9 273.27±1073.46 vs. 4.98±3142, respectively, with PCEA and CA 19-9, 3.5 ng/mL and 7.5 U/mL, respectively. While, a cut-off value for the presence of synchronous liver metastases of these two markers was 3.5ng/mL AND 5.5 U/mL. Our study showed that tumor makers, CEA and CA19-9, can be used as diagnostic factors regarding the severity of CRC specifically to suggest metastatic disease in CRC.

Thrombotic microangiopathy purpura in a patient with metastatic colorectal carcinoma

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Tea Nizič-Kos

2015-09-01

Full Text Available  AbstractBackground: Thrombotic microangiopathy (TMA is a rare syndrome that leads to excessive formation of blood clots, microthrombosis and is accompanied by non-autoimune haemolytic anemia and thrombocytopenia. Only few cases describing TMA caused by cancer are being reported in the literature.Patient: A 42-year old male patient with metastatic carcinoma of sigma and several accompanying diagnoses (pulmonary embolism, deep vein thrombosis, cerebrovascular insult had later developed clinical and laboratory signs of TMA. TMA was unresponsive to plasmapheresis, which was discontinued and first cycle of chemotherapy was applied. The patient died soon after. The autopsy did not provide any additional information about the disease, there were no signs of malignant bone marrow infiltration.Conclusion: The diagnosis of secondary TMA remains a diagnostic and therapeutic challenge. It appears as a rare complication in patients with cancer. Treatment is difficult because the cause of TMA (malignancy is hard to remove. Patients with cancer do not respond to plasmapheresis, which often delays the application of chemotherapy, the only effective treatment for TMA. Consequently this condition has poor prognosis.

CCR 20th Anniversary commentary: in search of cetuximab's first indication-combination therapy with irinotecan in colorectal cancer.

Science.gov (United States)

Hicklin, Daniel J

2015-04-01

The research article by Prewett and colleagues, published in the May 1, 2002, issue of Clinical Cancer Research, provided important translational data that extended earlier preclinical and clinical studies with the human-murine chimeric anti-EGFR monoclonal antibody C225. Subsequent clinical trials with C225 led to the demonstration of its efficacy in combination with irinotecan and regulatory approval for the treatment of metastatic colorectal cancer. ©2015 American Association for Cancer Research.

Treatment of Hormone Resistance with Docetaxel in Metastatic Prostate Cancer Patients: Results of a Clinical Experience at Omid Hospital, Isfahan, Iran

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Mina Tajvidi

2017-01-01

Full Text Available Background: Metastatic prostate cancer is one of the most important cancers among men worldwide. Androgen ablation therapy can be used in treatment of these patients; however, most will progress to metastatic hormone-refractory prostate cancer. In this regard, docetaxel has been approved to treat metastatic hormone-refractory prostate cancer in the United States. In this study, we aimed to investigate the results of this treatment modality in metastatic prostate cancer patients from Iran. Methods:We evaluated PSA response and bone pain relief in 18 metastatic prostate cancer patients who underwent treatment with docetaxel at a dose of 75 mg/m2 intravenously on the first day of treatment. The treatment was repeated every three weeks (6 cycles along with 10 mg of prednisolone. Results: Of 18 patients, 39% had >50% decline in PSA levels.There were 16% of the patients with a PSA decline of approximately 30% to 50% of the pre-treatment levels. In addition, 29% of the patients had progressive PSA levels during chemotherapy. Among them, 55% had significant pain relief. Conclusion: This research showed the effectiveness of docetaxel to decrease PSA levels in metastatic hormone-refractory prostate cancer patients from Iran. Docetaxel was also valuable in alleviation of pain in these patients. However, prospective studies should validate this approach.

Pretreatment costs of care and time to initial treatment for patients with cancer of unknown primary.

Science.gov (United States)

Walker, Mark S; Weinstein, Laura; Luo, Roger; Marino, Ingrid

2018-06-01

Time to treatment and pretreatment costs may be affected by unknown primary tumor site. This retrospective study used electronic medical record data from patients in ten US community oncology practices. Eligible patients were ≥18 years, diagnosed with cancer of unknown primary (CUP) or known metastatic solid tumor, and presented between 1 January 2012 and 30 June 2014. Patients with CUP (n = 294) had a longer interval than non-CUP patients (n = 92) from presentation to treatment initiation (1.18 vs 0.49 months, p < 0.0001), and had higher pretreatment costs (US$27,882 vs US$20,449, p = 0.0075). When analyzed as monthly cost, the difference between groups in log-cost per month was nonsignificant. Higher pretreatment costs in CUP patients appeared attributable to significantly longer time to initiation of therapy.

Personalizing therapy for colorectal cancer.