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Sample records for registered metastatic colorectal

  1. [Oral fluoropyrimidines registered for the treatment of metastatic colorectal carcinoma: a possible gain

    NARCIS (Netherlands)

    Croockewit, A.J.; Boer, J.E. de; Loenhout, J.W.A. van; Koopmans † , P.P.

    2002-01-01

    Up until now the standard treatment for metastasized colorectal carcinoma has been fluorouracil (5-FU) in combination with folonic acid in low doses administered intravenously, even after the recent registration of a number of new intravenously administered cytostatics, such as irinotecan and oxalip

  2. 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.

  3. Use of Bevacizumab in Metastatic Colorectal Cancer

    OpenAIRE

    Zinser-Sierra, Juan W.; Rodríguez-Ramírez, Saúl; Villalobos-Valencia, Ricardo; Ramírez-Márquez, Marcelino

    2012-01-01

    Colorectal cancer is one of the most common cancers worldwide, and although associated mortality rates in South American countries are generally among the lowest in the world, they are on the rise. The prognosis of patients diagnosed with metastatic colorectal cancer has improved markedly over the last 12 years, increasing from 5 months with best supportive care to almost 2 years with combination chemotherapy plus bevacizumab. New prognostic and predictive biomarkers have been identified to g...

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

    Directory of Open Access Journals (Sweden)

    Ocvirk Janja

    2016-06-01

    Full Text Available 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.

  5. Ziv-aflibercept in metastatic colorectal cancer

    Directory of Open Access Journals (Sweden)

    Patel A

    2013-12-01

    Full Text Available Anuj Patel, Weijing Sun Division of Hematology-Oncology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Abstract: The combination of cytotoxic chemotherapy and antiangiogenic agents has become a conventional treatment option for patients with metastatic colorectal cancer. Ziv-aflibercept is a fusion protein which acts as a decoy receptor for vascular endothelial growth factor (VEGF-A, VEGF-B, and placental growth factor (PlGF; it was approved in combination with 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI for the treatment of patients with metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin-containing fluoropyrimidine-based regimen. Herein we review the role of tumor angiogenesis as the rationale for antiangiogenic therapy, the clinical data associated with ziv-aflibercept, and its current role as a treatment option compared to other antiangiogenic agents, such as bevacizumab and regorafenib. Keywords: aflibercept, angiogenesis, colorectal cancer

  6. 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...

  7. Pharmacogenomics of cetuximab in metastatic colorectal carcinoma.

    Science.gov (United States)

    Silvestris, Nicola; Vincenzi, Bruno; Brunetti, Anna Elisabetta; Loupakis, Fotious; Dell'Aquila, Emanuela; Russo, Antonio; Scartozzi, Mario; Giampieri, Riccardo; Cascinu, Stefano; Lorusso, Vito; Tonini, Giuseppe; Falcone, Alfredo; Santini, Daniele

    2014-09-01

    Cetuximab is a chimeric monoclonal antibody that has revolutionized the treatment of metastatic colorectal cancer. Knowledge of the mechanisms that underlie its effectiveness, as well as the primary and secondary resistance mechanisms, have led to important developments in the understanding of cetuximab biology. In light of knowledge gained from recent trials, the efficacy of cetuximab has been clearly demonstrated to depend upon RAS mutational status, moreover cetuximab should only be used in a subset of patients who may benefit. In this article, we critically review clinical and pharmacogenetic issues of cetuximab, focusing on the cost-effectiveness involved with the use of the drug.

  8. 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......, 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...

  9. Intrahepatic therapy for liver-dominant metastatic colorectal cancer

    Institute of Scientific and Technical Information of China (English)

    Kerlijne; De; Groote; Hans; Prenen

    2015-01-01

    In patients with metastatic colorectal cancer, the liver is the most common site of metastatic disease. In patients with liver-dominant disease, consideration needs to be given to locoregional treatments such as hepatic arterial infusion chemotherapy, transarterial chemoembolisation and selective internal radiation therapy because hepatic metastases are a major cause of liver failure especially in chemorefractory disease. In this review we provide insights on the published literature for locoregional treatment of liver metastases in metastatic colorectal cancer.

  10. Metastatic colorectal cancer-past, progress and future

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    The clinical management of metastatic (stage Ⅳ)colorectal cancer (CRC) is a common challenge faced by surgeons and physicians. The last decade has seen exciting developments in the management of CRC, with significant improvements in prognosis for patients diagnosed with stage Ⅳ disease. Treatment options have expanded from 5-fluorouracil alone to a range of pharmaceutical and interventional therapies,improving survival, and providing a cure in selected cases. Enhanced understanding of the biologic pathways most important in colorectal carcinogenesis has led to a new generation of drugs showing promise in advanced disease. It is hoped that in the near future the treatment paradigm of metastatic CRC will be analogous to that of a chronic illness, rather than a rapidly terminal condition.This overview discusses the epidemiology of advanced CRC and currently available therapeutic options including medical, surgical, ablative and novel modalities in the management of metastatic colorectal cancer.

  11. Primary site resection is superior for incurable metastatic colorectal cancer

    Institute of Scientific and Technical Information of China (English)

    Yusuke; Tanoue; Nobutaka; Tanaka; Yukihiro; Nomura

    2010-01-01

    AIM:To investigate survival in patients treated with FOLFOX followed by primary site resection or palliative surgery for incurable metastatic colorectal cancer. METHODS:Between 2001 and 2009,a total of 98 patients with colorectal adenocarcinoma and non-resectable metastases were diagnosed and treated with the new systemic agent chemotherapy regimen FOLFOX. Primary site resection was carried out in 38 patients, creation of a colostomy or bypass without resection was carried out in 36 patients,and 23 were not...

  12. Visualising and quantifying angiogenesis in metastatic colorectal cancer

    DEFF Research Database (Denmark)

    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...

  13. Third-line therapy for metastatic colorectal cancer

    DEFF Research Database (Denmark)

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

    2008-01-01

    , 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...

  14. Metastatic colorectal cancer to a primary thyroid cancer

    Directory of Open Access Journals (Sweden)

    Swain Sarah

    2008-11-01

    Full Text Available Abstract Background Metastatic malignancy to the thyroid gland is generally uncommon due to an unfavourable local thyroid micro-environment which impairs the ability of metastatic cells to settle and thrive. Metastases to the thyroid gland have however been reported to occur occasionally particularly if there has been disruption to normal thyroid tissue architecture. Case presentation We report a patient with a history of surgically resected rectal adenocarcinoma who presents with a rising serum CEA level and an 18F-FDG PET scan positive thyroid nodule which was subsequently confirmed at surgery to be a focus of metastatic rectal adenocarcinoma within a primary poorly differentiated papillary thyroid carcinoma. Subsequent treatment involved right hemi-thyroidectomy, pulmonary wedge resection of oligometastatic metastatic colorectal cancer and chemotherapy. Conclusion Metastatic rectal carcinoma to the thyroid gland and in particular to a primary thyroid malignancy is rare and unusual. Prognosis is likely to be more dependent on underlying metastatic disease rather than the primary thyroid malignancy hence primary treatments should be tailored towards treating and controlling metastatic disease and less emphasis placed on the primary thyroid malignancy.

  15. Novel Therapies in Development for Metastatic Colorectal Cancer

    OpenAIRE

    Lee, Michael S.; Kopetz, Scott

    2014-01-01

    Colorectal cancer (CRC) is the second most common cause of cancer mortality in the United States. Despite advances in therapy, metastatic CRC remains lethal, and further improvements in therapy are needed. Growing understanding of cancer biology, particularly in growth factor signaling, angiogenesis, and cancer immunology, has translated into many novel therapies under investigation. Patients are increasingly selected for clinical trials rationally on the basis of integral biomarkers. This re...

  16. KRAS mutation testing in metastatic colorectal cancer

    Institute of Scientific and Technical Information of China (English)

    Cong Tan; Xiang Du

    2012-01-01

    The KRAS oncogene is mutated in approximately 35%-45% of colorectal cancers,and KRAS mutational status testing has been highlighted in recent years.The most frequent mutations in this gene,point substitutions in codons 12 and 13,were validated as negative predictors of response to anti-epidermal growth factor receptor antibodies.Therefore,determining the KRAS mutational status of tumor samples has become an essential tool for managing patients with colorectal cancers.Currently,a variety of detection methods have been established to analyze the mutation status in the key regions of the KRAS gene; however,several challenges remain related to standardized and uniform testing,including the selection of tumor samples,tumor sample processing and optimal testing methods.Moreover,new testing strategies,in combination with the mutation analysis of BRAF,PIK3CA and loss of PTEN proposed by many researchers and pathologists,should be promoted.In addition,we recommend that microsatellite instability,a prognostic factor,be added to the abovementioned concomitant analysis.This review provides an overview of KRAS biology and the recent advances in KRAS mutation testing.This review also addresses other aspects of status testing for determining the appropriate treatment and offers insight into the potential drawbacks of mutational testing.

  17. Tumor characteristics and metastatic sites may predict bevacizumab efficacy in the first-line treatment of metastatic colorectal cancer

    OpenAIRE

    Varol, Umut; Oktay, Esin; YILDIRIM, Mustafa; SURMELI, ZEKI GOKHAN; Dirican, Ahmet; Meydan, Nezih; KARACA, BURCAK; Karabulut, Bulent; Uslu, Ruchan

    2013-01-01

    Colorectal cancer (CRC) is among the most frequently diagnosed cancers and a major cause of cancer-related mortality worldwide. The aim of the present study was to determine whether there was an improvement in the time to disease progression (TTP) in patients with metastatic colorectal cancer (mCRC) treated with first-line bevacizumab plus chemotherapy, according to tumor characteristics and metastatic sites. Tumor characteristics and tumor burden were considered to be predictive markers of t...

  18. Economics of ramucirumab for metastatic colorectal cancer.

    Science.gov (United States)

    Zeichner, Simon B; Kohn, Christine G; Goldstein, Daniel A

    2016-12-01

    Despite its FDA approval and incorporation into the National Comprehensive Cancer Network (NCCN) treatment guidelines, ramucirumab (RAM) is associated with a drug acquisition cost that is substantially higher than other approved options. Given its substantial cost, the presence of a viable alternative treatment option, and its minimal survival improvement, the usefulness of RAM in clinical practice has been called into question. Areas covered: In this paper, we outline the cost, benefits, and economic implications of RAM from a US perspective, as it is used in the treatment of mCRC. We also dissect its use in other tumor types and in other healthcare systems around the world, and briefly compare it with similar drugs targeting the vascular endothelial growth factor pathway. We used the search engine PubMed using the following as search terms: cost-effectiveness; ramucirumab; metastatic colon cancer; angiogenesis; and value-based medicine. Expert commentary: The use of ramucirumab in the treatment of mCRC serves as a microcosm of the worsening healthcare crisis within the US and the ongoing controversy regarding oncology drug costs, benefits, and value. Therefore, there must be a joint effort in moving towards value based pricing models.

  19. Combining chemotherapy and targeted therapies in metastatic colorectal cancer

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Colorectal cancer remains one of the major causes of cancer death worldwide. During the past years, the development of new effective treatment options has led to a considerable improvement in the outcome of this disease. The advent of agents such as capecitabine, irinotecan, oxaliplatin, cetuximab and bevacizumab has translated into median survival times in the range of 2 years. Intense efforts have focused on identifying novel agents targeting specific growth factor receptors, critical signal transduction pathways or mediators of angiogenesis. In addition, several clinical trials have suggested that some of these molecularly targeted drugs can be safely and effectively used in combination with conventional chemotherapy. In this article we review various treatment options combining cytotoxic and targeted therapies currently available for patients with metastatic colorectal cancer.

  20. A novel antimetabolite: TAS-102 for metastatic colorectal cancer.

    Science.gov (United States)

    Miyamoto, Yuji; Lenz, Heinz-Josef; Baba, Hideo

    2016-01-01

    TAS-102 is a new oral anti-tumor drug, composed of a thymidine-based nucleoside analog (trifluridine: FTD) and a thymidine phosphorylase inhibitor (tipiracil hydrochloride: TPI). TAS-102 has been shown to significantly improve overall survival and progression-free survival in patients with refractory metastatic colorectal cancer (mCRC) in placebo-controlled randomized phase II and III trials. The current review summarizes mechanisms of action, pharmacokinetics/dynamics and preclinical and clinical data of TAS-102 in colorectal cancer. TAS-102 is a new salvage-line treatment option for patients with mCRC. TAS-102 is well tolerated and has great potential in future clinical drug combination therapies.

  1. Targeting metastatic colorectal cancer – present and emerging treatment options

    Directory of Open Access Journals (Sweden)

    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

  2. The clinical significance of circulating tumor cells in non-metastatic colorectal cancer - A review

    DEFF Research Database (Denmark)

    Thorsteinsson, M; Jess, Per

    2011-01-01

    with metastatic disease, but the prognostic role of CTC in non-metastatic colorectal cancer is less clear. The aim of this review is to examine the possible clinical significance of circulating tumor cells in non-metastatic colorectal cancer (TNM-stage I-III) with the primary focus on detection methods...... and prognosis. METHODS: The PubMed and Cochrane database and reference lists of relevant articles were searched for scientific literature published in English from January 2000 to June 2010. We included studies with non-metastatic colorectal cancer (TNM-stage I-III) and CTC detected pre- and/or post...

  3. Anti-angiogenic agents in metastatic colorectal cancer

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    Colorectal cancer (CRC) is a major public health concernbeing the third leading cause of cancer mortality inthe United States. The availability of better therapeuticoptions has led to a decline in cancer mortality in thesepatients. Surgical resection should be considered in allstages of the disease. The use of conversion therapyhas made surgery a potentially curative option even inpatients with initially unresectable metastatic disease.In this review we discuss the role of various antiangiogenicagents in patients with metastatic CRC(mCRC). We describe the mechanism of action of theseagents, and the rationale for their use in combinationwith chemotherapy. We also review important clinicalstudies that have evaluated the safety and efficacy ofthese agents in mCRC patients. Despite the discoveryof several promising anti-angiogenic agents, mCRCremains an incurable disease with a median overallsurvival of just over 2 years in patients exposed to allavailable treatment regimens. Further insights intotumor biology and tumor microenvironment may helpimprove outcomes in these patients.

  4. Cell-Free DNA in Metastatic Colorectal Cancer

    DEFF Research Database (Denmark)

    Spindler, Karen-Lise G; Boysen, Anders K; Pallisgård, 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...

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

    OpenAIRE

    2016-01-01

    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-mese...

  6. MRI of metastatic adenocarcinomas to the brain. Differential diagnosis of colorectal and pulmonary cancer

    Energy Technology Data Exchange (ETDEWEB)

    Fukusumi, Akio; Nakagawa, Hiroyuki; Takayama, Katsutoshi [Nara Medical Univ., Kashihara (Japan)] [and others

    1998-02-01

    To clarify the characteristic features of MR imagings of metastatic adenocarcinomas to the brain and search for differential points between the lesions from colorectal cancer and those of lung cancer, we evaluated retrospectively intraparenchymal metastatic lesions of 13 colorectal origins and 13 pulmonary origins on MR imagings, compared with resected specimens. Metastatic lesions from colorectal cancer showed marked hypointense solid components on T2WI, which correspond to the dense tumor cells and coagulated necrosis pathologically. Metastatic lesions from lung cancers showed mixed intensity and various components on T2WI, which correspond to various histological components, such as solid tumor cell`s nests, hemorrhage, necrosis and cystic fluid collection. Pathological specimens suggested that the low signal intensity on T2WI of MRI derived from concentration of tumor cells and coagulated necrosis including macrophages and lymphocytes. This study may contribute to make the differential diagnosis of metastatic adenocarcinomas to the brain from colorectal and pulmonary cancers. (author)

  7. Current controversies in the management of metastatic colorectal cancer.

    Science.gov (United States)

    Vera, Ruth; Alonso, Vicente; Gállego, Javier; González, Encarnación; Guillén-Ponce, Carmen; Pericay, Carles; Rivera, Fernando; Safont, M José; Valladares-Ayerbes, Manuel

    2015-10-01

    The factors affecting the decisions for the treatment for patients with metastatic colorectal cancer (mCRC) are related to the patient, the tumor, and the treatment itself. Both cetuximab and panitumumab are anti-EGFR monoclonal antibody options for patients with RAS wild-type tumors. Several trials comparing these agents with bevacizumab are analyzed in this paper. The liver is the most common site of metastases in patients with CRC, and perioperative chemotherapy has been shown to yield benefits in this setting. In the second-line treatment for mCRC, maintenance with bevacizumab after progression following first-line treatment is convenient in some groups of patients with mCRC. Also, aflibercept has demonstrated benefits in response rate, progression-free survival, and overall survival in second-line treatment, whereas regorafenib provides benefits to patients progressing on all standard therapies. Several novel therapeutic options for patients with mCRC are under development, and these are discussed.

  8. miR-345 in Metastatic Colorectal Cancer

    DEFF Research Database (Denmark)

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

    2014-01-01

    INTRODUCTION: MicroRNAs (miRNAs) have important regulatory functions in cellular processes and have shown promising potential as prognostic markers for disease outcome in patients with cancer. The aim of the present study was to find miRNA expression profiles in whole blood that were prognostic...... 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....

  9. Trifluridine/tipiracil and regorafenib: new weapons in the war against metastatic colorectal cancer

    National Research Council Canada - National Science Library

    Weinberg, Benjamin A; Marshall, John L; Salem, Mohamed E

    2016-01-01

    ...; nonetheless, we must keep striving for better outcomes. Trifluridine/tipiracil (TAS-102) and regorafenib are agents newly approved by the US Food and Drug Administration that show promise in the treatment of metastatic colorectal cancer...

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

    Directory of Open Access Journals (Sweden)

    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.

  11. Evolution in the treatment of metastatic colorectal carcinoma of the liver

    Institute of Scientific and Technical Information of China (English)

    Charlotte E Ariyan; Ronald R Salem

    2006-01-01

    Metastatic colorectal cancer to the liver is associated with a uniform poor prognosis without treatment. Advances in therapy over the past decades have now allowed surgical resections of the liver to occur with a low morbidity and mortality. Improvements in chemotherapy regimes have paralleled technical improvements and now allow a new group of patients to become eligible for surgical resection. This chapter will review the recent advances in surgical and chemotherapeutic regimes in metastatic colorectal cancer to the liver.

  12. Surgical therapies in metastatic colorectal cancer with a potential for cure.

    Science.gov (United States)

    Chua, Terence C; Liauw, Winston; Koong, Heng-Nung; Esquivel, Jesus

    2011-06-01

    Metastatic colorectal cancer has evolved from a paradigm that was previously centered upon the use of systemic chemotherapy to one of multimodality therapy. Hepatectomy, pulmonary metastasectomy, and cytoreductive surgery with hyperthermic intraperitoneal chemotherapy are surgical procedures that are now routinely performed in specialized institutions treating patients with metastatic colorectal cancer. Emerging evidence suggests that in selected patients, these procedures are safe and may be beneficial in contributing to long-term survival.

  13. Panitumumab: the evidence of its therapeutic potential in metastatic colorectal cancer care

    Science.gov (United States)

    Martinelli, Erika; Morgillo, Floriana; Troiani, Teresa; Tortora, Giampaolo; Ciardiello, Fortunato

    2007-01-01

    Introduction: Colorectal cancer is the fourth most common malignant disease. Of newly diagnosed patients, 40% have metastatic disease at diagnosis, and approximately 25% of patients with localized disease at diagnosis will ultimately develop metastatic disease. The benefits of systemic chemotherapy in the treatment of metastatic colorectal cancer over best supportive care have been established. Panitumumab (ABX-EGF) is the first fully human monoclonal antibody developed for use in colorectal cancer that targets the extracellular domains of epidermal growth factor receptor. Aims: The goal of this article is to review the published evidence for the use of panitumumab in the treatment of metastatic colorectal cancer to define its therapeutic potential. Evidence review: The major evidence of panitumumab activity in colorectal cancer has appeared in meeting report abstracts. One phase II study in monotherapy, one in combination with chemotherapy, and one phase III study have included only patients with metastatic colorectal cancer. Clinical potential: To date, in phase II clinical studies panitumumab has demonstrated antitumor activity in advanced, refractory colorectal cancer. As monotherapy it resulted in a 10% response rate with 38% of patients having stable disease, and a 36% response rate with 46% stable disease when combined with chemotherapy. A phase III study indicates a clinically significant advantage of panitumumab as third-line monotherapy over best supportive care. Panitumumab appears to have a good tolerability profile, with no maximum tolerated dose yet defined. PMID:21221177

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

    Directory of Open Access Journals (Sweden)

    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.

  15. The Place of Targeted Agents in the Treatment of Elderly Patients with Metastatic Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    Alexios Matikas

    2015-03-01

    Full Text Available Despite the high prevalence of colorectal cancer in a continuously aging population and the substantial advances in the treatment of metastatic disease during the past decade, the treatment of elderly patients with advanced, unresectable or metastatic colorectal cancer is a clearly unmet need. Since older patients are under-represented or even excluded from randomized trials, the evidence that oncologists use as guidance is weak. However, small prospective studies, pooled analyses and observational studies show that combination approaches are safe, efficacious and feasible in the geriatric population with metastatic colorectal cancer. The use of biologic agents targeting angiogenesis and the epidermal growth factor receptor, which have been shown to clearly improve outcomes in multiple prospective trials in patients with advanced colorectal cancer, is a vital component of the aforementioned combination approaches. Herein, we review all available data concerning the management of elderly patients with these agents and underscore the differences between this age subgroup and younger patients.

  16. Panitumumab: the evidence of its therapeutic potential in metastatic colorectal cancer care

    Directory of Open Access Journals (Sweden)

    Erika Martinelli

    2007-11-01

    Full Text Available Erika Martinelli1, Floriana Morgillo1, Teresa Troiani1, Giampaolo Tortora2, Fortunato Ciardiello11Cattedra di Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale “F. Magrassi e A. Lanzara”, Seconda Università degli Studi di Napoli, Napoli, Italy; 2Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinina, Università di Napoli Federico II, Napoli, ItalyIntroduction: Colorectal cancer is the fourth most common malignant disease. Of newly diagnosed patients, 40% have metastatic disease at diagnosis, and approximately 25% of patients with localized disease at diagnosis will ultimately develop metastatic disease. The benefits of systemic chemotherapy in the treatment of metastatic colorectal cancer over best supportive care have been established. Panitumumab (ABX-EGF is the first fully human monoclonal antibody developed for use in colorectal cancer that targets the extracellular domains of epidermal growth factor receptor.Aims: The goal of this article is to review the published evidence for the use of panitumumab in the treatment of metastatic colorectal cancer to define its therapeutic potential.Evidence review: The major evidence of panitumumab activity in colorectal cancer has appeared in meeting report abstracts. One phase II study in monotherapy, one in combination with chemotherapy, and one phase III study have included only patients with metastatic colorectal cancer.Clinical potential: To date, in phase II clinical studies panitumumab has demonstrated antitumor activity in advanced, refractory colorectal cancer. As monotherapy it resulted in a 10% response rate with 38% of patients having stable disease, and a 36% response rate with 46% stable disease when combined with chemotherapy. A phase III study indicates a clinically significant advantage of panitumumab as third-line monotherapy over best supportive care. Panitumumab appears to have a good tolerability profile, with no maximum tolerated

  17. Alternating XELFOX and XELFIRI in patients with metastatic colorectal cancer.

    Science.gov (United States)

    Recchia, Francesco; Candeloro, Giampiero; Necozione, Stefano; Bratta, Massimo; Bisegna, Roberta; Rea, Silvio

    2008-08-01

    To evaluate the antitumor activity and toxicity of 5-fluorouracil (FU)/leucovorin (LV) and capecitabine (C) given with either oxaliplatin (OX) or camptothecin (CPT-11) in the treatment of chemotherapy naive patients with metastatic colorectal cancer. The outpatient treatment, consisted of 2 consecutive days of LV, 200 mg/m(2), 5-FU 400 mg/m(2), and C 2000 mg/m(2) that, in one cycle, was preceded by 2 days of OX 50 mg/m(2), and, in the subsequent cycle, by CPT-11, 90 mg/m(2). All 54 patients were assessable for toxicity and response. Thirty-two patients responded, giving an overall response rate of 59.3%. Median progression-free survival was 12.3 months and median survival was 20.5 months. Toxicity included grade 3 to 4 neutropenia in 43% of patients, grade 3 diarrhea in 7% of patients, and grade 2 neurotoxicity in 6% of patients. The alternating, bimonthly schedule of OX and CPT-11 plus 5-FU/LV/C has substantial antitumor activity and is well tolerated.

  18. Metastatic Colorectal Cancer: Management With Trifluridine/Tipiracil
.

    Science.gov (United States)

    White, Teresa; Larson, Heidi; Minnella, Alexandra; Hochster, Howard S

    2017-04-01

    Treatment-related adverse events (AEs) are common in patients with metastatic colorectal cancer (mCRC) receiving chemotherapy. These AEs may affect patient adherence, particularly with completely oral regimens, such as trifluridine/tipiracil (TAS-102, Lonsurf®), an antimetabolite agent for patients with mCRC refractory or intolerant to standard therapies.
. This article reviews strategies for promoting adherence and educating patients and caregivers about oral therapy with trifluridine/tipiracil. 
. Recommended strategies for managing AEs are reviewed, with a focus on the most common AEs reported in patients with mCRC receiving trifluridine/tipiracil in clinical trials.
. Oncology nurses play an important role in educating and counseling patients regarding treatment and its potential side effects. Among patients with mCRC refractory or intolerant to standard therapies, trifluridine/tipiracil was found to have a favorable safety profile. It is associated with hematologic AEs as well as a low incidence of nausea, diarrhea, vomiting, anorexia, and fatigue.

  19. Oral drugs in the treatment of metastatic colorectal cancer.

    Science.gov (United States)

    Kwakman, J J M; Punt, C J A

    2016-07-01

    Intravenous administration of fluoropyrimidine-based chemotherapy has been the cornerstone of treatment in metastatic colorectal cancer (mCRC) for decades. The availability of oral capecitabine has improved the tolerability in monotherapy schedules, and has simplified combination schedules. Since then, other oral drugs have proven efficacy in this setting. We review the available evidence and most recent data concerning oral drugs with proven efficacy in mCRC, including capecitabine, S-1, trifluridine-tipiracil (TAS-102) and regorafenib. The use of capecitabine is widely implemented in the care of mCRC. However, with recent data supporting its prolonged use, the relatively high incidence of hand-foot syndrome (HFS) may impair quality of life. In Asian populations, S-1 is associated with equivalent efficacy but lower incidence of HFS compared to capecitabine. Further studies evaluating the effects of S-1 in Western populations are needed. Both regorafenib and TAS-102 improve the overall survival of patients in whom all other treatment options have failed. Since only a subset of patients appears to benefit, future studies to identify predictive biomarkers are needed.

  20. TAS-102 for the treatment of metastatic colorectal cancer.

    Science.gov (United States)

    Salvatore, Lisa; Rossini, Daniele; Moretto, Roberto; Cremolini, Chiara; Schirripa, Marta; Antoniotti, Carlotta; Marmorino, Federica; Loupakis, Fotios; Falcone, Alfredo; Masi, Gianluca

    2015-01-01

    The survival of patients with metastatic colorectal cancer has notably increased in the past 20 years, from 12 months to around 30 months. Nevertheless, the prognosis of patients pretreated with all available agents is poor and there is high unmet need for newer treatments. TAS-102 is an orally administered combination of the nucleoside analogue trifluridine and tipiracil hydrochloride, a thymidine phosphorylase inhibitor. In a randomized trial of 800 patients who had received at least two other treatments previously (most patients had received more than four treatments). TAS-102 demonstrated a significant prolongation of overall survival compared with placebo (median survival 7.1 vs. 5.3 months; hazard ratio 0 · 68, 95%CI: 0 · 58-0 · 81; p < 0 · 001). The toxicity was manageable, grade 3 or higher events occurred in 69% of patients in the TAS-102 group versus 52% in the placebo group, with neutropenia the most common event.

  1. Trifluridine/Tipiracil: A Review in Metastatic Colorectal Cancer.

    Science.gov (United States)

    Burness, Celeste B; Duggan, Sean T

    2016-09-01

    Trifluridine/tipiracil (Lonsurf(®)) is a novel, orally active, antimetabolite agent comprised of trifluridine, a thymidine-based nucleoside analogue, and tipiracil, a potent thymidine phosphorylase inhibitor. Trifluridine is incorporated into DNA via phosphorylation, ultimately inhibiting cell proliferation. Tipiracil increases systemic exposure of trifluridine when coadministered. Trifluridine/tipiracil has recently been approved for the treatment of adult patients with metastatic colorectal cancer (mCRC) who are refractory to or are not considered candidates for, current standard chemotherapy and biological therapy in the EU and USA and in unresectable advanced or recurrent CRC in Japan. The approved regimen of oral twice-daily trifluridine/tipiracil (35 mg/m(2) twice daily on days 1-5 and 8-12 of each 28-day cycle) significantly improved overall survival and progression-free survival and was associated with a significantly higher disease control rate than placebo when added to best supportive care in the multinational, pivotal phase III trial (RECOURSE) and a phase II Japanese trial. Trifluridine/tipiracil was associated with an acceptable tolerability profile, with adverse events generally being managed with dose reductions, temporary interruptions in treatment or administration of granulocyte-colony stimulating factor. The most common grade 3-4 adverse events (≥10 %) were anaemia, neutropenia, thrombocytopenia and leukopenia. In conclusion, trifluridine/tipiracil is a useful additional treatment option for the management of mCRC in patients who are refractory to, or are not considered candidates for, currently available therapies.

  2. KRAS discordance between primary and metastatic tumor in patients with metastatic colorectal carcinoma.

    Science.gov (United States)

    Siyar Ekinci, Ahmet; Demirci, Umut; Cakmak Oksuzoglu, Berna; Ozturk, Ayse; Esbah, Onur; Ozatli, Tahsin; Celik, Burcin; Budakoglu, Burcin; Turker, Ibrahim; Bal, Oznur; Turan, Nedim

    2015-01-01

    Adding targeted therapies to chemotherapy in metastatic colorectal cancer (CRC) improves response rates and survival. KRAS is a predictive indicator for anti-epidermal growth factor receptor (EGFR) treatments. The most important reasons for KRAS discordance are intratumoral heterogeneity and incorrect mutation analysis. Evaluating the status of KRAS in primary and metastatic lesions becomes even more crucial to ensure efficient usage of anti-EGFR treatments. Patients with metastatic CRC, whose primary disease and liver and/or lung metastases were operated, were retrospectively evaluated, and KRAS assessment was performed on 31 patients who were suitable for DNA analysis. Pyrosequencing with polymerase chain reaction (PCR) was used for KRAS analysis. The median age of 31 patients diagnosed with rectal cancer (N=13) and colon cancer (N=18) was 63 years (range 33-73). Metastasectomy locations included the liver (N=27), lung (N=3), and both lung and liver (N=1). KRAS discordance was detected in 22% (7/31) of the patients. While 3 patients with detected discordance had mutated KRAS in the primary material, wild type KRAS was detected in their liver or lung lesions. On the other hand, while 4 patients had wild type KRAS in the primary material, mutated KRAS was determined in their liver or lung lesions. The McNemar test revealed no significant discordance between primary and metastatic disease (p=1.00). No progression free survival (PFS) difference was detected between patients with determined discordance and patients with undetermined discordance (10.6 vs 14.7 months, p=0.719). This is the first study to evaluate KRAS discordance between primary and metastasis in CRC patients, who underwent metastasectomy, together with survival data. In the literature and recent studies with large patient numbers in which modern KRAS tests were used, the KRAS discordance rate varies between 3-12%. In our study, a higher KRAS discordance (22%) was detected, and no survival difference

  3. Excessive collagen turnover products are released during colorectal cancer progression and elevated in serum from metastatic colorectal cancer patients

    DEFF Research Database (Denmark)

    Kehlet, Stephanie Nina; Sanz-Pamplona, R.; Pedersen, Susanne Brix

    2016-01-01

    During cancer progression, the homeostasis of the extracellular matrix becomes imbalanced with an excessive collagen remodeling by matrix metalloproteinases. As a consequence, small protein fragments of degraded collagens are released into the circulation. We have investigated the potential...... of protein fragments of collagen type I, III and IV as novel biomarkers for colorectal cancer. Specific fragments of degraded type I, III and IV collagen (C1M, C3M, C4M) and type III collagen formation (Pro-C3) were assessed in serum from colorectal cancer patients, subjects with adenomas and matched healthy...... biomarkers were able to differentiate stage IV metastatic patients from all other stages. Combination of all markers with age and gender in a logistic regression model discriminated between metastatic and non-metastatic patients with an AUROC of 0.80. The data suggest that the levels of these collagen...

  4. Bevacizumab in combination with cetuximab and irinotecan after failure of cetuximab and irinotecan in patients with metastatic colorectal cancer

    DEFF Research Database (Denmark)

    Larsen, Finn Ole; Pfeiffer, Per; Nielsen, Dorte

    2011-01-01

    The efficacy and safety of concurrent administration of irinotecan with the two monoclonal antibodies cetuximab and bevacizumab as fourth line therapy in heavily pretreated patients with metastatic colorectal cancer were evaluated.......The efficacy and safety of concurrent administration of irinotecan with the two monoclonal antibodies cetuximab and bevacizumab as fourth line therapy in heavily pretreated patients with metastatic colorectal cancer were evaluated....

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

    Science.gov (United States)

    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.

  6. Factors influencing choice of chemotherapy in metastatic colorectal cancer (mCRC

    Directory of Open Access Journals (Sweden)

    Rossi L

    2013-11-01

    Full Text Available Luigi Rossi, Foteini Vakiarou, Federica Zoratto, Loredana Bianchi, Anselmo Papa, Enrico Basso, Monica Verrico, Giuseppe Lo Russo, Salvatore Evangelista, Guilia Rinaldi, Francesca Perrone-Congedi, Gian Paolo Spinelli, Valeria Stati, Davide Caruso, Alessandra Prete, Silverio TomaoDepartment of Medico-Surgical Sciences and Biotechnologies, "Sapienza" University of Rome, Rome, Italy; Oncology Unit, ICOT, Latina, ItalyAbstract: 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.Keywords: metastatic colorectal cancer, patient clinical features, tumor biology, multidisciplinary approach

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

    Directory of Open Access Journals (Sweden)

    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.

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

    DEFF Research Database (Denmark)

    Palshof, Jesper Andreas; Høgdall, 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 with metasta......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...

  9. Quantitative proteomics of extracellular vesicles derived from human primary and metastatic colorectal cancer cells

    OpenAIRE

    Gho, Yong Song; Choi, Dong-Sic; Choi, Do-Young; Hong, Bok Sil; Jang, Su Chul; Kim, Dae-Kyum; Lee, Jaewook; Kim, Yoon-Keun; Kim, Kwang Pyo

    2012-01-01

    Cancer cells actively release extracellular vesicles (EVs), including exosomes and microvesicles, into surrounding tissues. These EVs play pleiotropic roles in cancer progression and metastasis, including invasion, angiogenesis, and immune modulation. However, the proteomic differences between primary and metastatic cancer cell-derived EVs remain unclear. Here, we conducted comparative proteomic analysis between EVs derived from human primary colorectal cancer cells (SW480) and their metastat...

  10. Lower treatment intensity and poorer survival in metastatic colorectal cancer patients who live alone.

    Science.gov (United States)

    Cavalli-Björkman, N; Qvortrup, C; Sebjørnsen, S; Pfeiffer, P; Wentzel-Larsen, T; Glimelius, B; Sorbye, H

    2012-06-26

    Socioeconomic status (SES) and social support influences cancer survival. If SES and social support affects cancer treatment has not been thoroughly explored. A cohort consisting of all patients who were initially diagnosed with or who developed metastatic colorectal cancer (mCRC, n=781) in three Scandinavian university hospitals from October 2003 to August 2006 was set up. Clinical and socioeconomic data were registered prospectively. Patients living alone more often had synchronous metastases at presentation and were less often treated with combination chemotherapy than those cohabitating (HR 0.19, 95% CI 0.04-0.85, P=0.03). Surgical removal of metastases was less common in patients living alone (HR 0.29, 95% CI 0.10-0.86, P=0.02) but more common among university-educated patients (HR 2.22, 95% CI 1.10-4.49, P=0.02). Smoking, being married and having children did not influence treatment or survival. Median survival was 7.7 months in patients living alone and 11.7 months in patients living with someone (P<0.001). Living alone remained a prognostic factor for survival after correction for age and comorbidity. Patients living alone received less combination chemotherapy and less secondary surgery. Living alone is a strong independent risk factor for poor survival in mCRC.

  11. Interleukin-6 and C-reactive protein as prognostic biomarkers in metastatic colorectal cancer

    DEFF Research Database (Denmark)

    Thomsen, Maria; Kersten, Christian; Sorbye, Halfdan

    2016-01-01

    Objectives: The aim was to explore the prognostic significance of IL-6 and markers of systemic inflammatory response (SIR), in particular C-reactive protein (CRP), in metastatic colorectal cancer (mCRC) patients, in the total study population and according to RAS and BRAF mutation status. Results...

  12. 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

  13. Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer

    OpenAIRE

    Rubbia-Brandt, Laura; Audard, V; Sartoretti, Pascal Daniel; Roth, Arnaud; Brezault, C; Le Charpentier, M; Dousset, B.; Morel, Philippe; O. Soubrane; Chaussade, S; Mentha, Gilles; Terris, B

    2004-01-01

    In advanced metastatic colorectal adenocarcinoma, the addition of a neo-adjuvant systemic treatment to surgery might translate into a survival advantage, although this is yet to be confirmed by ongoing randomized trials. The objective of this study was to assess the effects of preoperative systemic chemotherapy on the morphology of non-tumoral liver.

  14. Prognostic significance of circulating tumor cells in patients with metastatic colorectal cancer.

    NARCIS (Netherlands)

    Cohen, S.J.; Punt, C.J.A.; Iannotti, N.; Saidman, B.H.; Sabbath, K.D.; Gabrail, N.Y.; Picus, J.; Morse, M.A.; Mitchell, E.; Miller, M.C.; Doyle, G.V.; Tissing, H.; Terstappen, L.W.; Meropol, N.J.

    2009-01-01

    BACKGROUND: We demonstrated that circulating tumor cell (CTC) number at baseline and follow-up is an independent prognostic factor in metastatic colorectal cancer (mCRC). This analysis was undertaken to explore whether patient and treatment characteristics impact the prognostic value of CTCs. PATIEN

  15. 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

  16. 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 ...

  17. RAS testing in metastatic colorectal cancer: excellent reproducibility amongst 17 Dutch pathology centers

    NARCIS (Netherlands)

    Boleij, A.; Tops, B.B.; Rombout, P.D.; Dequeker, E.M.; Ligtenberg, M.J.; Krieken, J.H.J.M. van

    2015-01-01

    In 2013 the European Medicine Agency (EMA) restricted the indication for anti-EGFR targeted therapy to metastatic colorectal cancer (mCRC) with a wild-type RAS gene, increasing the need for reliable RAS mutation testing. We evaluated the completeness and reproducibility of RAS-testing in the Netherl

  18. Primary tumor location and bevacizumab effectiveness in patients with metastatic colorectal cancer

    DEFF Research Database (Denmark)

    Boisen, M K; Johansen, J S; Dehlendorff, Christian

    2013-01-01

    There is an unmet need for predictive markers for the antiangiogenic agent bevacizumab in metastatic colorectal cancer (mCRC). We aimed to assess whether the location of the primary tumor is associated with bevacizumab effectiveness when combined with capecitabine and oxaliplatin (CAPEOX...

  19. Bevacizumab for metachronous metastatic colorectal cancer: A reflection of community based practice

    NARCIS (Netherlands)

    L.G.E.M. Razenberg (Lieke); Y.R.B.M. van Gestel (Yvette); I.H.J.T. de Hingh (Ignace); O.J.L. Loosveld (Olaf); G. Vreugdenhil (Gerard); L.V. Beerepoot (Laurens); G.J.M. Creemers (Geert-Jan); V.E.P.P. Lemmens (Valery)

    2016-01-01

    textabstractBackground: Although the efficacy of bevacizumab has been established in patients with metastatic colorectal cancer (mCRC), population-based studies are needed to gain insight into the actual implementation of bevacizumab in daily practice. Since these studies are lacking for patients

  20. Correlation between metastatic potential and variants from colorectal tumor cell line HT-29

    Institute of Scientific and Technical Information of China (English)

    Min Wang; Ilka Vogel; Holger Kalthoff

    2003-01-01

    AIM: To evaluate the relationship between uPA, PAI-1,CEA, PI3K and metastatic potential in three colorectal tumor cell lines.METHODS: Metastatic model in nude rats was established by variants HT-29c and HT-29d cell lines and the metastatic potential of two tumor cell variants was compared.Urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1) were determined using ELISA in colorectal carcinoma WiDr, HT29 and HT-29d cell lines with different metastatic potentials.Expression of carcinoembryonic antigen (CEA) and phosphoinositide 3-kinase (PI3-Kinase) was analyzed using immunohistochemistry (IHC) in these cell lines in vitro and in vivo. CEA expression was compared using fluorescence activated cell sorter (FACS)in vitro.RESULTS: The number of HT-29d cells arrested in liver dramatically decreased within the initial 24 hours after injection. The taking rate of liver metastases in the variant HT-29d increased as compared with parental HT-29 cells (70 % versus 50 %) and a variant HT-29b cells (70 % versus 60 %), and extensive organs were synchronously involved in metastases. The uPA concentration of variant HT-29d cell line was significantly higher than that of the non-metastatic WiDr and the low metastatic HT-29 cell lines. The variant HT-29d cells produced stronger PI3-kinase expression as compared with the non-metastatic WiDr cells and the low metastatic HT-29 cellsin vivo.CONCLUSION: The selected variant HT-29d cell exhibited an enhanced metastatic potential. The level of uPA and PAI-1 is positively correlated with the metastatic capacity of tumor cells. The expression of PI3-kinase correlates with tumor development and metastasis.

  1. Bevacizumab for metastatic colorectal cancer: a NICE single technology appraisal.

    Science.gov (United States)

    Whyte, Sophie; Pandor, Abdullah; Stevenson, Matt

    2012-12-01

    The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of bevacizumab (Roche Products) to submit evidence for the clinical and cost effectiveness of this drug for the treatment of patients with metastatic colorectal cancer (mCRC), as part of the Institute's Single Technology Appraisal (STA) process. The School of Health and Related Research (ScHARR) at the University of Sheffield was commissioned to act as the Evidence Review Group (ERG). This paper provides a description of the company submission, the ERG review and NICE's subsequent decisions. The ERG produced a critical review of the evidence for the clinical and cost effectiveness of the technology provided within the manufacturer's submission to NICE. The ERG also independently searched for relevant evidence and modified the manufacturer's decision analytic model to examine the impact of altering some of the key assumptions. The main clinical effectiveness data were derived from a phase III, multicentre, multinational, two-arm, randomized, open-label study with the primary objective of confirming the non-inferiority of oxaliplatin plus capecitabine (XELOX) compared with oxaliplatin plus 5-fluorouracil and folinic acid (FOLFOX-4) in adult patients with histologically confirmed mCRC who had not previously been treated. The ERG considered that the NO16966 trial was of reasonable methodological quality and demonstrated a significant improvement in both progression-free and overall survival when bevacizumab is added to either XELOX or FOLFOX-4. The ERG considered that the size of the actual treatment effect of bevacizumab was uncertain due to trial design limitations, imbalance of a known prognostic factor, relatively short treatment duration compared with that allowed within the trial protocol, and interpretation of the statistical analyses. The manufacturer's submission included a de novo economic evaluation using a cost-effectiveness model built in Microsoft® Excel. The ERG

  2. Role of the antiangiogenic agent bevacizumab in the treatment of elderly patients with metastatic colorectal cancer.

    Science.gov (United States)

    Di Bartolomeo, Maria; Pietrantonio, Filippo; Martinetti, Antonia; Buzzoni, Roberto; Gevorgyan, Arpine; Bajetta, Emilio

    2011-02-01

    Although major progress has been achieved in the treatment of metastatic colorectal cancer with the employment of biological antiangiogenic agents, several questions remain open for discussion regarding the use of this therapy in elderly patients with metastatic colorectal cancer. In Western countries, the total number of elderly patients with colorectal cancer is expected to increase in the future. As adverse physical or socioeconomic conditions are more common in the elderly, an assessment of the patient's suitability for this therapy should be performed before a treatment decision is made. Most patients in clinical trials of the antiangiogenic drug bevacizumab were aged <65 years and thus the efficacy and tolerability of this agent in older patients has been less well explored. However, this article shows that older and younger patients with metastatic colorectal cancer appeared to derive similar survival benefit from bevacizumab treatment. Elderly patients were also found to have significant prolongation of median progression-free survival with the addition of bevacizumab to their treatment, with a similar magnitude of improvement in this outcome being observed in younger and older patients. It should be emphasized that the patients included in the studies discussed in this article were eligible for clinical trials and therefore may not be representative of a more general elderly population. Careful selection of patients and monitoring of treatment effects are required to optimize use of the antiangiogenic agent bevacizumab in older patients.

  3. Neoplastic infiltration of the sphenoid wing: a rare manifestation of metastatic colorectal cancer.

    Science.gov (United States)

    Pinato, David James; Krell, Jonathan; Wasan, Harpreet; Sharma, Rohini

    2011-12-01

    Atypical patterns of metastatic spread from colorectal primary tumors are often misdiagnosed, with potential implications for the clinical outcome. Metastatic diffusion to the splanchnocranium is extremely rare in colorectal cancer. A histological proof of diagnosis is rarely obtained and therapeutic management is a challenge. We describe the case of a 46-year-old patient who presented with a radiologically proven sphenoid wing metastasis. The patient presented with left-sided exophthalmos while receiving systemic chemotherapy for relapsed high-risk colorectal cancer. A left sphenoid wing metastasis was proven by a head computed tomography scan. A metastatic spread to the sino-nasal tract is regarded as a poor prognosis determinant in colorectal cancer and presents a unique set of diagnostic and therapeutic challenges. The compression of noble structures such as the optic nerve holds serious implications in terms of quality of life but there is insufficient evidence clarifying whether radiotherapy or surgery represent the best option for these patients, leaving the therapeutic plan to be decided case by case.

  4. Molecular markers in circulating tumour cells from metastatic colorectal cancer patients.

    Science.gov (United States)

    Gazzaniga, Paola; Gradilone, Angela; Petracca, Arianna; Nicolazzo, Chiara; Raimondi, Cristina; Iacovelli, Roberto; Naso, Giuseppe; Cortesi, Enrico

    2010-08-01

    The prognosis of metastatic cancer patients is still largely affected by treatment failure, mainly due to drug resistance. The hypothesis that chemotherapy might miss circulating tumour cells (CTCs) and particularly a subpopulation of more aggressive, stem-like CTCs, characterized by multidrug resistance, has been recently raised. We investigated the prognostic value of drug resistance and stemness markers in CTCs from metastatic colorectal cancer patients treated with oxaliplatin (L-OHP) and 5-fluoruracil (5-FU) based regimens. Forty patients with metastatic colorectal cancer were enrolled. CTCs were isolated from peripheral blood and analysed for the expression of aldheyde dehydrogenase 1 (ALDH1), CD44, CD133 (used as markers of stemness), multidrug resistance related protein 5 (MRP5 used as marker of resistance to 5-FU and L-OHP) and survivin (used as a marker of apoptosis resistance). CTCs were found in 27/40 (67%) patients. No correlation was found between the expression of either CD44 and CD133 in CTCs and the outcome of patients, while a statistically significant shorter progression-free survival was found in patients with CTCs positive for the expression of ALDH1, survivin and MRP5. These results support the idea that isolating survivin and MRP5+ CTCs may help in the selection of metastatic colorectal cancer patients resistant to standard 5-FU and L-OHP based chemotherapy, for which alternative regimens may be appropriate.

  5. Clinical significance of subcellular localization of KL-6 mucin in primary colorectal adenocarcinoma and metastatic tissues

    Institute of Scientific and Technical Information of China (English)

    Qian Guo; Masatoshi Makuuchi; Wei Tang; Yoshinori Inagaki; Yutaka Midorikawa; Norihiro Kokudo; Yasuhiko Sugawara; Munehiro Nakata; Toshiro Konishi; Hirokazu Nagawa

    2006-01-01

    AIM: To assess subcellular localization of KL-6 mucin and its clinicopathological significance in colorectal carcinoma as well as metastatic lymph node and liver tissues.METHODS: Colorectal carcinoma tissues as well as metastatic lymph node and liver tissues were collected from 82 patients who underwent colorectomy or hepatectomy. Tissues were subjected to immunohistochemical analysis using KL-6 antibody.RESULTS: Of the 82 colorectal carcinoma patients, 6showed no staining, 29 showed positive staining only in the apical membrane, and 47 showed positive staining in the circumferential membrane and/or cytoplasm.Positive staining was not observed in non-cancerous colorectal epithelial cells surrounding the tumor tissues.The five-year survival rate was significantly lower in cases showing positive staining in the circumferential membrane and/or cytoplasm (63.0%) than those showing positive staining only in the apical membrane (85.7%) and those showing no staining (100%).Statistical analysis between clinicopathological factors and subcellular localization of KL-6 mucin showed that KL-6 localization in the circumferential membrane and/or cytoplasm was significantly associated with the presence of venous invasion (P=0.0003), lymphatic invasion (P<0.0001), lymph node metastasis (P<0.0001),liver metastasis (P=0.058), and advanced histological stage (P<0.0001). Positive staining was observed in all metastatic lesions tested as well as in the primary colorectal carcinoma tissues.CONCLUSION: The subcellular staining pattern of KL-6 in colorectal adenocarcinoma may be an important indicator for unfavorable behaviors such as lymph node and liver metastasis, as well as for the prognosis of patients.

  6. Clinical impact of FDG PET-CT in patients with potentially operable metastatic colorectal cancer

    Energy Technology Data Exchange (ETDEWEB)

    Briggs, R.H. [Department of Radiology, Calderdale and Huddersfield NHS Foundation Trust, Huddersfield (United Kingdom); Chowdhury, F.U. [Departments of Radiology and Nuclear Medicine, St James' s University Hospital, Leeds (United Kingdom); Lodge, J.P.A. [HPB and Transplant Unit, St James' s University Hospital, Leeds (United Kingdom); Scarsbrook, A.F., E-mail: andrew.scarsbrook@leedsth.nhs.uk [Departments of Radiology and Nuclear Medicine, St James' s University Hospital, Leeds (United Kingdom)

    2011-12-15

    Aim: To assess the clinical impact of 2-[{sup 18}F]-fluoro-2-deoxy-D-glucose (FDG) positron-emission tomography-computed tomography (PET-CT) in patients with potentially resectable metastatic colorectal cancer. Materials and methods: One hundred and two patients with potentially resectable metastatic colorectal cancer underwent FDG PET-CT in addition to conventional imaging over an 18-month period. The findings were compared to conventional imaging, with histological or clinico-radiological validation. The impact on subsequent management was evaluated using information from clinico-radiological databases. Results: Of 102 patients (mean age 67 years, range 27-85 years), 94 had liver, five had isolated lung, and three had limited peritoneal metastases. In 31 patients (30%) PET-CT had a major impact on subsequent management, by correctly clarifying indeterminate lesions on conventional imaging as inoperable metastatic disease in 16 patients, detecting previously unsuspected metastatic disease in nine patients, identifying occult second primary tumours in three patients, and correctly down-staging three patients. PET-CT had a minor impact in 12 patients (12%), no impact in 49 cases (48%), and a potentially negative impact in 10 cases (10%). Following PET-CT, 36 (35%) patients were no longer considered for surgery. Of those remaining operative 45 of 66 (68%) underwent potentially curative metastatic surgery. In this cohort PET-CT saved 16 futile laparotomies. Conclusion: FDG PET-CT has a valuable role in selected patients with metastatic colorectal cancer by improving staging accuracy and characterizing indeterminate lesions and helps triage patients to the appropriate treatment.

  7. Leptin receptor (Ob-R mRNA expression and serum leptin concentration in patients with colorectal and metastatic colorectal cancer

    Directory of Open Access Journals (Sweden)

    N. Erkasap

    Full Text Available The objective of the present study was to investigate the effect of leptin on the progression of colorectal carcinoma to metastatic disease by analyzing the serum leptin concentration and Ob-R gene expression in colon cancer tissues. Tissue samples were obtained from 31 patients who underwent surgical resection for colon (18 cases and metastatic colon (13 cases cancer. Serum leptin concentration was determined by an enzyme-linked immunosorbent assay (ELISA and Ob-R mRNA expression by real-time polymerase chain reaction (RT-PCR for both groups. ELISA data were analyzed by the Student t-test and RT-PCR data were analyzed by the Mann-Whitney U-test. RT-PCR results demonstrated that mRNA expression of Ob-R in human metastatic colorectal cancer was higher than in local colorectal cancer tissues. On the other hand, mean serum leptin concentration was significantly higher in local colorectal cancer patients compared to patients with metastatic colorectal cancer. The results of the present study suggest a role for leptin in the progression of colon cancer to metastatic disease without weight loss. In other words, significantly increased Ob-R mRNA expression and decreased serum leptin concentration in patients with metastatic colon cancer indicate that sensitization to leptin activity may be a major indicator of metastasis to the colon tissue and the determination of leptin concentration and leptin gene expression may be used to aid the diagnosis.

  8. Leptin receptor (Ob-R) mRNA expression and serum leptin concentration in patients with colorectal and metastatic colorectal cancer

    Energy Technology Data Exchange (ETDEWEB)

    Erkasap, N.; Ozkurt, M. [Department of Physiology, Osmangazi University Medical Faculty, Meselik, Eskisehir (Turkey); Erkasap, S.; Yasar, F. [Department of General Surgery, Osmangazi University Medical Faculty, Meselik, Eskisehir (Turkey); Uzuner, K. [Department of Physiology, Osmangazi University Medical Faculty, Meselik, Eskisehir (Turkey); Ihtiyar, E. [Department of General Surgery, Osmangazi University Medical Faculty, Meselik, Eskisehir (Turkey); Uslu, S.; Kara, M. [Department of Biochemistry, Osmangazi University Medical Faculty, Meselik, Eskisehir (Turkey); Bolluk, O. [Department of Biostatistics, Osmangazi University Medical Faculty, Meselik, Eskisehir (Turkey)

    2013-03-19

    The objective of the present study was to investigate the effect of leptin on the progression of colorectal carcinoma to metastatic disease by analyzing the serum leptin concentration and Ob-R gene expression in colon cancer tissues. Tissue samples were obtained from 31 patients who underwent surgical resection for colon (18 cases) and metastatic colon (13 cases) cancer. Serum leptin concentration was determined by an enzyme-linked immunosorbent assay (ELISA) and Ob-R mRNA expression by real-time polymerase chain reaction (RT-PCR) for both groups. ELISA data were analyzed by the Student t-test and RT-PCR data were analyzed by the Mann-Whitney U-test. RT-PCR results demonstrated that mRNA expression of Ob-R in human metastatic colorectal cancer was higher than in local colorectal cancer tissues. On the other hand, mean serum leptin concentration was significantly higher in local colorectal cancer patients compared to patients with metastatic colorectal cancer. The results of the present study suggest a role for leptin in the progression of colon cancer to metastatic disease without weight loss. In other words, significantly increased Ob-R mRNA expression and decreased serum leptin concentration in patients with metastatic colon cancer indicate that sensitization to leptin activity may be a major indicator of metastasis to the colon tissue and the determination of leptin concentration and leptin gene expression may be used to aid the diagnosis.

  9. Mitochondrial microsatellite instability in patients with metastatic colorectal cancer

    NARCIS (Netherlands)

    Venderbosch, S.; van Vliet, S.; Craenmehr, M. H C; Simmer, F.; de Haan, A. F J; Punt, C. J A; Koopman, M.; Nagtegaal, I. D.

    2015-01-01

    Mitochondrial microsatellite instability (mtMSI), a change in length in mtDNA microsatellite sequences between normal and tumor tissue, has been described as a frequent occurrence in colorectal cancer (CRC). We evaluated the prevalence and prognostic value of mtMSI and its relation to nuclear

  10. Treatment with capecitabine + bevacizumab following induction treatment with FOLFIRI + bevacizumab in metastatic colorectal carcinoma

    Science.gov (United States)

    Tatlı, Ali Murat; Coşkun, Hasan Şenol; Uysal, Mükremin; Arslan, Deniz; Sezgin Göksu, Sema; Güenay Gündüz, Şeyda; Çakal, Selda; Bozcuk, Hakan Şat; Savaş, Burhan

    2014-01-01

    Bevacizumab is a humanized monoclonal antibody that inhibits vascular endothelial growth factor, and it has been found to increase both progression-free survival and overall survival when it is combined with chemotherapeutic agents in the first-line and subsequent treatment of metastatic colorectal carcinoma. The objective of this study was to show the efficacy of maintenance treatment with capecitabine plus bevacizumab in patients with metastatic colorectal cancer who responded to treatment with FOLFIRI plus bevacizumab. The study included patients with metastatic colorectal cancer who received FOLFIRI plus bevacizumab as a first-line treatment. Patients who had objective response with FOLFIRI plus bevacizumab treatment after an average period of 6 months received a maintenance treatment with capecitabine plus bevacizumab (capecitabine 2 x 1000 mg/m2, 1 - 14 days, every 21 days, bevacizumab 7.5 mg/m2, every 21 days) until disease progression or toxicity. The time to progression on bevacizumab treatment was evaluated. A total of 29 patients (15 male, 14 female) were included. The mean age was 62 years. The mean number of cycles for maintenance treatment with capecitabine plus bevacizumab was 12. The median PFS was 16 ± 3 months, and OS was 42 ± 11 months. PFS and OS were remarkably higher in patients with a complete or near complete response to induction treatment. Fourteen patients (48%) experienced hand-foot syndrome associated with capecitabine plus bevacizumab treatment, without any severe toxicity. Inselected patients with metastatic colorectal carcinoma who had a remarkable objective response to FOLFIRI plus bevacizumab treatment, a maintenance treatment with capecitabine plus bevacizumab following FOLFIRI plus bevacizumab until disease progression may be a suitable, effective and tolerable regimen, which requires further studies. PMID:25232406

  11. 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...... cells that have not been cleared by the immune system to metastasize. In this paper we present an overview of studies where oxidative stress in relation to surgery has been linked to the development of metastatic disease....

  12. Molecular subtypes of metastatic colorectal cancer are associated with patient response to irinotecan-based therapies.

    Science.gov (United States)

    Del Rio, M; Mollevi, C; Bibeau, F; Vie, N; Selves, J; Emile, J-F; Roger, P; Gongora, C; Robert, J; Tubiana-Mathieu, N; Ychou, M; Martineau, P

    2017-05-01

    Currently, metastatic colorectal cancer is treated as a homogeneous disease and only RAS mutational status has been approved as a negative predictive factor in patients treated with cetuximab. The aim of this study was to evaluate if recently identified molecular subtypes of colon cancer are associated with response of metastatic patients to first-line therapy. We collected and analysed 143 samples of human colorectal tumours with complete clinical annotations, including the response to treatment. Gene expression profiling was used to classify patients in three to six classes using four different molecular classifications. Correlations between molecular subtypes, response to treatment, progression-free and overall survival were analysed. We first demonstrated that the four previously described molecular classifications of colorectal cancer defined in non-metastatic patients also correctly classify stage IV patients. One of the classifications is strongly associated with response to FOLFIRI (P=0.003), but not to FOLFOX (P=0.911) and FOLFIRI + Bevacizumab (P=0.190). In particular, we identify a molecular subtype representing 28% of the patients that shows an exceptionally high response rate to FOLFIRI (87.5%). These patients have a two-fold longer overall survival (40.1 months) when treated with FOLFIRI, as first-line regimen, instead of FOLFOX (18.6 months). Our results demonstrate the interest of molecular classifications to develop tailored therapies for patients with metastatic colorectal cancer and a strong impact of the first-line regimen on the overall survival of some patients. This however remains to be confirmed in a large prospective clinical trial. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Cetuximab plus FOLFOX6 or FOLFIRI in metastatic colorectal cancer: CECOG trial

    Institute of Scientific and Technical Information of China (English)

    Janja; Ocvirk; Thomas; Brodowicz; Fritz; Wrba; Tudor; E; Ciuleanu; Galina; Kurteva; Semir; Beslija; Ivan; Koza; Zsuzsanna; Pápai; Diethelm; Messinger; Ugur; Yilmaz; Zsolt; Faluhelyi; Suayib; Yalcin; Demetris; Papamichael; Miklós; Wenczl; Zrinka; Mrsic-Krmpotic; Einat; Shacham-Shmueli; Damir; Vrbanec; Regina; Esser; Werner; Scheithauer; Christoph; C; Zie-linski

    2010-01-01

    AIM: To investigate efficacy and safety of cetuximab combined with two chemotherapy regimens in patients with unresectable metastatic colorectal cancer (mCRC). METHODS: Randomized patients received cetuximab with 5-fluorouracil (5-FU), folinic acid (FA) and oxaliplatin (FOLFOX) 6 (arm A, n = 74) or 5-FU, FA and irinotecan (FOLFIRI) (arm B, n = 77). KRAS mutation status was determined retrospectively in a subset of tumors (n = 117). RESULTS: No significant difference was found between treatment arms A and B ...

  14. Tumor budding predicts response to anti-EGFR therapies in metastatic colorectal cancer patients

    Institute of Scientific and Technical Information of China (English)

    Inti; Zlobec; Francesca; Molinari; Vittoria; Martin; Luca; Mazzucchelli; Piercarlo; Saletti; Rosangela; Trezzi; Sara; De; Dosso; Tatjana; Vlajnic; Milo; Frattini; Alessandro; Lugli

    2010-01-01

    AIM:To investigate whether the evaluation of tumor budding can complement K-RAS analysis to improve the individualized prediction of response to anti-epidermal growth factor receptor based therapies in metastatic colorectal cancer (mCRC) patients. METHODS:Forty-three patients with mCRC treated with cetuximab or panitumumab were entered into this study. According to the Response Evaluation Criteria in Solid Tumors criteria, 30 patients had stable or progressive disease (non-responsive), while 13 patients had...

  15. Capecitabine and bevacizumab as first-line treatment in elderly patients with metastatic colorectal cancer

    OpenAIRE

    Feliu Batlle, Jaime; Safont, María José; Salud, Antonieta T.; Losa, Ferrán C.; García-Girón, Carlos; Bosch, Carles J A; Escudero, Pilar; López Manzanera, Rafael; Madroñal, C; Bolaños, Margarita; Gil, Mireia; Llombart, Antonio C.; Castro-Carpeño, J; González Barón, Manuel

    2010-01-01

    BACKGROUND: The efficacy and safety of capecitabine and bevacizumab in elderly patients with metastatic colorectal cancer (mCRC) considered unsuitable for receiving first-line chemotherapy with an irinotecan or oxaliplatin-based combination were assessed in a phase II, open, multicentre, uncontrolled study. METHODS: Treatment consisted of capecitabine 1250 mgm 2 (or 950 mgm 2 for patients with a creatinine clearance of 30–50ml min 1) twice daily on days 1–14 and bevacizumab (7.5 m...

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

    OpenAIRE

    2016-01-01

    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 c...

  17. Trifluridine/tipiracil and regorafenib: new weapons in the war against metastatic colorectal cancer.

    Science.gov (United States)

    Weinberg, Benjamin A; Marshall, John L; Salem, Mohamed E

    2016-08-01

    Colorectal cancer (CRC) is the second leading cause of cancer-related death in the United States. Approximately 20% of patients have metastatic disease at diagnosis, and a vast number of these patients die within 5 years. The advent of modern chemotherapeutics has improved median overall survival for these patients; nonetheless, we must keep striving for better outcomes. Trifluridine/tipiracil (TAS-102) and regorafenib are agents newly approved by the US Food and Drug Administration that show promise in the treatment of metastatic colorectal cancer. These drugs have the benefit of being formulated for oral administration and have different side effect profiles. These differences are important in the selection of the best therapy for each patient, especially if the patient is prone to a side effect that is unique to just one of the treatments. In this review, we discuss the mechanism of action, side effect profile, and clinical efficacy of trifluridine/tipiracil, and compare them with those of regorafenib. Future trials will evaluate the use of these drugs in earlier lines of therapy, alone and in combination with other agents. We now have 2 more agents in the arsenal against metastatic colorectal cancer and the future is looking brighter for patients, although we still have a long way to go.

  18. Subcutaneous preconditioning increases invasion and metastatic dissemination in mouse colorectal cancer models

    Directory of Open Access Journals (Sweden)

    Patricia Alamo

    2014-03-01

    Full Text Available Mouse colorectal cancer (CRC models generated by orthotopic microinjection of human CRC cell lines reproduce the pattern of lymphatic, haematological and transcoelomic spread but generate low metastatic efficiency. Our aim was to develop a new strategy that could increase the metastatic efficiency of these models. We used subcutaneous implantation of the human CRC cell lines HCT116 or SW48 prior to their orthotopic microinjection in the cecum of nude mice (SC+ORT. This subcutaneous preconditioning significantly enhanced metastatic dissemination. In the HCT116 model it increased the number and size of metastatic foci in lymph nodes, lung, liver and peritoneum, whereas, in the SW48 model, it induced a shift from non-metastatic to metastatic. In both models the number of apoptotic bodies in the primary tumour in the SC+ORT group was significantly reduced compared with that in the direct orthotopic injection (ORT group. Moreover, in HCT116 tumours the number of keratin-positive tumour buddings and single epithelial cells increased at the invasion front in SC+ORT mice. In the SW48 tumour model, we observed a trend towards a higher number of tumour buds and single cells in the SC+ORT group but this did not reach statistical significance. At a molecular level, the enhanced metastatic efficiency observed in the HCT116 SC+ORT model was associated with an increase in AKT activation, VEGF-A overexpression and downregulation of β1 integrin in primary tumour tissue, whereas, in SW48 SC+ORT mice, the level of expression of these proteins remained unchanged. In summary, subcutaneous preconditioning increased the metastatic dissemination of both orthotopic CRC models by increasing tumour cell survival and invasion at the tumour invasion front. This approach could be useful to simultaneously study the mechanisms of metastases and to evaluate anti-metastatic drugs against CRC.

  19. Subcutaneous preconditioning increases invasion and metastatic dissemination in mouse colorectal cancer models

    Science.gov (United States)

    Alamo, Patricia; Gallardo, Alberto; Pavón, Miguel A.; Casanova, Isolda; Trias, Manuel; Mangues, Maria A.; Vázquez, Esther; Villaverde, Antonio; Mangues, Ramon; Céspedes, Maria V.

    2014-01-01

    Mouse colorectal cancer (CRC) models generated by orthotopic microinjection of human CRC cell lines reproduce the pattern of lymphatic, haematological and transcoelomic spread but generate low metastatic efficiency. Our aim was to develop a new strategy that could increase the metastatic efficiency of these models. We used subcutaneous implantation of the human CRC cell lines HCT116 or SW48 prior to their orthotopic microinjection in the cecum of nude mice (SC+ORT). This subcutaneous preconditioning significantly enhanced metastatic dissemination. In the HCT116 model it increased the number and size of metastatic foci in lymph nodes, lung, liver and peritoneum, whereas, in the SW48 model, it induced a shift from non-metastatic to metastatic. In both models the number of apoptotic bodies in the primary tumour in the SC+ORT group was significantly reduced compared with that in the direct orthotopic injection (ORT) group. Moreover, in HCT116 tumours the number of keratin-positive tumour buddings and single epithelial cells increased at the invasion front in SC+ORT mice. In the SW48 tumour model, we observed a trend towards a higher number of tumour buds and single cells in the SC+ORT group but this did not reach statistical significance. At a molecular level, the enhanced metastatic efficiency observed in the HCT116 SC+ORT model was associated with an increase in AKT activation, VEGF-A overexpression and downregulation of β1 integrin in primary tumour tissue, whereas, in SW48 SC+ORT mice, the level of expression of these proteins remained unchanged. In summary, subcutaneous preconditioning increased the metastatic dissemination of both orthotopic CRC models by increasing tumour cell survival and invasion at the tumour invasion front. This approach could be useful to simultaneously study the mechanisms of metastases and to evaluate anti-metastatic drugs against CRC. PMID:24487410

  20. KRAS, BRAF, PIK3CA, and PTEN mutations: implications for targeted therapies in metastatic colorectal cancer.

    Science.gov (United States)

    De Roock, Wendy; De Vriendt, Veerle; Normanno, Nicola; Ciardiello, Fortunato; Tejpar, Sabine

    2011-06-01

    The discovery of mutant KRAS as a predictor of resistance to epidermal growth-factor receptor (EGFR) monoclonal antibodies brought a major change in the treatment of metastatic colorectal cancer. This seminal finding also highlighted our sparse knowledge about key signalling pathways in colorectal tumours. Drugs that inhibit oncogenic alterations such as phospho-MAP2K (also called MEK), phospho-AKT, and mutant B-RAF seem promising as single treatment or when given with EGFR inhibitors. However, our understanding of the precise role these potential drug targets have in colorectal tumours, and the oncogenic dependence that tumours might have on these components, has not progressed at the same rate. As a result, patient selection and prediction of treatment effects remain problematic. We review the role of mutations in genes other than KRAS on the efficacy of anti-EGFR therapy, and discuss strategies to target these oncogenic alterations alone or in combination with receptor tyrosine-kinase inhibition.

  1. Trefoil factor family (TFF) proteins as potential serum biomarkers in patients with metastatic colorectal cancer.

    Science.gov (United States)

    Vocka, M; Langer, D; Petrtyl, J; Vockova, P; Hanus, T; Kalousova, M; Zima, T; Petruzelka, L

    2015-01-01

    Trefoil factor family (TFF) is composed of three secretory proteins (TFF1, TFF2 and TFF3) that play an important role in mucosal protection of gastrointestinal tract. Their overexpression in colorectal tumors seems to be associated with more aggressive disease. We collected serum samples from 79 healthy controls and 97 patients with metastatic colorectal cancer at the time of diagnosis or at progression. Serum levels of TTF1-3, CEA and CA19-9 were measured by ELISA. Serum TFF1 and TFF3 levels were significantly higher in patients with colorectal cancer compared to healthy controls (p TFF3 correlated with extent of liver involvement in patient without pulmonary metastases and patients with higher TFF3 levels had significantly worse outcome (p TFF3 had higher sensitivity and the same specificity. Our results indicate that TFF3 is an effective biomarker in patients with metastatic colorectal cancer with higher sensitivity than CEA a CA19-9. TFF3 levels strongly correlate with extension of liver disease and seem to have prognostic value.

  2. Primary Colorectal Adenocarcinoma Metastatic to the Breast: Case Report and Review of Nineteen Cases

    Directory of Open Access Journals (Sweden)

    Rodney E. Shackelford

    2011-01-01

    Full Text Available Metastases to the breast from extramammary primaries are uncommon and account for 0.5–6% of all breast malignancies (Georgiannos et al., 2001, and Vizcaíno et al., 2001. Malignant melanoma, lymphoma, and lung and gastric carcinomas are the most frequently encountered nonmammary metastases to the breast in adults (Georgiannos et al., 2001, and Chaignaud et al., 1994. Primary colorectal adenocarcinoma (CRC metastatic to the breast is extremely rare, with the medical literature having only 19 recorded cases. Typically CRC metastatic to the breast is indicative of widely disseminated disease and a poor prognosis. Here we present a case of poorly differentiated colon cancer metastatic to the breast and review the current literature on this rare event.

  3. Primary colorectal adenocarcinoma metastatic to the breast: case report and review of nineteen cases.

    Science.gov (United States)

    Shackelford, Rodney E; Allam-Nandyala, Pushpa; Bui, Marilyn M; Kiluk, John V; Esposito, Nicole Nicosia

    2011-01-01

    Metastases to the breast from extramammary primaries are uncommon and account for 0.5-6% of all breast malignancies (Georgiannos et al., 2001, and Vizcaíno et al., 2001). Malignant melanoma, lymphoma, and lung and gastric carcinomas are the most frequently encountered nonmammary metastases to the breast in adults (Georgiannos et al., 2001, and Chaignaud et al., 1994). Primary colorectal adenocarcinoma (CRC) metastatic to the breast is extremely rare, with the medical literature having only 19 recorded cases. Typically CRC metastatic to the breast is indicative of widely disseminated disease and a poor prognosis. Here we present a case of poorly differentiated colon cancer metastatic to the breast and review the current literature on this rare event.

  4. Large scale systematic proteomic quantification from non-metastatic to metastatic colorectal cancer

    Science.gov (United States)

    Yin, Xuefei; Zhang, Yang; Guo, Shaowen; Jin, Hong; Wang, Wenhai; Yang, Pengyuan

    2015-07-01

    A systematic proteomic quantification of formalin-fixed, paraffin-embedded (FFPE) colorectal cancer tissues from stage I to stage IIIC was performed in large scale. 1017 proteins were identified with 338 proteins in quantitative changes by label free method, while 341 proteins were quantified with significant expression changes among 6294 proteins by iTRAQ method. We found that proteins related to migration expression increased and those for binding and adherent decreased during the colorectal cancer development according to the gene ontology (GO) annotation and ingenuity pathway analysis (IPA). The integrin alpha 5 (ITA5) in integrin family was focused, which was consistent with the metastasis related pathway. The expression level of ITA5 decreased in metastasis tissues and the result has been further verified by Western blotting. Another two cell migration related proteins vitronectin (VTN) and actin-related protein (ARP3) were also proved to be up-regulated by both mass spectrometry (MS) based quantification results and Western blotting. Up to now, our result shows one of the largest dataset in colorectal cancer proteomics research. Our strategy reveals a disease driven omics-pattern for the metastasis colorectal cancer.

  5. Hypermethylation of the TPEF/HPP1 Gene in Primary, Metastatic Colorectal Cancers

    Directory of Open Access Journals (Sweden)

    Matthias P.A. Ebert

    2005-08-01

    Full Text Available The role of promoter methylation in the process of cancer cell metastasis has not yet been studied. Recently, methylation of the TPEF (transmembrane protein containing epidermal growth factor, follistatin domain gene was reported in human colon, gastric, bladder cancer cells. Using the Methylight assay, TPEF/HPP1 gene methylation was assessed in primary colorectal cancers (n = 47, matched normal colon mucosa, as well as in the liver metastasis of 24 patients with colorectal cancer, compared to the methylation status of the TIMP-3, APC, DAPK, caveolin-2, p16 genes. TPEF was frequently methylated in primary colorectal cancers (36 of 47 compared to the normal colon mucosa (1 of 21 (P < .0001. Interestingly, promoter methylation was significantly more frequent in proximal nonrectal cancers (P < .05. Furthermore, a high degree of methylation of the TPEF gene was also observed in liver metastasis. (19 of 24. In summary, we observed frequent TPEF methylation in primary colorectal cancers, liver metastases, indicating that epigenetic alterations are not only present in the early phases of carcinogenesis, but are also common in metastatic lesions. The high frequency of TPEF methylation in this series of colorectal cancers underscores the importance of epigenetic changes as targets for the development of molecular tests for cancer diagnosis.

  6. Metastatic Colorectal Cancer Resembling Severe Preeclampsia in Pregnancy

    Directory of Open Access Journals (Sweden)

    Raminder Kaur Khangura

    2015-01-01

    Full Text Available Although colorectal cancer (CRC is the third most common cancer in women, it is a rare malignancy in pregnancy. Symptoms of CRC such as fatigue, malaise, nausea, vomiting, rectal bleeding, anemia, altered bowel habits, and abdominal mass are often considered typical symptoms of pregnancy. Many cases of CRC are diagnosed in advanced stages due to missed warning signs of CRC, which may be misinterpreted as normal symptoms related to pregnancy. This report reviews 2 cases of CRC diagnosed within a 4-month interval at our institution. Both cases were initially thought to be atypical presentations of preeclampsia. Prenatal history, hospital course, and postpartum course were reviewed for both patients. CRC is often diagnosed at advanced stages in pregnancy. Common physiological symptoms of pregnancy should be scrutinized carefully and worked up appropriately, especially if symptoms remain persistent or increase in intensity or severity.

  7. Randomized trial of TAS-102 for refractory metastatic colorectal cancer.

    Science.gov (United States)

    Mayer, Robert J; Van Cutsem, Eric; Falcone, Alfredo; Yoshino, Takayuki; Garcia-Carbonero, Rocio; Mizunuma, Nobuyuki; Yamazaki, Kentaro; Shimada, Yasuhiro; Tabernero, Josep; Komatsu, Yoshito; Sobrero, Alberto; Boucher, Eveline; Peeters, Marc; Tran, Ben; Lenz, Heinz-Josef; Zaniboni, Alberto; Hochster, Howard; Cleary, James M; Prenen, Hans; Benedetti, Fabio; Mizuguchi, Hirokazu; Makris, Lukas; Ito, Masanobu; Ohtsu, Atsushi

    2015-05-14

    Early clinical trials conducted primarily in Japan have shown that TAS-102, an oral agent that combines trifluridine and tipiracil hydrochloride, was effective in the treatment of refractory colorectal cancer. We conducted a phase 3 trial to further assess the efficacy and safety of TAS-102 in a global population of such patients. In this double-blind study, we randomly assigned 800 patients, in a 2:1 ratio, to receive TAS-102 or placebo. The primary end point was overall survival. The median overall survival improved from 5.3 months with placebo to 7.1 months with TAS-102, and the hazard ratio for death in the TAS-102 group versus the placebo group was 0.68 (95% confidence interval [CI], 0.58 to 0.81; P<0.001). The most frequently observed clinically significant adverse events associated with TAS-102 were neutropenia, which occurred in 38% of those treated, and leukopenia, which occurred in 21%; 4% of the patients who received TAS-102 had febrile neutropenia, and one death related to TAS-102 was reported. The median time to worsening performance status (a change in Eastern Cooperative Oncology Group performance status [on a scale of 0 to 5, with 0 indicating no symptoms and higher numbers indicating increasing degrees of disability] from 0 or 1 to 2 or more) was 5.7 months with TAS-102 versus 4.0 months with placebo (hazard ratio, 0.66; 95% CI, 0.56 to 0.78; P<0.001). In patients with refractory colorectal cancer, TAS-102, as compared with placebo, was associated with a significant improvement in overall survival. (Funded by Taiho Oncology-Taiho Pharmaceutical; RECOURSE ClinicalTrials.gov number, NCT01607957.).

  8. Cell-SELEX-based selection of aptamers that recognize distinct targets on metastatic colorectal cancer cells.

    Science.gov (United States)

    Li, Wan-Ming; Bing, Tao; Wei, Jia-Yi; Chen, Zhe-Zhou; Shangguan, Di-Hua; Fang, Jin

    2014-08-01

    The development of diagnostic/therapeutic strategies against metastasis-related molecular targets is critical for improving the survival rate of cancer patients. Subtractive Cell-SELEX was performed using highly metastatic colorectal cancer (CRC) LoVo cells and non-metastatic HCT-8 cells as the target and negative cells, respectively, for the selection of metastatic-specific aptamers. This process generated seven aptamers that displayed highly specific binding to the target cells with Kds in the nanomolar range. Based on the distinct chemical/biological properties of their individual cell surface targets, the aptamers were separately functionalized: the receptor-targeting aptamer W14 was used as a carrier for doxorubicin, resulting in the specific delivery of the drug to the target cells and a significant reduction of its cytotoxicity to non-target cells, and the non-receptor-binding aptamer W3 was used as a molecular probe conjugated to quantum dots for the targeted imaging of metastatic cancer cell lines, spontaneous lung metastasis murine tissue, and metastatic CRC patient tissues. In addition, these aptamers can be used in combination due to their lack of detectable mutual-binding interference. The study demonstrates that a panel of aptamers that recognize distinct features of target molecules can be obtained through single Cell-SELEX selection, and the selected aptamers may be individually functionalized for specific applications and/or utilized in combination. Copyright © 2014 Elsevier Ltd. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    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

  10. 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.

  11. Reliability of KRAS mutation testing in metastatic colorectal cancer patients across five laboratories

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    Feigelson Heather

    2012-04-01

    Full Text Available Abstract Background Mutations in the KRAS gene are associated with poor response to epidermal growth factor receptor inhibitors used in the treatment of metastatic colorectal cancer. Factors influencing KRAS test results in tumor specimens include: tumor heterogeneity, sample handling, slide preparation, techniques for tumor enrichment, DNA preparation, assay design and sensitivity. We evaluated comparability and consistency of KRAS test results among five laboratories currently being used to determine KRAS mutation status of metastatic colorectal cancer specimens in a large, multi-center observational study. Findings Twenty formalin-fixed paraffin-embedded human colorectal cancer samples from colon resections previously tested for KRAS mutations were selected based on mutation status (6 wild type, 8 codon 12 mutations, and 6 codon 13 mutations. We found good agreement across laboratories despite differences in mutation detection methods. Eighteen of twenty samples (90% were concordant across all five labs. Discordant results are likely not due to laboratory error, but instead to tumor heterogeneity, contamination of the tumor sample with normal tissue, or analytic factors affecting assay sensitivity. Conclusions Our results indicate commercial and academic laboratories provide reliable results for the common KRAS gene mutations at codons 12 and 13 when an adequate percentage of tumor cells is present in the sample.

  12. Selumetinib and Cyclosporine in Treating Patients With Advanced Solid Tumors or Advanced or Metastatic Colorectal Cancer

    Science.gov (United States)

    2017-09-04

    Recurrent Colorectal Carcinoma; Solid Neoplasm; Stage IIIA Colorectal Cancer AJCC v7; Stage IIIB Colorectal Cancer AJCC v7; Stage IIIC Colorectal Cancer AJCC v7; Stage IVA Colorectal Cancer AJCC v7; Stage IVB Colorectal Cancer AJCC v7

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

    Directory of Open Access Journals (Sweden)

    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.

  14. Study on adherence to capecitabine among patients with colorectal cancer and metastatic breast cancer.

    Science.gov (United States)

    Figueiredo Junior, Adiel Goes de; Forones, Nora Manoukian

    2014-01-01

    Capecitabine, an oral drug, is as effective as traditional chemotherapy drugs. 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. 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. 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. 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.

  15. Clinical values of detecting excision repair cross complementing 1 and top-oisomerase I in individualized therapies of metastatic colorectal cancer

    Institute of Scientific and Technical Information of China (English)

    邱继刚

    2014-01-01

    Objective To explore the clinical values of detecting drug related molecules excision repair cross complementing 1(ERCC1)and top-oisomeraseⅠ(TOPOⅠ)in individualized therapies of metastatic colorectal cancer.Methods From June 2009 to December 2011,90 patients at Huadong Hospital with metastatic colorectal cancer were randomly

  16. 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.

  17. Palliative treatment of metastatic colorectal cancer: what is the optimal approach?

    Science.gov (United States)

    Strickler, John H; Hurwitz, Herbert I

    2014-01-01

    Worldwide, colorectal cancer (CRC) is responsible for over 600,000 deaths annually and remains a significant public health concern. Because of therapeutic advancements over the past two decades, patients with metastatic CRC are living longer with an improved quality of life. This review will highlight recent trial evidence that improves outcomes for patients with metastatic disease. Topics will include the optimal use of first-line combination chemotherapy, bevacizumab in patients with advanced age or comorbidities, maintenance chemotherapy, first-line use of anti-EGFR therapies, first-line cetuximab versus bevacizumab, anti-angiogenic therapies past progression, and management of treatment-refractory disease. Clinical trial evidence will be presented, along with guidance on how to integrate recent evidence into clinical practice. Finally, this review will examine innovative drug development strategies, and will discuss potentially actionable targets identified by molecular testing.

  18. Panitumumab: the evidence for its use in the treatment of metastatic colorectal cancer

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    Rossana Berardi

    2010-09-01

    Full Text Available Rossana Berardi1, Azzurra Onofri2, Mirco Pistelli2, Elena Maccaroni2, Mario Scartozzi1, Chiara Pierantoni1, Stefano Cascinu11Clinica di Oncologia Medica, Università Politecnica delle Marche, Ospedali Riuniti Umberto I-GM Lancisi-G Salesi di Ancona, Italy; 2Scuola di Specializzazione in Oncologia Medica, Università Politecnica delle Marche, Ancona, ItalyAbstract: Panitumumab is the first fully human monoclonal antibody to Epidermal Growth Factor Receptor (EGFR to enter clinical trials for the treatment of solid tumors. The anti-tumor activity of panitumumab has been tested in vitro and in vivo, and inhibition of tumor growth has been observed in numerous cancer models, particularly lung, kidney and colorectal (CRC. Preclinical and clinical studies have established a role for panitumumab in metastatic colorectal cancer (mCRC refractory to multiple chemotherapeutic regimens. Based on these encouraging findings, panitumumab was approved by the US Food and Drug Administration for the treatment of patients with epidermal growth factor receptor-expressing mCRC refractory to fluoropyrimidine-, oxaliplatin-, and/or irinotecan-containing chemotherapeutic regimens. The improvement in progression free survival (PFS and response rate (RR produced by panitumumab monotherapy was significantly greater in patients with non mutated (wild-type K-RAS than in those with mutant K-RAS. Therefore implementing routine K-RAS screening and limiting the use of EGFR inhibitors to patients with wild-type K-RAS appears the better strategy for select only the patients who could benefit from the therapy with panitumumab and also may have the potential for cost savings. The purpose of this review was to evaluate the patient-related, disease-related and economic-related evidence for the use of panitumumab in the treatment of metastatic colorectal cancer in clinical practice.Keywords: colorectal cancer, EGFR; K-RAS, panitumumab 

  19. Interleukin-6 and C-reactive protein as prognostic biomarkers in metastatic colorectal cancer

    DEFF Research Database (Denmark)

    Thomsen, Maria; Kersten, Christian; Sorbye, Halfdan

    2016-01-01

    OBJECTIVES: The aim was to explore the prognostic significance of IL-6 and markers of systemic inflammatory response (SIR), in particular C-reactive protein (CRP), in metastatic colorectal cancer (mCRC) patients, in the total study population and according to RAS and BRAF mutation status. RESULTS...... 24.3 months to 12.3 months, (P BRAF mutation (interaction P = 0.004). MATERIALS AND METHODS: IL-6 and CRP were determined in pre-treatment serum samples...... with impaired prognosis in mCRC. IL-6 and CRP give independent prognostic information in addition to RAS and BRAF mutation status....

  20. KRAS-mutated plasma DNA as predictor of outcome from irinotecan monotherapy in metastatic colorectal cancer

    DEFF Research Database (Denmark)

    Spindler, K G; Appelt, A L; Pallisgaard, N

    2013-01-01

    Background:We investigated the clinical implications of KRAS and BRAF mutations detected in both archival tumor tissue and plasma cell-free DNA in metastatic colorectal cancer patients treated with irinotecan monotherapy.Methods:Two hundred and eleven patients receiving second-line irinotecan (350...... with mutations detectable in plasma responded to therapy. Response rate and disease control rate in plasma KRAS wt patients were 19 and 66% compared with 0 and 37%, in patients with pKRAS mutations, (P=0.04 and 0.01). Tumor KRAS status was not associated with PFS but with OS in the validation cohort. Plasma BRAF...

  1. Plasma TIMP-1 levels and treatment outcome in patients treated with XELOX for metastatic colorectal cancer

    DEFF Research Database (Denmark)

    Frederiksen, C.; Qvortrup, C.; Christensen, I.J.

    2011-01-01

    .17-2.78]. Furthermore, increase in TIMP-1 levels from baseline to immediately before the second cycle of chemotherapy had a significant negative effect on survival (P = 0.03, HR = 1.30, 95% CI: 1.02-1.65) while a decrease in TIMP-1 was significantly associated with a higher objective response rate (P = 0......BACKGROUND: The aim was to evaluate the association between plasma tissue inhibitor of metalloproteinase-1 (TIMP-1) and serum carcinoembryonic antigen (CEA) levels and outcome in patients with metastatic colorectal cancer (mCRC) receiving XELOX (combination chemotherapy with capecitabine...

  2. Intraarticular hemorrhage due to bevacizumab in a patient with metastatic colorectal cancer: a case report

    Directory of Open Access Journals (Sweden)

    Uysal Mukremin

    2012-07-01

    Full Text Available Abstract Introduction Bevacizumab is a monoclonal antibody against vascular endothelial growth factor. It is widely used in the treatment of metastatic colorectal cancer. It has some specific side effects including severe bleeding, wound healing problems, gastrointestinal perforation, proteinuria and hypertension. Case presentation We present the case of a 65-year old Asian man with synovial metastasis of the knee who experienced intraarticular hemorrhage after bevacizumab treatment. He presented with monoarthritis of the left knee. Conclusion Bevacizumab-related hemorrhage can cause serious morbidity and unusual sites of hemorrhage may be seen.

  3. Limited effect of lymph node status on the metastatic pattern in colorectal cancer.

    Science.gov (United States)

    Knijn, Nikki; van Erning, Felice N; Overbeek, Lucy I H; Punt, Cornelis J A; Lemmens, Valery E P P; Hugen, Niek; Nagtegaal, Iris D

    2016-05-31

    Regional lymph node metastases in colorectal cancer (CRC) decrease outcome. Whether nodal metastases function as a biomarker, i.e. as a sign of advanced disease, or are in fact involved in the metastatic process is unclear. We evaluated metastatic patterns of CRC according to the lymph node status of the primary tumor.A retrospective review of 1393 patients with metastatic CRC who underwent autopsy in the Netherlands was performed. Metastatic patterns of regional lymph node positive and negative CRC were compared and validated by population-based data from the Eindhoven Cancer Registry (ECR).Patients with regional lymph node positive CRC more often developed peritoneal metastases (28% vs. 21%, p=0.003) and distant lymph node metastases (25% vs. 15%, p <0.001). Incidences of liver and lung metastases were comparable. Data from the ECR confirmed our findings regarding peritoneal (22.4% vs. 17.0%, p=0.003) and distant lymph node metastases (15.8% vs. 9.7%, p <0.001).Regional lymph node positive CRC show a slightly different dissemination pattern, with higher rates of peritoneal and distant lymph nodes metastases. Comparable incidences of liver and lung metastases support the hypothesis that dissemination to distant organs occurs independently of lymphatic spread.

  4. PROGNOSTIC FACTORS FOR SURVIVAL IN PATIENTS WITH METASTATIC COLORECTAL CANCER TREATED WITH FIRST - LINE CHEMOTHERAPY

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    Deyan Davidov

    2017-05-01

    Full Text Available Objective: The aim of this study was to investigate the prognostic significance for survival of certain clinical and pathological factors in patients with advanced or metastatic colorectal carcinoma (CRC treated with first- line chemotherapy. Methods: From 2002 to 2011 seventy- four consecutive patients with advanced or metastatic CRC, treated in UMHAT- Dr. G. Stranski, Department of Medical Oncology entered the study. Some patient’s characteristics, hematological and pathological parameters, were evaluated for their role as predictors of overall survival. The therapeutic regimens included FOLFOX or FOlFIRI. Survival analysis was evaluated by Kaplan- Meier test. The influence of pretreatment characteristics as prognostic factor for survival was analyzed using multivariate stepwise Cox regression analyses. Results: In multivariate analysis a significant correlation was exhibited between survival, poor performance status and multiple sites of metastasis. Variables significantly associated with overall survival in univariate analysis were performance status>1, thrombocytosis, anemia and number of metastatic sites >1. Conclusion: These results indicated that poor performance status, anemia, thrombocytosis as well as multiple site of metastasis could be useful prognostic factors in patients with metastatic CRC.

  5. 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...... to and following therapy, via the use of 18-fluoride fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT). On baseline 18F-FDG PET/CT scans (n=51), volumes of interest (VOI) were obtained from tumor-free tissue (aortic arch, liver and spleen) and SUVs normalized to total...... 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...

  6. Randomised phase III trial of S-1 versus capecitabine in the first-line treatment of metastatic colorectal cancer: SALTO study by the Dutch Colorectal Cancer Group.

    Science.gov (United States)

    Kwakman, J J M; Simkens, L H J; van Rooijen, J M; van de Wouw, A J; Ten Tije, A J; Creemers, G J M; Hendriks, M P; Los, M; van Alphen, R J; Polée, M B; Muller, E W; van der Velden, A M T; van Voorthuizen, T; Koopman, M; Mol, L; van Werkhoven, E; Punt, C J A

    2017-04-05

    Hand-foot syndrome (HFS) is a common side effect of capecitabine. S-1 is an oral fluoropyrimidine with comparable efficacy to capecitabine in gastrointestinal cancers but associated with a lower incidence of HFS in Asian patients. This study compares the incidence of HFS between S-1 and capecitabine as first-line treatment in Western metastatic colorectal cancer (mCRC) patients.

  7. UGT1A1*28 genotype and irinotecan dosage in patients with metastatic colorectal cancer: a Dutch Colorectal Cancer Group study.

    NARCIS (Netherlands)

    Kweekel, D.M.; Gelderblom, H.; Straaten, T Van der; Antonini, N.F.; Punt, C.J.A.; Guchelaar, H.J.

    2008-01-01

    The aim of the study was to investigate the associations between UGT1A1(*)28 genotype and (1) response rates, (2) febrile neutropenia and (3) dose intensity in patients with metastatic colorectal cancer treated with irinotecan. UGT1A1(*)28 genotype was determined in 218 patients receiving irinotecan

  8. High preoperative serum ferritin predicted poor prognosis in non-metastatic colorectal cancer.

    Science.gov (United States)

    Tingting, Hong; Di, Shen; Xiaoping, Chen; Xiaohong, Wu; Dong, Hua

    2017-03-01

    To validate the prognostic significance of preoperative serum iron metabolism parameters in non-metastatic colorectal cancer patients treated with curative resection.   Methods: We conducted a prospective cohort study in the Department of Surgical Oncology, WuXi 4th People's Hospital, WuxiChina, between  March 2010 and September 2013.  The relationships of serum iron metabolism parameters with other variables were examined. The prognostic significance was evaluated using the Kaplan Meier curve and Cox proportional hazards regression model.  Results: Five hundred and fourteen patients were eligible for analysis. The levels of the 3 iron metabolism parameters were interdependent. Hemoglobin level was positively correlated with serum iron and transferrin, and was negatively correlated with ferritin. Compared with peri-neural invasion (PNI)-negative patients, PNI-positive patients had higher serum iron (p=0.03) and ferritin levels (p=0.01). Compared with patients with the lowest quartile level of ferritin, patients with the highest quartile level of ferritin had a 2.21 (95% CI: 1.18-4.14) fold increased mortality risk in the univariate and 2.56 (95% CI: 1.10-5.96) in the multivariate Cox proportional hazards models. When stratified by TNM stages, it was only in stage III patients that serum ferritin remained statistically prognostically significant. Conclusions: Preoperative serum ferritin appeared as an independent adverse risk factor in non-metastatic colorectal cancer.

  9. Role of capecitabine in treating metastatic colorectal cancer in Chinese patients

    Directory of Open Access Journals (Sweden)

    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

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  11. 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.

  12. Chemotherapeutic strategies in metastatic colorectal cancer: an overview of current clinical trials.

    Science.gov (United States)

    Köhne-Wömpner, C H; Schmoll, H J; Harstrick, A; Rustum, Y M

    1992-04-01

    5-Fluorouracil (5-FU) is still the mainstay of chemotherapy in patients with metastatic colorectal cancer. A prolonged infusion of 5-FU is more active than any other schedule of 5-FU used to date. Cisplatin does not improve treatment results compared with 5-FU alone and is not recommended outside clinical trials. Biomodulation of 5-FU is a major step forward in the treatment of colorectal cancer patients and as the standard chemotherapy for advanced colorectal cancer. Two schedules of folinic acid daily for 5-day (low and high doses) and weekly high dose in combination with daily or weekly 5-FU are the most widely used schedules. Although the response rates to either schedule are comparable, the profile of toxicity is different, being stomatitis for the daily schedule and diarrhea for the weekly schedule as the dose-limiting toxicity. Modulation of 5-FU by methotrexate is time dependent. An interval of 24 hours between methotrexate and 5-FU is necessary for effective modulation. Other modulators, like interferon and N-phosphonoactyl-L-aspartate (PALA), are promising treatment options currently under investigation in randomized trials. The data from phase II and III trials using modulation of 5-FU by folinic acid, PALA, or methotrexate, or using continuous infusion 5-FU indicate that all of these strategies are active. Randomized trials are currently underway to further investigate these therapeutic approaches and whether a specific modulation offers more therapeutic advantages.

  13. Maintenance Therapy With Cetuximab Every Second Week in the First-Line Treatment of Metastatic Colorectal Cancer

    DEFF Research Database (Denmark)

    Pfeiffer, Per; Sorbye, Hafdan; Qvortrup, Camilla

    2015-01-01

    BACKGROUND: In the NORDIC-7.5 trial, how cetuximab might safely and conveniently be added to an intermittent treatment strategy in patients with prospectively selected Kirsten rat sarcoma viral oncogene homolog wild type (KRASwt) metastatic colorectal cancer (mCRC) was investigated. Patients were...

  14. Markers for EGFR pathway activation as predictor of outcome in metastatic colorectal cancer patients treated with or without cetuximab.

    NARCIS (Netherlands)

    Tol, J.; Dijkstra, J.R.; Klomp, M.; Teerenstra, S.; Dommerholt, M.; Vink-Borger, M.E.; Cleef, P.H. van; Krieken, J.H.J.M. van; Punt, C.J.A.; Nagtegaal, I.D.

    2010-01-01

    BACKGROUND: Anti-EGFR monoclonal antibodies in metastatic colorectal cancer (mCRC) treatment are only effective in patients with KRAS wild type tumours. Here we assess the predictive value of other potential relevant markers involved in the epidermal growth factor receptor (EGFR) signalling pathways

  15. Phase I Study of Everolimus, Cetuximab and Irinotecan as Second-line Therapy in Metastatic Colorectal Cancer

    NARCIS (Netherlands)

    Hecht, J.R.; Reid, T.R.; Garrett, C.R.; Beck, J.T.; Davidson, S.J.; Mackenzie, M.J.; Brandt, U.; Rizvi, S.; Sharma, S.

    2015-01-01

    AIM: To evaluate feasible doses of weekly everolimus and irinotecan given with cetuximab for previously treated metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Adults with mCRC that progressed after 5-fluorouracil or capecitabine-plus-oxaliplatin were treated using a sequential dose escal

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    Al-Temaimi, Rabeah A; Tan, Tuan Zea; Marafie, Makia J; Thiery, Jean Paul; Quirke, Philip; Al-Mulla, Fahd

    2016-04-28

    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.

  18. Current Options for Third-Line Treatment of Metastatic Colorectal Cancer.

    Science.gov (United States)

    Grothey, Axel; Marshall, John L; Seery, Tara E

    2016-03-01

    Until recently, treatment options for patients with metastatic colorectal cancer (CRC) were limited to chemotherapy, vascular endothelial growth factor–targeted therapy, and, for patients with RAS-wild type tumors, epidermal growth factor receptor–targeted therapy. For patients with disease progression after treatment, newer agents are now available: the multitargeted tyrosine kinase inhibitor regorafenib and the cytotoxic combination of trifluridine and tipiracil (TAS-102). Both regorafenib and trifluridine/tipiracil have demonstrated significant improvements in overall survival in patients with refractory metastatic CRC. Durable responses exceeding a year have been reported with regorafenib. The agents differ in their safety profiles. Regorafenib is associated with hand-foot skin reaction and fatigue, primarily in the first cycle. Alternative dosing strategies appear to improve the tolerability of regorafenib, and randomized dosing studies are underway to define the optimal strategy. Trifluridine/tipiracil is associated primarily with myelosuppression. Sequencing of these agents can be guided by patient characteristics, such as comorbidities and adverse reactions to previous treatments. Patients with a poor performance status are not likely to benefit from regorafenib. Ongoing studies are further defining the role of regorafenib and trifluridine/tipiracil in the treatment of metastatic CRC.

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

    Science.gov (United States)

    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.

  20. Changes in mutational status during third-line treatment for metastatic colorectal cancer

    DEFF Research Database (Denmark)

    Spindler, Karen-Lise Garm; Pallisgaard, Niels; Andersen, Rikke Fredslund

    2014-01-01

    KRAS and BRAF mutations are responsible for primary resistance to epidermal growth factor receptor (EGFR) MoAbs in metastatic colorectal cancer (mCRC), but it is unknown what causes wildtype (wt) patients to develop resistance during treatment. We measured circulating free DNA (cfDNA), KRAS...... and BRAF in plasma and report the changes during third line treatment with cetuximab and irinotecan. One-hundred-and-eight patients received irinotecan 350 mg/m2 q3w and weekly cetuximab (250 mg/m2) until progression (RECIST) or unacceptable toxicity. cfDNA and number of mutated KRAS/BRAF alleles in plasma...... different types of mutations detected in the plasma, including synchronous KRAS and BRAF. Twelve patients had a primary KRAS mutant tumor, but wild-type disease according to baseline plasma analysis, eight of these obtained stabilization of disease. In five patients with primary wt disease a mutation...

  1. Spotlight on bevacizumab in metastatic colorectal cancer: patient selection and perspectives

    Directory of Open Access Journals (Sweden)

    Bupathi M

    2016-06-01

    Full Text Available Manojkumar Bupathi, Daniel H Ahn, Tanios Bekaii-Saab Department of Medical Oncology, Richard Solove Research Institute and James Cancer Hospital, The Ohio State University Wexner Medical Center, Columbus, OH, USAAbstract: Metastatic colorectal cancer (mCRC is a prevalent disease for which combination cytotoxic chemotherapy is the mainstay of treatment. With the use of targeted therapy, including anti-angiogenic agents, there have been significant improvements in overall outcome of patients with mCRC. Bevacizumab, a monoclonal antibody targeting the vascular endothelial growth factor ligand A, is approved for use in mCRC patients in both the first and second lines of therapy. With a better understanding of the disease through molecular profiling, identification of prognostic biomarkers may lead to better patient selection with improved outcomes for those affected by this disease. Keywords: VEGF, colon, rectum, cancer

  2. Circulating free DNA as biomarker and source for mutation detection in metastatic colorectal cancer

    DEFF Research Database (Denmark)

    Spindler, Karen Lise Garm; Pallisgaard, Niels; Andersen, Rikke Fredslund

    2015-01-01

    BACKGROUND: Circulating cell-free DNA (cfDNA) in plasma has shown potential as biomarker in various cancers and could become an importance source for tumour mutation detection. The objectives of our study were to establish a normal range of cfDNA in a cohort of healthy individuals and to compare...... this with four cohorts of metastatic colorectal cancer (mCRC) patients. We also investigated the prognostic value of cfDNA and analysed the tumour-specific KRAS mutations in the plasma. METHODS: The study was a prospective biomarker evaluation in four consecutive Phase II trials, including 229 patients...... the prognostic value of cfDNA measurement in plasma and utility for mutation detection with the method presented....

  3. Novel therapeutics in metastatic colorectal cancer: molecular insights and pharmacogenomic implications.

    Science.gov (United States)

    Hanna, Diana L; Lenz, Heinz-Josef

    2016-08-01

    Although the survival of metastatic colorectal cancer (mCRC) patients has improved five-fold over the last century, CRC remains a significant global health burden. Impressive strides have been made in identifying new regimens, employing maintenance strategies to limit treatment toxicities, and combining multidisciplinary approaches to achieve cure in oligometastatic disease. Attempts at personalized integration of targeted agents have been limited by the ability to identify molecularly enriched patient populations most likely to benefit. In this review, we discuss novel therapeutics and regimens recently approved and in development for mCRC. In addition, we discuss using older agents in novel combination and maintenance strategies, and highlight evidence for implementing pharmacogenomic data and non-invasive monitoring into the personalized management of mCRC patients.

  4. Bevacizumab-based therapies in the first-line treatment of metastatic colorectal cancer.

    Science.gov (United States)

    Strickler, John H; Hurwitz, Herbert I

    2012-01-01

    Since its approval for the first-line treatment of metastatic colorectal cancer (mCRC), bevacizumab has become a standard treatment option in combination with chemotherapy for patients with mCRC. Bevacizumab has demonstrated efficacy in combination with a number of different backbone chemotherapy regimens, and its widespread use has introduced several important questions regarding the selection and optimization of bevacizumab-based treatment regimens, its use in various patient populations, and the identification of associated adverse events. This review discusses the results of several phase II and phase III clinical trials, as well as large observational studies, to address the use of bevacizumab in the treatment of patients with mCRC in the first-line setting.

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

    Directory of Open Access Journals (Sweden)

    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

  6. Angiogenesis inhibitors and symptomatic anal ulcers in metastatic colorectal cancer patients (*).

    Science.gov (United States)

    Bergamo, Francesca; Lonardi, Sara; Salmaso, Beatrice; Lacognata, Carmelo; Battaglin, Francesca; Cavallin, Francesco; Saadeh, Luca; Murgioni, Sabina; Caruso, Antonino; Aliberti, Camillo; Zagonel, Vittorina; Castoro, Carlo; Scarpa, Marco

    2017-07-15

    Angiogenesis inhibitors are a standard first-line treatment for metastatic colorectal cancer. Anal canal pain is a common adverse event, but its cause has never been described. The aim of the study was to evaluate the association between the use of angiogenesis inhibitors and symptomatic anal ulcer development. This retrospective cohort study included all 601 consecutive metastatic colorectal cancer patients undergoing first line treatment from January 2010 to June 2016 at the Veneto Institute of Oncology. Details about patient characteristics, treatment and proctology reports were retrieved and compared. Vascularization of the anal canal was evaluated with contrast MRI. Fifty out of 601 patients reported perianal complaints during treatment and underwent proctologic evaluation. Among those, 16 were found to have an anal ulcer. Symptomatic anal ulcers occurred only in patients receiving bevacizumab (4.2% vs. 0% with other regimens, p = .009). The peak incidence was 4-8 weeks after treatment start. Vascularization of anal canal was significantly lower in patients treated with bevacizumab (p = .03). Hypertension and hemorrhoids were associated with a lower risk of anal ulcer occurrence (p = .009 and p = .036). Pain intensity was severe. All attempts at symptomatic treatment only led to transient benefit. The absence of symptomatic ulcers was protective against earlier permanent discontinuation of treatment (HR = .22, 95%CI: 0.04-0.62). The development of symptomatic anal ulcers in patients receiving angiogenesis inhibitor is a common adverse event which can compromise the continuation of cancer therapy. We recommend an early proctologic evaluation in case of anal symptoms with the aim to prevent and timely manage such complication.

  7. Bevacizumab treatment in the elderly patient with metastatic colorectal cancer

    Directory of Open Access Journals (Sweden)

    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

  8. Role of cetuximab in first-line treatment of metastatic colorectal cancer.

    Science.gov (United States)

    Sotelo, Miguel Jhonatan; García-Paredes, Beatriz; Aguado, Carlos; Sastre, Javier; Díaz-Rubio, Eduardo

    2014-04-21

    The treatment of metastatic colorectal cancer (mCRC) has evolved considerably in the last decade, currently allowing most mCRC patients to live more than two years. Monoclonal antibodies targeting the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor play an important role in the current treatment of these patients. However, only antibodies directed against EGFR have a predictive marker of response, which is the mutation status of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS). Cetuximab has been shown to be effective in patients with KRAS wild-type mCRC. The CRYSTAL study showed that adding cetuximab to FOLFIRI (regimen of irinotecan, infusional fluorouracil and leucovorin) significantly improved results in the first-line treatment of KRAS wild-type mCRC. However, results that evaluate the efficacy of cetuximab in combination with oxaliplatin-based chemotherapy in this setting are contradictory. On the other hand, recent advances in the management of colorectal liver metastases have improved survival in these patients. Adding cetuximab to standard chemotherapy increases the response rate in patients with wild-type KRAS and can thus increase the resectability rate of liver metastases in this group of patients. In this paper we review the different studies assessing the efficacy of cetuximab in the first-line treatment of mCRC.

  9. 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

  10. Targeted Therapies in Elderly Patients with Metastatic Colorectal Cancer: A Review of the Evidence.

    Science.gov (United States)

    Tapia Rico, Gonzalo; Townsend, Amanda R; Broadbridge, Vy; Price, Timothy J

    2017-03-01

    Metastatic colorectal cancer (mCRC) is the third leading cause of cancer deaths worldwide. As the population of the western world ages, the incidence of colorectal tumours among elderly patients is increasing and consequently so is the demand for treatments for elderly patients. Unfortunately, elderly patients (≥65 years) often go untreated and they are also under-represented in clinical trials. Yet there is some evidence suggesting that 'fit' elderly patients have similar outcomes and tolerance to chemotherapy treatment to their younger counterparts (although the definition of fitness in the elderly population is still a matter of debate). The evidence supporting the administration of new targeted therapies in patients older than 65 years is scarce and more research is needed. In this paper, we review all the available data concerning the use of targeted therapies for mCRC in patients older than 65 years of age and discuss the differences between this age subgroup and younger patients.

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

    Science.gov (United States)

    Pfeiffer, Per; Qvortrup, Camilla; Bjerregaard, Jon K

    2009-01-01

    Purpose: 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. PMID:20616891

  12. TAS-102 (Lonsurf) for the Treatment of Metastatic Colorectal Cancer. A Concise Review.

    Science.gov (United States)

    Zaniboni, Alberto; Bertocchi, Paola; Barni, Sandro; Petrelli, Fausto

    2016-12-01

    Within the past several years, no chemotherapy has been sufficient to increase the overall survival of patients with chemorefractory colorectal cancer. TAS-102 (Lonsurf) is an oral fluoropyrimidine that is formed by the combination of 2 active drugs: trifluridine (a nucleoside analog) and tipiracil hydrochloride (a thymidine phosphorylase inhibitor). This drug extended the median overall survival by approximately 2 months compared with placebo in a randomized phase III trial composed of Asian and non-Asian patients with refractory (or intolerant) metastatic colorectal cancer. The clinical development of TAS-102 began approximately a decade ago and included 2 pivotal randomized studies, which are discussed in this review. This drug has just been approved in Japan, and as soon as possible, it will be marketed in Western countries as well; it will therefore become the standard of care for this patient population. The optimal combination of TAS-102 with other agents, as well as the mechanism of resistance to this regimen should be defined in the near future. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. An Australian translational study to evaluate the prognostic role of inflammatory markers in patients with metastatic ColorEctal caNcer Treated with bevacizumab (Avastin™) [ASCENT

    National Research Council Canada - National Science Library

    Clarke, Stephen; Burge, Matt; Cordwell, Cassandra; Gibbs, Peter; Reece, William; Tebbutt, Niall

    2013-01-01

    .... The aim of the ASCENT study [an Australian translational Study to evaluate the prognostic role of inflammatory markers in patients with metastatic ColorEctal caNcer Treated with bevacizumab (Avastin...

  14. Prolyl Hydroxylase 3 Attenuates MCL-1-Mediated ATP Production to Suppress the Metastatic Potential of Colorectal Cancer Cells.

    Science.gov (United States)

    Radhakrishnan, Praveenkumar; Ruh, Nadine; Harnoss, Jonathan M; Kiss, Judit; Mollenhauer, Martin; Scherr, Anna-Lena; Platzer, Lisa K; Schmidt, Thomas; Podar, Klaus; Opferman, Joseph T; Weitz, Juergen; Schulze-Bergkamen, Henning; Koehler, Bruno C; Ulrich, Alexis; Schneider, Martin

    2016-04-15

    Hypoxia is a common feature of solid tumors. Prolyl hydroxylase enzymes (PHD1-3) are molecular oxygen sensors that regulate hypoxia-inducible factor activity, but their functions in metastatic disease remain unclear. Here, we assessed the significance of PHD enzymes during the metastatic spread of colorectal cancer. PHD expression analysis in 124 colorectal cancer patients revealed that reduced tumoral expression of PHD3 correlated with increased frequency of distant metastases and poor outcome. Tumorigenicity and metastatic potential of colorectal tumor cells over and underexpressing PHD3 were investigated in orthotopic and heterotopic tumor models. PHD3 overexpression in a syngeneic tumor model resulted in fewer liver metastases, whereas PHD3 knockdown induced tumor spread. The migration of PHD3-overexpressing tumor cells was also attenuated in vitro Conversely, migratory potential and colony formation were enhanced in PHD3-deficient cells, and this phenotype was associated with enhanced mitochondrial ATP production. Furthermore, the effects of PHD3 deficiency were accompanied by increased mitochondrial expression of the BCL-2 family member, member myeloid cell leukemia sequence 1 (MCL-1), and could be reversed by simultaneous inhibition of MCL-1. MCL-1 protein expression was likewise enhanced in human colorectal tumors expressing low levels of PHD3. Therefore, we demonstrate that downregulation of PHD3 augments metastatic spread in human colorectal cancer and identify MCL-1 as a novel downstream effector of oxygen sensing. Importantly, these findings offer new insight into the possible, context-specific deleterious effects of pharmacologic PHD inhibition. Cancer Res; 76(8); 2219-30. ©2016 AACR.

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

    OpenAIRE

    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-vas...

  16. A randomized phase III trial on maintenance treatment with bevacizumab alone or in combination with erlotinib after chemotherapy and bevacizumab in metastatic colorectal cancer

    DEFF Research Database (Denmark)

    Johnsson, Anders; Hagman, H; Frödin, J-E

    2013-01-01

    The main objective was to study the effect on progression-free survival (PFS) of adding erlotinib to bevacizumab as maintenance treatment following chemotherapy and bevacizumab as first-line treatment of metastatic colorectal cancer (mCRC).......The main objective was to study the effect on progression-free survival (PFS) of adding erlotinib to bevacizumab as maintenance treatment following chemotherapy and bevacizumab as first-line treatment of metastatic colorectal cancer (mCRC)....

  17. Nuclear beta-catenin overexpression in metastatic sentinel lymph node is associated with synchronous liver metastasis in colorectal cancer

    Directory of Open Access Journals (Sweden)

    Cheng Hongxia

    2011-11-01

    Full Text Available Abstract Background Beta-catenin, a component of the Wingless/Wnt signaling pathway, can activate target genes linking with the adenomatous polyposis coli (APC gene in colorectal cancer. The purpose of this study is to investigate whether nuclear beta-catenin overexpression in metastatic sentinel lymph node(s [SLN(s] is associated with synchronous liver metastasis. Methods Clinicopathological data from 355 patients (93 cases with liver metastasis and 262 cases without liver metastasis were reviewed. Beta-catenin expression in metastatic SLN(s and liver metastatic lesions was examined by immunohistochemistry. The association of nuclear beta-catenin expression in metastatic SLN(s and liver metastatic lesions was evaluated, and the relationship between nuclear beta-catenin expression and clinicopathological characteristics was analyzed. Finally, univariate and logistic multivariate regression analyses were adopted to discriminate the risk factors of liver metastasis. Results Nuclear beta-catenin overexpression in metastatic SLN(s was observed in 70 patients with liver metastasis and 31 patients without liver metastasis (75.3% vs. 11.8%; P Conclusions Nuclear beta-catenin overexpression in metastatic SLN(s is strongly associated with liver metastasis and may contribute to predict liver metastasis.

  18. The Nlrp3 Inflammasome Suppresses Colorectal Cancer Metastatic Growth in the Liver by Promoting Natural Killer Cell Tumoricidal Activity.

    Science.gov (United States)

    Dupaul-Chicoine, Jeremy; Arabzadeh, Azadeh; Dagenais, Maryse; Douglas, Todd; Champagne, Claudia; Morizot, Alexandre; Rodrigue-Gervais, Ian Gaël; Breton, Valérie; Colpitts, Sara L; Beauchemin, Nicole; Saleh, Maya

    2015-10-20

    The crosstalk between inflammation and tumorigenesis is now clearly established. However, how inflammation is elicited in the metastatic environment and the corresponding contribution of innate immunity pathways in suppressing tumor growth at secondary sites are poorly understood. Here, we show that mice deficient in Nlrp3 inflammasome components had exacerbated liver colorectal cancer metastatic growth, which was mediated by impaired interleukin-18 (IL-18) signaling. Control of tumor growth was independent of differential cancer cell colonization or proliferation, intestinal microbiota effects, or tumoricidal activity by the adaptive immune system. Instead, the inflammasome-IL-18 pathway impacted maturation of hepatic NK cells, surface expression of the death ligand FasL, and capacity to kill FasL-sensitive tumors. Our results define a regulatory signaling circuit within the innate immune system linking inflammasome activation to effective NK-cell-mediated tumor attack required to suppress colorectal cancer growth in the liver. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Co-evolution of somatic variation in primary and metastatic colorectal cancer may expand biopsy indications in the molecular era.

    Directory of Open Access Journals (Sweden)

    Richard Kim

    Full Text Available Metastasis is thought to be a clonal event whereby a single cell initiates the development of a new tumor at a distant site. However the degree to which primary and metastatic tumors differ on a molecular level remains unclear. To further evaluate these concepts, we used next generation sequencing (NGS to assess the molecular composition of paired primary and metastatic colorectal cancer tissue specimens.468 colorectal tumor samples from a large personalized medicine initiative were assessed by targeted gene sequencing of 1,321 individual genes. Eighteen patients produced genomic profiles for 17 paired primary:metastatic (and 2 metastatic:metastatic specimens.An average of 33.3 mutations/tumor were concordant (shared between matched samples, including common well-known genes (APC, KRAS, TP53. An average of 2.3 mutations/tumor were discordant (unshared among paired sites. KRAS mutational status was always concordant. The overall concordance rate for mutations was 93.5%; however, nearly all (18/19 (94.7% paired tumors showed at least one mutational discordance. Mutations were seen in: TTN, the largest gene (5 discordant pairs, ADAMTS20, APC, MACF1, RASA1, TP53, and WNT2 (2 discordant pairs, SMAD2, SMAD3, SMAD4, FBXW7, and 66 others (1 discordant pair.Whereas primary and metastatic tumors displayed little variance overall, co-evolution produced incremental mutations in both. These results suggest that while biopsy of the primary tumor alone is likely sufficient in the chemotherapy-naïve patient, additional biopsies of primary or metastatic disease may be necessary to precisely tailor therapy following chemotherapy resistance or insensitivity in order to adequately account for tumor evolution.

  20. FIRST LINE 5-FU-BASED CHEMOTHERAPY WITH/WITHOUT BEVACIZUMAB FOR METASTATIC COLORECTAL CANCER: TISSUE BIOMARKER CANDIDATES

    OpenAIRE

    Assia Konsoulova; Ivan Donev; Nikolay Conev; Sonya Draganova; Nadezhda Petrova; Eleonora Dimitrova; Hristo Popov; Kameliya Bratoeva; Petar Ghenev

    2016-01-01

    Purpose: Colorectal cancer is the second leading cause of cancer mortality in the USA. According to Bulgarian National Statistics Institute, 2370 colon and 1664 rectal cancer cases were diagnosed in 2012 with total number of patients 29995. Adding bevacizumab to chemotherapy in patients with metastatic disease improves progression-free survival (PFS) but no predictive markers have been proven in the clinical practice. In our study we examined two tissue biomarkers that may correlate with resp...

  1. Insurance Status and Hospital Payer Mix Are Linked With Variation in Metastatic Site Resection in Patients With Advanced Colorectal Cancers.

    Science.gov (United States)

    Healy, Mark A; Pradarelli, Jason C; Krell, Robert W; Regenbogen, Scott E; Suwanabol, Pasithorn A

    2016-11-01

    Despite substantially improved survival with metastatic site resection in colorectal cancers, uptake of aggressive surgical approaches remains low among certain patients. It is unknown whether financial determinants of care, such as insurance status, play a role in this treatment gap. We sought to evaluate the effect of insurance status on metastasectomy in patients with advanced colorectal cancers. This was a retrospective cohort study. Using the National Cancer Data Base Participant User File, incident cases of colorectal cancer metastatic to the lung and/or liver with diagnosis from 2010 to 2013 were identified. We identified 42,300 patients in our cohort with a mean age 64 years. Controlling for patient, tumor, and hospital characteristics, hierarchical regression was used to examine associations between hospital payer mix and metastatic site resection. Metastatic site resection occurred in 12.3% of all patients. Adjusting for patient and hospital fixed effects, we found that patients who were uninsured or on Medicaid were 38% less likely to undergo metastasectomy (OR = 0.62 (95% CI, 0.56-0.66)). Patients in hospitals with staff treating a high percentage of uninsured patients or patients with Medicaid were less likely to undergo metastasectomy, even after controlling for individual patient insurance status. The study was limited by its retrospective design and the granularity and accuracy of the National Cancer Data Base. Differences in insurance status and hospital payer mix are associated with differences in rates of metastatic site resection in patients with colorectal cancer that is metastatic to the lung and/or liver. There is a need for improved access to metastatic site resection for individual patients who are uninsured or who have Medicaid insurance, as well as for all patients who seek care at hospitals treating a large proportion of patients who are uninsured or on Medicaid. Remedies for individual patients could include improved access to private

  2. A Phase II Study of Gefitinib, 5-Fluorouracil, Leucovorin, and Oxaliplatin (IFOX) in Previously Untreated Patients with Metastatic Colorectal Cancer

    Science.gov (United States)

    Fisher, George A.; Kuo, Timothy; Ramsey, Meghan; Schwartz, Erich; Rouse, Robert V.; Cho, Cheryl D.; Halsey, Joanne; Sikic, Branimir I.

    2008-01-01

    Purpose: To investigate the IFOX regimen (gefitinib, 5-fluorouracil [5-FU], leucovorin and oxaliplatin) as first-line therapy in patients with metastatic colorectal cancer. Experimental Design: Eligible patients had stage IV colorectal adenocarcinoma, and had not received prior chemotherapy for metastatic disease. Each cycle consisted of 14 days. Cycle 1 consisted of FOLFOX-4 (oxaliplatin, leucovorin, and 5-FU). All subsequent cycles consisted of FOLFOX-4 with gefitinib at 500 mg PO daily throughout the 14 days cycle. Results: Forty-five patients were enrolled and are assessable for toxicity. Forty-three patients are assessable for response. Thirty-one of the 43 patients (72%), had either a complete or partial response by RECIST criteria. Median overall survival was 20.5 months. Median time to progression was 9.3 months. Commonly encountered grade 3/4 toxicities included diarrhea in 67% of patients and neutropenia in 60%. Grade 2 acneiform skin rash typical of gefitinib occurred in 60% of patients. Conclusions: IFOX is an active first-line regimen in patients with metastatic colorectal adenocarcinoma, demonstrating higher response rates but also increased toxicities compared with FOLFOX-4 alone in a similar patient population. PMID:18981005

  3. 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

  4. Prognostic significance of K-Ras mutation rate in metastatic colorectal cancer patients

    Science.gov (United States)

    Vincenzi, Bruno; Cremolini, Chiara; Sartore-Bianchi, Andrea; Russo, Antonio; Mannavola, Francesco; Perrone, Giuseppe; Pantano, Francesco; Loupakis, Fotios; Rossini, Daniele; Ongaro, Elena; Bonazzina, Erica; Dell'Aquila, Emanuela; Imperatori, Marco; Zoccoli, Alice; Bronte, Giuseppe; De Maglio, Giovanna; Fontanini, Gabriella; Natoli, Clara; Falcone, Alfredo; Santini, Daniele; Onetti-Muda, Andrea; Siena, Salvatore; Tonini, Giuseppe; Aprile, Giuseppe

    2015-01-01

    Introduction: Activating mutations of K-Ras gene have a well-established role as predictors of resistance to anti-EGFR monoclonal antibodies in metastatic colorectal cancer (mCRC) patients. Their prognostic value is controversial, and no data regarding the prognostic value of mutation rate, defined as the percentage of mutated alleles/tumor sample, are available. We aimed to evaluate the prognostic value of K-Rasmutation rate in a homogenous cohort of mCRC patients receiving first-line doublet plus bevacizumab. Patients and Methods: This retrospective study enrolled 397 K-Ras mutant mCRC patients from 6 Italian centers, and 263 patients were fully evaluable for our analysis. K-Ras mutation rate was assessed by pyrosequencing. Patients with less than 60% of cancer cells in tumor tissue were excluded. No patients received anti-EGFR containing anticancer therapy, at any time. Median mutation rate was 40% and was adopted as cut-off. The primary and secondary endpoints were PFS and OS respectively. Results: At univariate analysis, K-Ras mutation rate higher than 40% was significantly associated with lower PFS (7.3 vs 9.1 months; P < 0.0001) and OS (21 vs 31 months; P = 0.004). A multivariate model adjusted for age at diagnosis, site of origin of tumor tissue (primary vs metastases), referral center, number of metastatic sites, and first-line chemotherapy backbone, showed that K-Ras mutation rate remained a significant predictor of PFS and OS in the whole population. Discussion: Our data demonstrate an association between K-Ras mutation rate and prognosis in mCRC patients treated with bevacizumab-containing first-line therapy. These data deserve to be verified in an independent validation set. PMID:26384309

  5. Update on the Role of Imaging in Management of Metastatic Colorectal Cancer

    Science.gov (United States)

    Tirumani, Sree Harsha; Kim, Kyung Won; Nishino, Mizuki; Howard, Stephanie A.; Krajewski, Katherine M.; Jagannathan, Jyothi P.; Cleary, James M.; Ramaiya, Nikhil H.

    2014-01-01

    Evolution in the treatment of metastatic colorectal cancer (mCRC) has led to significant improvement in the survival of these patients. Surgery is useful in patients with resectable disease. Liver-directed therapies such as hepatic arterial infusion, transarterial radio- and chemoembolization, and percutaneous ablation are sometimes used by oncologists when the liver is the only site of metastatic disease. Unresectable mCRC is typically treated with systemic chemotherapy. First-line systemic chemotherapeutic regimens for mCRC are FOLFOX (combination of 5-fluorouracil/leucovorin [5-FU/LV] and oxaliplatin) and FOLFIRI (combination of 5-FU/LV and irinotecan) combined with molecular targeted drugs. Molecular targeted therapies that are effective in treating mCRC include antiangiogenic agents such as bevacizumab—an antibody against vascular endothelial growth factor—and antibodies directed against epidermal growth factor receptor (EGFR). EGFR-directed antibodies such as cetuximab and panitumumab have been shown to produce activity only in wild-type KRAS tumors. Imaging modalities such as multidetector computed tomography (CT), magnetic resonance imaging, and positron emission tomography/CT play a major role in the selection of appropriate treatment strategies. Assessment of treatment response in patients who undergo liver-directed and systemic therapy requires imaging at regular intervals. Recent studies have shown that alternative treatment response criteria may be more predictive of pathologic response in mCRC than conventional criteria such as Response Evaluation Criteria in Solid Tumors. Awareness of unusual response patterns, as well as of complications and toxicities, is helpful in guiding patient management. ©RSNA, 2014 PMID:25384292

  6. Therapeutic potential and critical analysis of trastuzumab and bevacizumab in combination with different chemotherapeutic agents against metastatic breast/colorectal cancer affecting various endpoints.

    Science.gov (United States)

    Wahid, Mohd; Mandal, Raju K; Dar, Sajad A; Jawed, Arshad; Lohani, Mohtashim; Areeshi, Mohammad Y; Akhter, Naseem; Haque, Shafiul

    2016-08-01

    Researchers are working day and night across the globe to eradicate or at least lessen the menace of cancer faced by the mankind. The two very frequently occurring cancers faced by the human beings are metastatic breast cancer and metastatic colorectal cancer. The various chemotherapeutic agents like anthracycline, cyclophosphamide, paclitaxel, irinotecan, fluorouracil and leucovorin etc., have been used impressively for long. But the obstinate character of metastatic breast cancer and metastatic colorectal cancer needs more to tackle the threat. So, the scientists found the use of monoclonal antibodies trastuzumab (Herceptin(®)) and bevacizumab (Avastin(®)) for the same. The current study critically investigates the therapeutic potential of trastuzumab and bevacizumab in combination with various chemotherapeutic agents against metastatic breast cancer and metastatic colorectal cancer. To the best of our knowledge, this is the very first critical analysis showing percent wise increase in various positive endpoints like median time to disease progression, median survival, and progression free survival etc. for the treatment of metastatic breast/colorectal cancer using trastuzumab and bevacizumab in combination with different chemotherapeutic agents and provides the rational for the success and failure of the selected monoclonal antibodies.

  7. Mutational analysis of primary and metastatic colorectal cancer samples underlying the resistance to cetuximab-based therapy

    Directory of Open Access Journals (Sweden)

    Nemecek R

    2016-07-01

    Full Text Available Radim Nemecek,1 Jitka Berkovcova,2 Lenka Radova,3 Tomas Kazda,4 Jitka Mlcochova,3 Petra Vychytilova-Faltejskova,1,3 Ondrej Slaby,1,3 Marek Svoboda1 1Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Masaryk University, Brno, Czech Republic; 2Department of Oncological and Experimental Pathology, Masaryk Memorial Cancer Institute, Brno, Czech Republic; 3Central European Institute of Technology, Masaryk University, Brno, Czech Republic; 4Department of Radiation Oncology, Masaryk Memorial Cancer Institute, Masaryk University, Brno, Czech Republic Purpose: Although several molecular markers predicting resistance to cetuximab- or panitumumab-based therapy of metastatic colorectal cancer were described, mutations in RAS proto-oncogenes remain the only predictors being used in daily clinical practice. However, 35%–45% of wild-type RAS patients still do not respond to this anti-epidermal growth factor receptor (anti-EGFR monoclonal antibody-based therapy, and therefore the definition of other predictors forms an important clinical need. The aim of the present retrospective single-institutional study was to evaluate potential genes responsible for resistance to anti-EGFR therapy in relation to mutational analysis of primary versus metastatic lesions. Patients and methods: Twenty-four paired primary and corresponding metastatic tissue samples from eight nonresponding and four responding metastatic colorectal cancer patients treated with cetuximab-based therapy were sequenced using a next-generation sequencing panel of 26 genes involved in EGFR signaling pathway and colorectal carcinogenesis. Results: Mutational status of primary tumors and metastatic lesions was highly concordant in TP53, APC, CTNNB1, KRAS, PIK3CA, PTEN, and FBXW7 genes. Metastatic samples harbor significantly more mutations than primary tumors. Potentially negative predictive value of FBXW7 mutations in relationship to anti-EGFR treatment outcomes was confirmed

  8. Predictors of irinotecan toxicity and efficacy in treatment of metastatic colorectal cancer.

    Science.gov (United States)

    Paulík, Adam; Grim, Jirí; Filip, Stanislav

    2012-01-01

    The colorectal cancer ranks high among the malignant tumours in incidence and mortality and irinotecan is standardly used in palliative treatment of metastatic disease in every therapeutic line. Unfortunately, the treatment with irinotecan is often associated with severe toxicities, especially neutropenia and diarrhea. The majority of the toxic manifestation is caused by the insufficient deactivation (glucuronidation) of irinotecan active metabolite SN-38 by UGT1A enzyme. The elevated SN-38 plasma concentration is responsible for the hematological and gastrointestinal toxicity that can become life-threatening. The patients carrying the mutation of the gene encoding UGT1A enzyme lack the ability of bilirubin glucuronidation, and suffer from the inherited un-conjugated hyperbilirubinemia (Gilbert syndrome, Crigler-Najjar type 1 and 2 syndrome). The mutations in other enzyme systems also play role in the etiopathogenesis of the irinotecan toxicity: CYP3A (cytochrome P-450), ABC family of transmembrane transporters (adenosine-triphosphate binding cassette). The goal of the contemporary research is to determine the predictive factors that will enable the individual adjustment of the individual drug dosage while minimising the adverse effects and maintaining the treatment benefit.

  9. Correlation between non-metastatic protein 23 expression and clinicopathological features of colorectal cancer in Asians.

    Science.gov (United States)

    Fu, J W; Chu, X Q

    2015-12-02

    The current meta-analysis was performed to investigate the association between non-metastatic protein 23 (NM23) expression, tumor pathology, and disease prognosis in colorectal cancer (CRC) among Asians. English and Chinese language-based electronic databases (e.g., PubMed, EBSCO, Ovid, Springerlink, Wiley, Web of Science, Wanfang databases, China National Knowledge Infrastructure, VIP databases) were searched using search terms to identify published studies relevant to NM23 and CRC with immunohistochemistry. In total, 289 studies were identified through database searches, and 16 cohort studies (4 studies in English, 12 in Chinese) were chosen for meta-analysis, which included 1592 CRC patients. The results revealed that NM23 protein expression in CRC tissue was higher in patients with Dukes stages A and B than in patients with Dukes stages C and D. The NM23 protein was expressed at higher levels in well- and moderately differentiated tumors than in poorly differentiated tumors. The 5-year survival rate was also higher in CRC patients with NM23-positive tumors than in CRC patients with NM23-negative tumors. Significantly, 5-year tumor relapse and metastasis were lower in patients with NM23-positive tumors than in CRC patients with NM23-negative tumors. The findings suggest that NM23 expression status is associated with tumor aggressiveness and survival in CRC among Asians. Importantly, CRC patients with NM23-positive tumors had a better prognosis, and thus NM23 expression maybe used as a key prognostic indicator for CRC.

  10. Management of a Patient with Metastatic Colorectal Cancer and Liver Metastases

    Directory of Open Access Journals (Sweden)

    Muhammad Wasif Saif

    2014-01-01

    Full Text Available Liver metastases are commonly encountered in patients presenting with metastatic colorectal cancer (mCRC; resection is the treatment of choice. A number of systemic treatment options are currently available for such patients, including the use of 5-fluorouracil-based chemotherapies and oxaliplatin (e.g., FOLFOX in combination with biologic agents that target angiogenesis (e.g., bevacizumab. For patients with progression following first-line treatment, current second-line options include a change in chemotherapy with bevacizumab (for patients who did or did not receive prior bevacizumab or FOLFIRI in combination with aflibercept, a more recently approved antiangiogenesis therapy. Neurotoxicity is a well-established adverse event of oxaliplatin-based therapy. The current case details an mCRC patient with liver metastases who was treated with a capecitabine and oxaliplatin regimen (XELOX, and experienced two episodes of transient cortical blindness possibly related to oxaliplatin. After disease progression, the patient was switched to a regimen of FOLFIRI and aflibercept and did well on this second-line regimen.

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

    DEFF Research Database (Denmark)

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

    2012-01-01

    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......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...... that is strong enough to predict overall survival (OS). In 153 patients with mCRC and 139 healthy subjects from three Danish hospitals, we profiled two independent sets of serum samples in a prospective phase II study. In the training set, (1)H-NMR metabolomic profiling could discriminate patients with mCRC from...

  12. Prognostic value of neutrophil-to-lymphocyte ratio in metastatic colorectal cancer

    Institute of Scientific and Technical Information of China (English)

    Qianqian Yu; Hong Qiu; Mingsheng Zhang; Guangyuan Hu; Liu Huang; Xianglin Yuan 

    2016-01-01

    Objective This study investigated the prognostic value of the neutrophil-to-lymphocyte ratio (NLR) in predicting clinical outcomes of patients with metastatic colorectal cancer (mCRC) undergoing irinotecan-based first-line chemotherapy. Methods This study was based on a Chinese prospective multicenter trial (NCT01282658). Baseline complete blood cel counts were performed. Survival was determined using the Kaplan-Meier method. Multivariate analyses based on the Cox regression model were performed to determine the ef ects of inde-pendent biomarkers. Results A total of 139 patients were evaluated. Values below the median NLR were associated with bet-ter progression-free survival (PFS) (9.9 vs 7.7 months, P = 0.043) and overal survival (OS) (21.8 vs 15.1 months, P = 0.013). These ef ects remained significant in multivariate analysis. Conclusion NLR is an independent prognostic marker of mCRC treated with first-line irinotecan-based therapy in a Chinese population.

  13. Moderately differentiated colorectal adenocarcinoma as a lymph node metastatic phenotype: comparison with well differentiated counterparts

    Directory of Open Access Journals (Sweden)

    Tamura Koichi

    2010-03-01

    Full Text Available Abstract Background The differences between the metastatic property of moderately (Mod and well (Wel differentiated colorectal adenocarcinoma remain unclear. Since Mod is unable to form complete acini, therefore an epithelial-mesenchymal transition (EMT can occur in that structure. Herein, we hypothesized that Mod metastasizes more easily than the Wel counterparts. Methods The medical records of 283 consecutive patients with Mod (n = 71 or Wel (n = 212 who underwent surgery were reviewed between January 1, 2001, and December 31, 2003, for actual 5-year overall survival. We examined the differences between the clinicopathological characteristics of the Mod and the Wel groups. Results The lymph node involvement (p p = 0.0291, Relative Risk of 1.991: 95% Confidence Interval: 1.073-3.697. A Kaplan-Meier survival curve showed that Mod had a trend towards a poor survival (p = 0.0517. Conclusion Mod metastasizes to the lymph nodes more easily in comparison to Wel. Therefore, patients with Mod may be considered the existence of lymph node involvement.

  14. Plasma TIMP-1 levels and treatment outcome in patients treated with XELOX for metastatic colorectal cancer.

    Science.gov (United States)

    Frederiksen, C; Qvortrup, C; Christensen, I J; Glimelius, B; Berglund, A; Jensen, B V; Nielsen, S E; Keldsen, N; Nielsen, H J; Brünner, N; Pfeiffer, P

    2011-02-01

    The aim was to evaluate the association between plasma tissue inhibitor of metalloproteinase-1 (TIMP-1) and serum carcinoembryonic antigen (CEA) levels and outcome in patients with metastatic colorectal cancer (mCRC) receiving XELOX (combination chemotherapy with capecitabine and oxaliplatin) as first-line treatment. One hundred and twenty patients were included. Blood samples were collected before treatment and 3 weeks later before the next treatment cycle. Plasma TIMP-1 and serum CEA levels were correlated to treatment outcome. No significant associations between baseline TIMP-1 or CEA levels and best response to treatment or progression-free survival (PFS) could be demonstrated. In contrast, high baseline plasma TIMP-1 levels were associated with poor overall survival (OS), P = 0.008, hazard ratio (HR) = 1.80 [95% confidence interval (CI): 1.17-2.78]. Furthermore, increase in TIMP-1 levels from baseline to immediately before the second cycle of chemotherapy had a significant negative effect on survival (P = 0.03, HR = 1.30, 95% CI: 1.02-1.65) while a decrease in TIMP-1 was significantly associated with a higher objective response rate (P = 0.03). Both high baseline and subsequent increase in TIMP-1 levels were associated with shorter OS in patients with mCRC receiving XELOX as first-line treatment, whereas baseline TIMP-1 levels were not associated with response or PFS following XELOX treatment.

  15. Strategies to overcome resistance to epidermal growth factor receptor monoclonal antibody therapy in metastatic colorectal cancer.

    Science.gov (United States)

    Jeong, Woo-Jeong; Cha, Pu-Hyeon; Choi, Kang-Yell

    2014-08-07

    Administration of monoclonal antibodies (mAbs) against epidermal growth factor receptor (EGFR) such as cetuximab and panitumumab in combination with conventional chemotherapy substantially prolongs survival of patients with metastatic colorectal cancer (mCRC). However, the efficacy of these mAbs is limited due to genetic variation among patients, in particular K-ras mutations. The discovery of K-ras mutation as a predictor of non-responsiveness to EGFR mAb therapy has caused a major change in the treatment of mCRC. Drugs that inhibit transformation caused by oncogenic alterations of Ras and its downstream components such as BRAF, MEK and AKT seem to be promising cancer therapeutics as single agents or when given with EGFR inhibitors. Although multiple therapeutic strategies to overcome EGFR mAb-resistance are under investigation, our understanding of their mode of action is limited. Rational drug development based on stringent preclinical data, biomarker validation, and proper selection of patients is of paramount importance in the treatment of mCRC. In this review, we will discuss diverse approaches to overcome the problem of resistance to existing anti-EGFR therapies and potential future directions for cancer therapies related to the mutational status of genes associated with EGFR-Ras-ERK and PI3K signalings.

  16. Capecitabine and bevacizumab as first-line treatment in elderly patients with metastatic colorectal cancer.

    Science.gov (United States)

    Feliu, J; Safont, M J; Salud, A; Losa, F; García-Girón, C; Bosch, C; Escudero, P; López, R; Madroñal, C; Bolaños, M; Gil, M; Llombart, A; Castro-Carpeño, J; González-Barón, M

    2010-05-11

    The efficacy and safety of capecitabine and bevacizumab in elderly patients with metastatic colorectal cancer (mCRC) considered unsuitable for receiving first-line chemotherapy with an irinotecan or oxaliplatin-based combination were assessed in a phase II, open, multicentre, uncontrolled study. Treatment consisted of capecitabine 1250 mg m(-2) (or 950 mg m(-2) for patients with a creatinine clearance of 30-50 ml min(-1)) twice daily on days 1-14 and bevacizumab (7.5 mg kg(-1)) on day 1 every 3 weeks. A total of 59 patients aged >or=70 years with mCRC were enrolled. In an intention-to-treat analysis, the overall response rate was 34%, with 71% of patients achieving disease control. Median progression-free survival and overall survival were 10.8 months and 18 months, respectively. In all, 32 patients (54%) had grade 3/4 adverse events (AEs), the most common being hand-foot syndrome (19%), diarrhoea (9%) and deep venous thrombosis (7%). Four patients died because of treatment-related AEs. A relationship was detected between creatinine clearance

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

  19. Common toxicities and objective response rate in metastatic colorectal cancer patients treated with irinotecan based regimens

    Institute of Scientific and Technical Information of China (English)

    Liu Huang; Xin Liao; Qianqian Yu; Qiang Fu; Kai Qin; Huanlei Wu; Lihong Zhang; Xianglin Yuan

    2013-01-01

    Objective: The aim of our study was to investigate if common toxicities are correlated to objective response rate (ORR) in metastatic colorectal cancer (mCRC) patients treated by irinotecan based regimens. Methods: Univariate and multivariate logistic regression analyses were performed to evaluate correlations between common toxicities and binary ORR in 106 mCRC patients from a prospective cohort treated with irinotecan based regimens. Results: The most frequent severe toxicities (Grade 3/4) were as follows: neutropenia (27.4%), diarrhea (16.9%), leucopenia (12.6%), vomiting (3.2%) and thrombocytopenia (2.1%). Thrombocytosis was observed in 25 (26.3%) patients. ORR was 25.3%. Thrombocytopenia (P = 0.014), line of chemotherapy (P = 0.028) and thrombocytosis (P = 0.033) were correlated with ORR in univariate analysis. In multivariate analysis, thrombocytopenia (odds ratio [OR] = 8.600, 95% confidence interval [CI] = 1.705–43.385, P = 0.009) and first line chemotherapy (OR = 5.155, 95% CI = 1.153–23.256, P = 0.032) positively related to ORR. Conclusion: Throm-bocytopenia may be an indicator of ORR in mCRC patients treated by irinotecan plus 5-fluorouracil/capecitabine. Evidence is not strong enough to prove that irinotecan based regimens-induced diarrhea, leucopenia, neutropenia or vomiting is associ-ated with ORR.

  20. Treatment decisions in metastatic colorectal cancer - Beyond first and second line combination therapies.

    Science.gov (United States)

    Vogel, A; Hofheinz, R D; Kubicka, S; Arnold, D

    2017-09-01

    Median overall survival (OS) of patients with metastatic colorectal cancer (mCRC) has reached up to 30months in recent clinical trials of first line therapies. Following disease progression after the standard in both, 1st and 2nd line, combination chemotherapy with monoclonal antibodies, many patients maintain a good performance status and a significant proportion is motivated to undergo further therapy. Choices of treatment beyond the second line setting for mCRC are therefore becoming increasingly important. New options have entered the therapeutic field recently: Regorafenib is a multikinase inhibitor approved for mCRC patients who have progressed on chemotherapy (including fluoropyrimidines, irinotecan, and oxaliplatin), plus VEGF inhibitor(s) and - if RAS wild-type - an anti-EGFR inhibitor. Regorafenib significantly improved OS, compared to placebo, in two phase III trials (CORRECT and CONCUR) in mCRC patients. Trifluridine/Tipiracil, an oral fluoropyrimidine, also resulted in significantly improved OS when compared to placebo in the phase III RECOURSE trial, which was conducted in a similar patient population to CORRECT. Reintroduction of previously administered therapy is another valid and commonly used approach, especially for those regimens which were discontinued before progression, e.g. if associated with cumulative toxicities, such as peripheral neuropathy or due to treatment breaks. Re-challenge of drugs to which patients developed resistance is also feasible although evidence for this strategy is limited. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

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

    Science.gov (United States)

    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.

  2. Use of biguanides and the risk of colorectal cancer: a register-based cohort study.

    Science.gov (United States)

    Knapen, Lotte M; Dittrich, Suzanne T A M; de Vries, Frank; Starup-Linde, Jakob; Vestergaard, Peter; Henry, Ronald M A; Stolk, Leo M L; Neef, Cees; Bazelier, Marloes T

    2013-11-01

    Observational studies have shown conflicting results on the potential protecting effect of biguanide use with the risk of colorectal neoplasms. In addition, the cellular mechanism can either support or oppose biguanides influence on colorectal carcinoma. Our objective was to evaluate the association between biguanide use and colorectal carcinoma. A population-based cohort study using healthcare data from the Danish National database (1996-2007), was conducted. Oral antidiabetic drug users (n = 177,281) were matched 1:3 with a population-based reference group. Cox proportional hazard models estimated hazard ratios (HRs) of colorectal carcinoma. Stratification was performed to analyse the risk of colorectal cancer in current biguanide users. Two sub-analyses were performed, to investigate the risk of colorectal cancer associated with discontinuous and prolonged use of biguanides. Instead of a protective effect, we found that current biguanide users had a 1.2-fold increased risk of colorectal cancer (HR = 1.19, 95% CI = 1.08-1.30) as compared with the non-diabetes reference group. Prolonged use was not inversely associated with colorectal cancer either. When studying colorectal risk with biguanides, the underlying T2DM should be taken into account since a 1.3-1.6-fold increased risk was found in oral antidiabetic drug users compared to controls unexposed to diabetic medication. This study could not detect a protective effect of biguanide use with colorectal cancer. Therefore, this study does not support a further investigation of the effectiveness of biguanides to prevent colorectal carcinoma in clinical studies.

  3. The association between preoperative chemotherapy and the prevalence of hepatic steatosis in hepatectomy for metastatic colorectal cancer.

    Science.gov (United States)

    Kalil, Antonio Nocchi; Coral, Gabriela Perdomo; Santos, Félix Antônio Insaurriaga dos; Gonzalez, Maria Cristina; Neutzling, Cristiane Becker

    2014-01-01

    Some studies have suggested that preoperative chemotherapy for hepatic colorectal metastases may cause hepatic injury and increase perioperative morbidity and mortality. To evaluate the prevalence of hepatic steatosis in patients undergoing preoperative chemotherapy for metastatic colorectal cancer. Observational retrospective cohort study in which 166 patients underwent 185 hepatectomies for metastatic colorectal cancer with or without associated preoperative chemotherapy from 2004 to 2011. The data were obtained from a review of the medical records and an analysis of the anatomopathological report on the non-tumor portion of the surgical specimen. The study sample was divided into two groups: those who were exposed and those who were unexposed to chemotherapy. From the hepatectomies, 136 cases (73.5%) underwent preoperative chemotherapy, with most (62.5%) using a regimen of 5-fluorouracil + leucovorin. A 40% greater risk of cell damage was detected in 62% of the exposed group. The predominant histological pattern of the cell damage was steatosis, which was detected in 51% of the exposed cases. Exposure to chemotherapy increased the risk of steatosis by 2.2 fold. However, when the risk factors were controlled, only the presence of risk of hepatopathy was associated with steatosis, with a relative risk of 4 (2.7-5.9). Patients exposed to chemotherapy have 2.2 times the risk of developing hepatic steatosis, and its occurrence is associated with the presence of predisposing factors such as diabetes mellitus and hepatopathy.

  4. Survival after liver resection in metastatic colorectal cancer: review and meta-analysis of prognostic factors

    Directory of Open Access Journals (Sweden)

    Kanas GP

    2012-11-01

    relationship with survival, and certain prognostic factors may prove useful in determining optimal therapeutic options. Due to the increasing complexity of surgical interventions for CLM and the inclusion of patients with higher disease burdens, future studies should consider the potential for selection and referral bias on survival.Keywords: metastatic colorectal cancer, liver resection, survival, meta-analysis

  5. Bevacizumab plus chemotherapy as salvage treatment in chemorefractory patients with metastatic colorectal cancer

    Directory of Open Access Journals (Sweden)

    Geva R

    2013-01-01

    Full Text Available Ravit Geva,1,2 Loredana Vecchione,2 Sabine Tejpar,2 Hubert Piessevaux,3 Eric Van Cutsem,2 Hans Prenen21Gastrointestinal Malignancies Service, Oncology Division, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; 2Department of Gastroenterology, Digestive Oncology Unit, University Hospitals Leuven, Leuven, Belgium; 3Department of Gastroenterology, Cliniques Universitaires Saint-Luc, Brussels, BelgiumPurpose: The combination of chemotherapy and bevacizumab, a monoclonal antibody targeting the vascular endothelial growth factor, is consistently being used as first- and second-line treatment in patients with metastatic colorectal cancer (mCRC. There is little data of the activity of bevacizumab in chemorefractory mCRC patients. The aim of this retrospective single center study was to evaluate the activity of bevacizumab combined with chemotherapy in this study population.Methods: Forty-six consecutive mCRC patients treated in the University Hospital Gasthuisberg (Leuven, Belgium receiving bevacizumab in advanced lines following failure of conventional chemotherapy were included in this study. Treatment regimen consisted of bevacizumab 5 mg/kg in combination with leucovorin, 5-fluorouracil, and oxaliplatin (FOLFOX or leucovorin, 5-fluorouracil, and irinotecan (FOLFIRI.Results: Bevacizumab plus chemotherapy was used in third-line treatment in eight (17% patients and in fourth-line treatment or more in 38 patients (83%. All patients previously failed irinotecan-based chemotherapy, 44 (96% failed oxaliplatin-based regimens, and 40 (87% failed treatment with cetuximab. Bevacizumab was given in combination with irinotecan-based chemotherapy in 36 patients, oxaliplatin-based chemotherapy in nine patients, and with single agent 5-fluorouracil in one patient. Objective response was demonstrated in ten patients (22% and disease control in 38 (83% with a median progression-free survival of 8.9 months and a median overall survival of 13.8 months. Only four

  6. Effect and safety of bevacizumab-containing chemotherapy treatment in Chinese patients with metastatic colorectal cancer

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    Wu Q

    2013-04-01

    Full Text Available Qian Wu, Yan Shi, Li Chen, Xiaoyi Xiao, Guanghai Dai Department of Multimodality Therapy Oncology, Chinese PLA General Hospital, Beijing, People’s Republic of China Purpose: To review the clinical data and treatment efficacy of bevacizumab in Chinese patients with metastatic colorectal cancer (mCRC. Patients and methods: A total of 96 patients with mCRC treated by chemotherapy plus bevacizumab in the PLA General Hospital between December 2005 and August 2012 were analyzed retrospectively by overall response rate, disease-control rate, progression-free survival (PFS, and overall survival (OS. The tumor responses were assessed by the Response Evaluation Criteria in Solid Tumors guidelines. Results: A total of 96 patients with mCRC were identified. Median age was 53.6 years. Eastern Cooperative Oncology Group performance status was 0–2. By the end of follow-up (August 20, 2012, 54 patients exhibited progression (56.3%, and 39 (40.6% patients had died. A total of 27 (28.1% achieved partial response, and 48 patients (50.0% had stable disease, exhibiting an overall response rate of 28.1% and a disease-control rate of 78.1%. The response rates of the first-line, second-line, and third-line (or later therapy were 41.7%, 21.9%, and 15.8%, respectively. The median durations of the PFS and OS were 8.13 months and 14.80 months, respectively. The median durations of the PFS were 12.70 months, 8.30 months, and 6.40 months for first-line, second-line, and third-line (or later therapy, respectively, and the median durations of the OS were 24.03 months, 14.90 months, and 11.03 months for first-line, second-line, and third-line (or later therapy, respectively. Conclusion: A bevacizumab-containing chemotherapy regimen was well tolerated and effective in Chinese patients with mCRC. Keywords: colorectal cancer, metastasis, Chinese, bevacizumab, efficacy

  7. Treatment of metastatic colorectal carcinomas by systemic inhibition of vascular endothelial growth factor signaling in mice

    Institute of Scientific and Technical Information of China (English)

    Volker Schmitz; Miroslaw Kornek; Tobias Hilbert; Christian Dzienisowicz; Esther Raskopf; Christian Rabe; Tilman Sauerbruch; Cheng Qian; Wolfgang H Caselmann

    2005-01-01

    AIM: Tumor angiogenesis has been shown to be promoted by vascular endothelial growth factor (VEGF) via stimulating endothelial cell proliferation, migration, and survival.Blockade of VEGF signaling by different means has been demonstrated to result in reduced tumor growth and suppression of tumor angiogenesis in distinct tumor entities.Here, we tested a recombinant adenovirus, AdsFlt1-3,that encodes an antagonistically acting fragment of the VEGF receptor 1 (Flt-1), for systemic antitumor effects in pre-established subcutaneous CRC tumors in mice.METHODS: Murine colorectal carcinoma cells (CT26) were inoculated subcutaneously into Balb/c mice forin vivo studies. Tumor size and survival were determined. 293cell line was used for propagation of the adenoviral vectors.Human lung cancer line 4549 and human umbilical vein endothelial cells were transfected forin vitro experiments.RESULTS: Infection of tumor cells with AdsFlt1-3 resulted in protein secretion into cell supernatant, demonstrating correct vector function. As expected, the secreted sFlt1-3 protein had no direct effect on CT26 tumor cell proliferation in vitro, but endothelial cell function was inhibited by about 46% as compared to the AdLacZ control in a tube formation assay. When AdsFlt1-3 (5×109 PFU/animal) was applied to tumor bearing mice, we found a tumor inhibition by 72% at d 12 after treatment initiation. In spite of these antitumoral effects, the survival time was not improved.According to reduced intratumoral microvessel density in AdsFlt1-3-treated mice, the antitumor mechanism can be attributed to angiostatic vector effects. We did not detect increased systemic VEGF levels after AdsFlt1-3 treatment and liver toxicity was low as judged by serum alanine aminotransferase determination.CONCLUSION: In this study we confirmed the value of a systemic administration of AdsFlt1-3 to block VEGF signaling as antitumor therapy in an experimental metastatic colorectal carcinoma model in mice.

  8. Prognosis of patients with peritoneal metastatic colorectal cancer given systemic therapy : an analysis of individual patient data from prospective randomised trials from the Analysis and Research in Cancers of the Digestive System (ARCAD) database

    NARCIS (Netherlands)

    Franko, Jan; Shi, Qian; Meyers, Jeffrey P.; Maughan, Timothy S.; Adams, Richard A.; Seymour, Matthew T.; Saltz, Leonard; Punt, Cornelis J A; Koopman, Miriam; Tournigand, Christophe; Tebbutt, Niall C.; Diaz-Rubio, Eduardo; Souglakos, John; Falcone, Alfredo; Chibaudel, Benoist; Heinemann, Volker; Moen, Joseph; De Gramont, Aimery; Sargent, Daniel J.; Grothey, Axel

    2016-01-01

    BACKGROUND: Patients with peritoneal metastatic colorectal cancer have reduced overall survival compared with patients with metastatic colorectal cancer without peritoneal involvement. Here we further investigated the effect of the number and location of metastases in patients receiving first-line s

  9. Next generation sequencing identifies ‘interactome’ signatures in relapsed and refractory metastatic colorectal cancer

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    Cooke, Laurence; Mahadevan, Daruka

    2017-01-01

    Background In the management of metastatic colorectal cancer (mCRC), KRAS, NRAS and BRAF mutational status individualizes therapeutic options and identify a cohort of patients (pts) with an aggressive clinical course. We hypothesized that relapsed and refractory mCRC pts develop unique mutational signatures that may guide therapy, predict for a response and highlight key signaling pathways important for clinical decision making. Methods Relapsed and refractory mCRC pts (N=32) were molecularly profiled utilizing commercially available next generation sequencing (NGS) platforms. Web-based bioinformatics tools (Reactome/Enrichr) were utilized to elucidate mutational profile linked pathways-networks that have the potential to guide therapy. Results Pts had progressed on fluoropyrimidines, oxaliplatin, irinotecan, bevacizumab, cetuximab and/or panitumumab. Most common histology was adenocarcinoma (colon N=29; rectal N=3). Of the mutations TP53 was the most common, followed by APC, KRAS, PIK3CA, BRAF, SMAD4, SPTA1, FAT1, PDGFRA, ATM, ROS1, ALK, CDKN2A, FBXW7, TGFBR2, NOTCH1 and HER3. Pts had on average had ≥5 unique mutations. The most frequent activated signaling pathways were: HER2, fibroblast growth factor receptor (FGFR), p38 through BRAF-MEK cascade via RIT and RIN, ARMS-mediated activation of MAPK cascade, and VEGFR2. Conclusions Dominant driver oncogene mutations do not always equate to oncogenic dependence, hence understanding pathogenic ‘interactome(s)’ in individual pts is key to both clinically relevant targets and in choosing the next best therapy. Mutational signatures derived from corresponding ‘pathway-networks’ represent a meaningful tool to (I) evaluate functional investigation in the laboratory; (II) predict response to drug therapy; and (III) guide rational drug combinations in relapsed and refractory mCRC pts. PMID:28280605

  10. Capecitabine Maintenance Therapy after First-Line Chemotherapy in Patients with Metastatic Colorectal Cancer

    Institute of Scientific and Technical Information of China (English)

    Yan Li; Jing Li; Ming Lu; Xi-cheng Wang; Lin Shen

    2010-01-01

    Objective:To evaluate the efficacy and toxicity of capecitabine maintenance therapy in metastatic colorectal cancer(mCRC)patients.Methods:From June 2001 to November 2006,after they had achieved clinical response from first-line chemotherapy,patients with mCRC in our hospital received two different treatment strategies.Thirty-three patients non-maintenance group did not receive any further chemotherapy.Results:Patients in maintenance group and non-maintenance group both received FOLFOX,FOLFIRI and XELOX as first-line therapy.The median chemotherapy cycles the two groups received were the same(6 vs 6).The response rates of first-line chemotherapy were 33.3% in maintenance group and 32.7% in non-maintenance group.Patients in maintenance group received 3-9 cycles of capecitabine therapy(median cycle 4).29/33(87.9%)patients in maintenance group and 47/52(90.4%)in non-maintenance group received following second-line chemotherapy,and no patients underwent targeted therapy.The median survival time and TTP were 40.4 months(95%CI:24.2-56.6)and 9.0 months(95%CI:6.7-11.3)in maintenance group,as compared with 21.5 months(95%CI:14.9-28.0,P=0.015)and 6.5 months(95%CI:4.4-8.5,P=0.007)in non-maintenance group.No severe adverse event was observed in the capecitabine maintenance group.Conclusion:mCRC patients could benefit from capecitabine maintenance therapy by prolonging survival time and TTP.

  11. 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.

  12. 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

  13. Mechanisms of resistance to anti-epidermal growth factor receptor inhibitors in metastatic colorectal cancer

    Science.gov (United States)

    Sforza, Vincenzo; Martinelli, Erika; Ciardiello, Fortunato; Gambardella, Valentina; Napolitano, Stefania; Martini, Giulia; della Corte, Carminia; Cardone, Claudia; Ferrara, Marianna L; Reginelli, Alfonso; Liguori, Giuseppina; Belli, Giulio; Troiani, Teresa

    2016-01-01

    The prognosis of patients with metastatic colorectal cancer (mCRC) remain poor despite the impressive improvement of treatments observed over the last 20 years that led to an increase in median overall survival from 6 mo, with the only best supportive care, to approximately 30 mo with the introduction of active chemotherapy drugs and targeted agents. The monoclonal antibodies (moAbs) cetuximab and panitumumab, directed against the epidermal growth factor receptor (EGFR), undoubtedly represent a major step forward in the treatment of mCRC, given the relevant efficacy in terms of progression-free survival, overall survival, response rate, and quality of life observed in several phase III clinical trials among different lines of treatment. However, the anti-EGFR moAbs were shown only to be effective in a subset of patients. For instance, KRAS and NRAS mutations have been identified as biomarkers of resistance to these drugs, improving the selection of patients who might derive a benefit from these treatments. Nevertheless, several other alterations might affect the response to these drugs, and unfortunately, even the responders eventually become resistant by developing secondary (or acquired) resistance in approximately 13-18 mo. Several studies highlighted that the landscape of responsible alterations of both primary and acquired resistance to anti-EGFR drugs biochemically converge into MEK-ERK and PIK3CA-AKT pathways. In this review, we describe the currently known mechanisms of primary and acquired resistance to anti-EGFR moAbs together with the various strategies evaluated to prevent, overcame or revert them. PMID:27605871

  14. Clinico-pathological nomogram for predicting BRAF mutational status of metastatic colorectal cancer

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    Loupakis, Fotios; Moretto, Roberto; Aprile, Giuseppe; Muntoni, Marta; Cremolini, Chiara; Iacono, Donatella; Casagrande, Mariaelena; Ferrari, Laura; Salvatore, Lisa; Schirripa, Marta; Rossini, Daniele; De Maglio, Giovanna; Fasola, Gianpiero; Calvetti, Lorenzo; Pilotto, Sara; Carbognin, Luisa; Fontanini, Gabriella; Tortora, Giampaolo; Falcone, Alfredo; Sperduti, Isabella; Bria, Emilio

    2016-01-01

    Background: In metastatic colorectal cancer (mCRC), BRAFV600E mutation has been variously associated to specific clinico-pathological features. Methods: Two large retrospective series of mCRC patients from two Italian Institutions were used as training-set (TS) and validation-set (VS) for developing a nomogram predictive of BRAFV600E status. The model was internally and externally validated. Results: In the TS, data from 596 mCRC patients were gathered (RAS wild-type (wt) 281 (47.1%); BRAFV600E mutated 54 (9.1%)); RAS and BRAFV600E mutations were mutually exclusive. In the RAS-wt population, right-sided primary (odds ratio (OR): 7.80, 95% confidence interval (CI) 3.05–19.92), female gender (OR: 2.90, 95% CI 1.14–7.37) and mucinous histology (OR: 4.95, 95% CI 1.90–12.90) were independent predictors of BRAFV600E mutation, with high replication at internal validation (100%, 93% and 98%, respectively). A predictive nomogram was calculated: patients with the highest score (right-sided primary, female and mucinous) had a 81% chance to bear a BRAFV600E-mutant tumour; accuracy measures: AUC=0.812, SE:0.034, sensitivity:81.2% specificity:72.1%. In the VS (508 pts, RAS wt: 262 (51.6%), BRAFV600E mutated: 49 (9.6%)), right-sided primary, female gender and mucinous histology were confirmed as independent predictors of BRAFV600E mutation with high accuracy. Conclusions: Three simple and easy-to-collect characteristics define a useful nomogram for predicting BRAF status in mCRC with high specificity and sensitivity. PMID:26575603

  15. Joint prognostic effect of obesity and chronic systemic inflammation in patients with metastatic colorectal cancer.

    Science.gov (United States)

    Shah, Manasi S; Fogelman, David R; Raghav, Kanwal Pratap Singh; Heymach, John V; Tran, Hai T; Jiang, Zhi-Qin; Kopetz, Scott; Daniel, Carrie R

    2015-09-01

    Obesity is strongly linked with chronic systemic inflammation, and each has been linked with disease progression and survival in patients with colorectal cancer (CRC). The authors investigated the joint prognostic effects of obesity and circulating cytokines in patients with metastatic CRC (mCRC), an understudied patient group. In 242 chemotherapy-naive patients with mCRC, the authors measured a multiplex cytokine panel and abstracted clinicopathological features, height, and weight from medical records. Overall survival (OS) was calculated from the date of mCRC diagnosis until the date of death from any cause and evaluated by Kaplan-Meier analysis and multivariable Cox proportional hazards regression models. Cut points for cytokines were determined by restricted cubic spline regression. In multivariable models, elevated interleukin (IL)-8, IL-2 receptor alpha, and lactate dehydrogenase (LDH) emerged as significant predictors of poor OS (hazard ratio [HR] and 95% confidence interval [95% CI] for above vs below the (referent) knot point: 2.5 [95% CI, 1.7-3.7], 1.9 [95% CI, 1.3-2.7], and 2.2 [95% CI, 1.6-3.1], respectively; all PObesity (body mass index ≥30 kg/m(2) ) was not found to be associated with OS, but appeared to modify the relationships observed with IL-8 and LDH, which were associated with a significant 4-fold and 5-fold risk of death, respectively, in obese patients compared with a 2-fold risk of death in nonobese patients (P for interaction of .06 and .04, respectively). Similar results emerged from joint effects analysis, in which obese patients with high IL-8 (or LDH) experienced the highest risk of death. Although obesity itself was not found to be independently associated with survival in patients with mCRC, the adverse prognostic significance of LDH and IL-8 was found to be enhanced in obese patients. © 2015 American Cancer Society.

  16. 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.

  17. Mitomycin C pharmacokinetics in patients with recurrent or metastatic colorectal carcinoma.

    Science.gov (United States)

    Erlichman, C; Rauth, A M; Battistella, R; Fine, S

    1987-03-01

    The pharmacokinetics of mitomycin C as a single agent have been determined in 25 treatment courses given to 18 patients with recurrent or metastatic colorectal carcinoma using a high performance liquid chromatography (HPLC) assay to analyze plasma and urine samples. The plasma pharmacokinetics conformed to a two-compartment linear model in 21 of 25 courses monitored with a mean t1/2 lambda 1 of 9.8 +/- 1.2 (SEM) min and mean t1/2 lambda z of 64.1 +/- 8.9 (SEM) min. The large variation observed in t1/2 lambda z was not related to dose or treatment, but an interaction of these two factors approached significance (p = 0.057). Renal excretion in the 12 courses in which it was determined averaged only 2.3% of the total administered dose during the first 4 h monitored and no mitomycin C metabolites were detected in plasma or urine by the HPLC technique used. The most common toxicity, thrombocytopenia, did not correlate with t1/2 lambda z or the area under the curve. This may be due to a failure to monitor active metabolites of mitomycin C; other factors besides plasma drug concentrations that mediate toxicity towards marrow elements; or the small number of courses associated with thrombocytopenia (less than 100,000/mm3). Our study indicates that an interaction of drug dose and treatment course may be associated with increasing t1/2 lambda z; the renal clearance contributes a small component of mitomycin C elimination; metabolites of mitomycin C cannot be detected by the present HPLC technique; and routine monitoring of mitomycin C using present methods cannot be recommended for clinical use to predict toxicity.

  18. Should hepatic metastatic colorectal cancer patients with extrahepatic disease undergo liver resection/ablation?

    Science.gov (United States)

    Byam, Jerome; Reuter, Nathaniel P; Woodall, Charles E; Scoggins, Charles R; McMasters, Kelly M; Martin, Robert C G

    2009-11-01

    Surgical therapy has been proven to be the mainstay of treatment for hepatic metastases from colorectal cancer (CRM) in the appropriate patient. Previous contraindications were patients with extrahepatic disease (EHD) do not benefit from liver resection or ablation. We hypothesized that the survival of patients with EHD who receive aggressive multimodality care would be the same as those without EHD. A review of our 1305 patient prospective hepato-pancreatico-biliary database from August 1995 to April 2008 identified 383 patients with surgical management of metastatic CRM to the liver. A total of 39 patients with limited EHD underwent liver resection/ablation vs 344 patients without EHD. There were no significant differences in hepatic disease burden (mean clinical risk score of 2.3 and 2.1 in patients with and without EHD, P=.19, and median number of hepatic metastases of 2 in each group, P=.88) or size of the largest lesion (mean 4.6 vs 4.5 cm with and without EHD, P=.84). EHD consisted of lung metastases in 33%, nodal metastases in 21%, peritoneal in 15%, unknown in 15%, and other in 15%. There was no difference in patients with and without EHD undergoing surgical with resection only in 41% vs 48%, ablation only in 31% vs 30%, and combined resection and ablation in 28% vs 22% (P=.61). Overall survival in patients with EHD was not significantly different (median survival 24 vs 33 months, P=.06). A thorough understanding of the biology of disease and appropriate multimodality care can lead to improved survival in patients with EHD, when compared with chemotherapy alone.

  19. KRAS genotypic changes of circulating tumor cells during treatment of patients with metastatic colorectal cancer.

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    Aristea Kalikaki

    Full Text Available INTRODUCTION: Circulating tumor cells (CTCs could represent a non-invasive source of cancer cells used for longitudinal monitoring of the tumoral mutation status throughout the course of the disease. The aims of the present study were to investigate the detection of KRAS mutations in CTCs from patients with metastatic colorectal cancer (mCRC and to compare their mutation status during treatment or disease progression with that of the corresponding primary tumors. MATERIALS AND METHODS: Identification of the seven most common KRAS mutations on codons 12 and 13 was performed by Peptide Nucleic Acid (PNA-based qPCR method. The sensitivity of the assay was determined after isolation of KRAS mutant cancer cells spiked into healthy donors' blood, using the CellSearch Epithelial Cell kit. Consistent detection of KRAS mutations was achieved in samples containing at least 10 tumor cells/7.5 ml of blood. RESULTS: The clinical utility of the assay was assessed in 48 blood samples drawn from 31 patients with mCRC. All patients had PIK3CA and BRAF wild type primary tumors and 14 KRAS mutant tumors. CTCs were detected in 65% of specimens obtained from 74% of patients. KRAS mutation analysis in CTC-enriched specimens showed that 45% and 16.7% of patients with mutant and wild type primary tumors, respectively, had detectable mutations in their CTCs. Assessing KRAS mutations in serial blood samples revealed that individual patient's CTCs exhibited different mutational status of KRAS during treatment. CONCLUSIONS: The current findings support the rationale for using the CTCs as a dynamic source of tumor cells which, by re-evaluating their KRAS mutation status, could predict, perhaps more accurately, the response of mCRC patients to targeted therapy.

  20. 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.

  1. 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.

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

    Science.gov (United States)

    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.

  3. [Neoadjuvant chemotherapy with capecitabine plus oxaliplatin and bevacizumab for the treatment of patients with resectable metastatic colorectal cancer].

    Science.gov (United States)

    Kemmochi, Takeshi; Egawa, Tomohisa; Mihara, Koki; Ito, Yasuhiro; Ohkubo, Yusuke; Mori, Takayuki; Nagashima, Atsushi; Makino, Hiroyuki; Yamamuro, Wataru

    2013-11-01

    We analyzed the clinical efficacy and safety of capecitabine plus oxaliplatin( XELOX) and bevacizumab( BV) as neoadjuvant chemotherapy, administered for the treatment of patients with resectable metastatic colorectal cancer between October 2009 and December 2012. Of the 15 patients who received chemotherapy, 9 received XELOX plus BV and 6 patients received XELOX alone. The median number of therapy courses was 4. The overall response rate was 73.3%. All patients underwent R0 resection. The median disease-free survival was 522 days. The median follow-up time was 607 days. No major Grade 3 or 4 adverse events occurred during chemotherapy and no perioperative complications were noted. Our findings suggest that XELOX (plus BV) as neoadjuvant therapy is useful for the prevention of early recurrence and is clinically efficacious and safe for the treatment of colorectal cancer with resectable metastases.

  4. Bevacizumab in combination with cetuximab and irinotecan after failure of cetuximab and irinotecan in patients with metastatic colorectal cancer.

    Science.gov (United States)

    Larsen, Finn Ole; Pfeiffer, Per; Nielsen, Dorte; Skougaard, Kristin; Qvortrup, Camilla; Vistisen, Kirsten; Fromm, Anne-Lene; Jørgensen, Trine L; Bjerregaard, Jon K; Hoegdall, Estrid; Jensen, Benny V

    2011-05-01

    The efficacy and safety of concurrent administration of irinotecan with the two monoclonal antibodies cetuximab and bevacizumab as fourth line therapy in heavily pretreated patients with metastatic colorectal cancer were evaluated. Patients with metastatic colorectal cancer who had progressed on therapy with 5-FU, oxaliplatin and irinotecan in the first and second line setting and on the combination of irinotecan and cetuximab in third line setting independent of their KRAS mutation status, were treated with irinotecan and cetuximab combined with bevacizumab in a dosage of 5 mg/kg. All drugs were administered every second week. From January 2007 to November 2008 27 patients were treated with cetuximab, irinotecan and bevacizumab. The triple-combination was well tolerated. Progression free survival (PFS) was 8.3 months and median overall survival (mOS) was 12.0 months. Two patients without KRAS mutation (7%) obtained a partial response and 17 (63%) had stable disease for at least two months. A retrospective KRAS mutation analysis revealed that there was a trend toward longer PFS and mOS in patients without KRAS mutations compared to patients with KRAS mutations with a PFS of 8.9 vs. 5.1 months and a mOS of 12.7 vs. 9.0 months. Bevacizumab is safe to add to irinotecan and cetuximab with a toxicity profile that seems to be similar to what would be expected from the agents alone. The results indicate that adding bevacizumab to irinotecan and cetuximab in a fourth line setting may induce a high rate of disease control in heavily pretreated patients with metastatic colorectal cancer.

  5. How to find the Ariadne's thread in the labyrinth of salvage treatment options for metastatic colorectal cancer?

    Science.gov (United States)

    Bronte, Giuseppe; Rolfo, Christian; Peeters, Marc; Russo, Antonio

    2014-06-01

    Since a chance for cure was found out in metastatic colorectal cancer (mCRC) patients undergoing a resection of liver and lung metastases, high tumor shrinkage by chemotherapy regimens and their combination with targeted agents have been addressed in potentially resectable mCRC. However, most mCRC patients cannot reach this opportunity because of tumor burden or metastatic sites. For these patients a salvage systemic therapy could be offered to prolong survival. To date, a huge number of clinical trials provided some evidences for the achievement of this goal. A lot of chemotherapeutic regimens in combination with biological therapies are now available. We tried to propose a simple way to choose the best options and to plan an optimal sequence of treatments. This tool could help the oncologists worldwide to better and easily manage mCRC patients who need salvage systemic therapy.

  6. Survey of oxaliplatin-associated neurotoxicity using an interview-based questionnaire in patients with metastatic colorectal cancer

    Directory of Open Access Journals (Sweden)

    Thomas Rebecca R

    2005-09-01

    Full Text Available Abstract Background New chemotherapy regimens for patients with colorectal cancer have improved survival, but at the cost of clinical toxicity. Oxaliplatin, an agent used in first-line therapy for metastatic colorectal cancer, causes acute and chronic neurotoxicity. This study was performed to carefully assess the incidence, type and duration of oxaliplatin neurotoxicity. Methods A detailed questionnaire was completed after each chemotherapy cycle for patients with metastatic colorectal cancer enrolled in a phase I trial of oxaliplatin and capecitabine. An oxaliplatin specific neurotoxicity scale was used to grade toxicity. Results Eighty-six adult patients with colorectal cancer were evaluated. Acute neuropathy symptoms included voice changes, visual alterations, pharyngo-laryngeal dysesthesia (lack of awareness of breathing; peri-oral or oral numbness, pain and symptoms due to muscle contraction (spasm, cramps, tremors. When the worst neurotoxicity per patient was considered, grade 1/2/3/4 dysesthesias and paresthesias were seen in 71/12/5/0 and 66/20/7/1 percent of patients. By cycles 3, 6, 9, and 12, oxaliplatin dose reduction or discontinuation was needed in 2.7%, 20%, 37.5% and 62.5% of patients. Conclusion Oxaliplatin-associated acute neuropathy causes a variety of distressing, but transient, symptoms due to peripheral sensory and motor nerve hyperexcitability. Chronic neuropathy may be debilitating and often necessitates dose reductions or discontinuation of oxaliplatin. Patients should be warned of the possible spectrum of symptoms and re-assured about the transient nature of acute neurotoxicity. Ongoing studies are addressing the treatment and prophylaxis of oxaliplatin neurotoxicity.

  7. Genetic Diversity of the KIR/HLA System and Outcome of Patients with Metastatic Colorectal Cancer Treated with Chemotherapy

    OpenAIRE

    De Re, Valli; Caggiari, Laura; De Zorzi, Mariangela; Talamini, Renato; Racanelli, Vito; Andrea, Mario D’; Buonadonna, Angela; Zagonel, Vittorina; Cecchin, Erika; Innocenti, Federico; Toffoli, Giuseppe

    2014-01-01

    Objective To explore genes of the killer-cell immunoglobulin-like receptor (KIR) and of the HLA ligand and their relationship with the outcome of metastatic colorectal cancer (mCRC) patients treated with first-line 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI). Methods A total of 224 mCRC patients were screened for KIR/HLA typing. The determination of the KIR/HLA combinations was based upon the gene content and variants. Genetic associations with complete response (CR), time to progres...

  8. Simultaneous laparoscopic resection of colorectal cancer and synchronous metastatic liver tumor.

    Science.gov (United States)

    Hayashi, Michihiro; Komeda, Koji; Inoue, Yoshihiro; Shimizu, Tetsunosuke; Asakuma, Mitsuhiro; Hirokawa, Fumitoshi; Okuda, Junji; Tanaka, Keitaro; Kondo, Keisaku; Tanigawa, Nobuhiko

    2011-01-01

    Laparoscopic colorectal resection has been applied to advanced colorectal cancer. Synchronous liver metastasis of colorectal cancer would be treated safely and effectively by simultaneous laparoscopic colorectal and hepatic resection. Seven patients with colorectal cancer and synchronous liver metastasis treated by simultaneous laparoscopic resection were analyzed retrospectively. Three patients received a hybrid operation using a small skin incision, 2 patients underwent hand-assisted laparoscopic surgery using a small incision produced for colonic anastomosis, and 2 patients were treated with pure laparoscopic resection. The mean total operation duration was 407 minutes, and mean blood loss was 207 mL. Negative surgical margins were achieved in all cases. Mean postoperative hospital stay was 16.4 days. No recurrence at the surgical margin was observed in the liver. For selected patients with synchronous liver metastasis of colorectal cancer, simultaneous laparoscopic resection is useful for minimizing operative invasiveness while maintaining safety and curability, with satisfying short- and long-term results.

  9. Correlation of IL-8 with induction, progression and metastatic potential of colorectal cancer

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    AIM: To investigate the expression profile of IL-8 in inflammatory and malignant colorectal diseases to evaluate its potential role in the regulation of colorectal cancer (CRC) and the development of colorectal liver metastases (CRLM).METHODS: IL-8 expression was assessed by quantitative real-time PCR (Q-RT-PCR) and the enzyme-linked immunosorbent assay (ELISA) in resected specimens from patients with ulcerative colitis (UC, n = 6)colorectal adenomas (CRA, n = 8), different stages of colorectal cancer (n = 48) as well as synchronous and metachronous CRLM along with their corresponding primary colorectal tumors (n = 16).RESULTS: IL-8 mRNA and protein expression was significantly up-regulated in all pathological colorectal entities investigated compared with the corresponding neighboring tissues. However, in the CRC specimens IL-8 revealed a significantly more pronounced overexpression in relation to the CRA and UC tissues with an average 30-fold IL-8 protein up-regulation in the CRC specimens in comparison to the CRA tissues. Moreover, IL-8 expression revealed a close correlation with tumor grading. Most interestingly, IL-8 up-regulation was most enhanced in synchronous and metachronous CRLM, if compared with the corresponding primary CRC tissues.Herein, an up to 80-fold IL-8 overexpression in individual metachronous metastases compared to normal tumor neighbor tissues was found.CONCLUSION: Our results strongly suggest an association between IL-8 expression, induction and progression of colorectal carcinoma and the development of colorectal liver metastases.

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

    Directory of Open Access Journals (Sweden)

    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

  11. An interview with Alfredo Falcone and Lisa Salvatore: RECOURSE and trifluridine/tipiracil in metastatic colorectal cancer.

    Science.gov (United States)

    Falcone, Alfredo; Salvatore, Lisa

    2016-09-01

    Professor Alfredo Falcone and Dr Lisa Salvatore speak to Roshaine Gunawardana, Managing Commissioning Editor: Professor Alfredo Falcone is the Director of the Department of Oncology and the Specialization School at the University Hospital of Pisa, Italy. He trained in Pisa and Genoa, Italy, and has held major positions in Italian oncology since 2000. He currently has more than 300 publications, including papers in peer-reviewed international and national journals, book chapters, and more than 600 abstracts of presentations to international and national conferences. The majority of his papers regard clinical and translational research, with a particular focus on metastatic colorectal cancer. Dr Lisa Salvatore is a medical oncologist in the Department of Translational Research and New Technologies in Medicine and Surgery at the University of Pisa. She has been an author on about 40 publications in major peer-reviewed publications and has made numerous presentations in national and international conferences. Her main interest is focused on clinical and translational research in metastatic colorectal cancer.

  12. Total lesion glycolysis (TLG) as an imaging biomarker in metastatic colorectal cancer patients treated with regorafenib

    Energy Technology Data Exchange (ETDEWEB)

    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.)

  13. Cetuximab plus irinotecan in pretreated metastatic colorectal cancer patients: The ELSIE study

    Science.gov (United States)

    Lim, Robert; Sun, Yan; Im, Seock-Ah; Hsieh, Ruey-Kuen; Yau, Tsz Kok; Bonaventura, Anthony; Cheirsilpa, Arkom; Esser, Regina; Mueser, Matthias; Advani, Suresh

    2011-01-01

    AIM: To evaluate the efficacy and safety of cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer (mCRC) patients from South-East Asia and Australia. METHODS: In this open-label, phase II study, the main eligibility criteria were epidermal growth factor receptor-positive mCRC with progressive disease within 3 mo of an irinotecan-based regimen as the most recent chemotherapy. Patients received cetuximab 400 mg/m2 initially, then 250 mg/m2 every week, with the same regimen of irinotecan on which the patients had progressed (4 pre-defined regimens allowed). The primary objective was evaluation of progression-free survival (PFS) at 12 wk. Secondary objectives included a further investigation of PFS, and an assessment of the overall response rate (ORR), duration of response, time to treatment failure (TTF), overall survival and the safety profile. RESULTS: One hundred and twenty nine patients were enrolled from 25 centers in the Asia-Pacific region and of these 123 received cetuximab plus irinotecan. The most common recent irinotecan regimen used was 180 mg/m2 every 2 wk which had been used in 93 patients (75.6%). The PFS rate at 12 wk was 50% (95% confidence interval (CI, 41-59) and median PFS time was 12.1 wk (95% CI: 9.7-17.7). The ORR was 13.8% (95% CI: 8.3-21.2) and disease control rate was 49.6% (95% CI: 40.5-58.8). Median duration of response was 31.1 wk (95% CI: 18.0-42.6) and median overall survival was 9.5 mo (95% CI, 7.5-11.7). The median TTF was 11.7 wk (95% CI: 9.1-17.4). Treatment was generally well tolerated. The most common grade 3/4 adverse events were diarrhea (13.8%), neutropenia (8.9%), rash (5.7%) and vomiting (5.7%). CONCLUSION: In patients from Asia and Australia, this study confirms the activity and safety of cetuximab plus irinotecan observed in previous studies in Europe and South America. PMID:21528063

  14. The Prognostic Significance of Metabolic Response Heterogeneity in Metastatic Colorectal Cancer.

    Directory of Open Access Journals (Sweden)

    Alain Hendlisz

    Full Text Available Tumoral heterogeneity is a major determinant of resistance in solid tumors. FDG-PET/CT can identify early during chemotherapy non-responsive lesions within the whole body tumor load. This prospective multicentric proof-of-concept study explores intra-individual metabolic response (mR heterogeneity as a treatment efficacy biomarker in chemorefractory metastatic colorectal cancer (mCRC.Standardized FDG-PET/CT was performed at baseline and after the first cycle of combined sorafenib (600mg/day for 21 days, then 800mg/day and capecitabine (1700 mg/m²/day administered D1-14 every 21 days. MR assessment was categorized according to the proportion of metabolically non-responding (non-mR lesions (stable FDG uptake with SUVmax decrease <15% among all measurable lesions.Ninety-two patients were included. The median overall survival (OS and progression-free survival (PFS were 8.2 months (95% CI: 6.8-10.5 and 4.2 months (95% CI: 3.4-4.8 respectively. In the 79 assessable patients, early PET-CT showed no metabolically refractory lesion in 47%, a heterogeneous mR with at least one non-mR lesion in 32%, and a consistent non-mR or early disease progression in 21%. On exploratory analysis, patients without any non-mR lesion showed a significantly longer PFS (HR 0.34; 95% CI: 0.21-0.56, P-value <0.001 and OS (HR 0.58; 95% CI: 0.36-0.92, P-value 0.02 compared to the other patients. The proportion of non-mR lesions within the tumor load did not impact PFS/OS.The presence of at least one metabolically refractory lesion is associated with a poorer outcome in advanced mCRC patients treated with combined sorafenib-capecitabine. Early detection of treatment-induced mR heterogeneity may represent an important predictive efficacy biomarker in mCRC.ClinicalTrials.gov NCT01290926.

  15. Association between bevacizumab-related hypertension and response to treatment in patients with metastatic colorectal cancer

    Science.gov (United States)

    Dionísio de Sousa, Isabel José; Ferreira, Joana; Rodrigues, Joana; Bonito, Nuno; Jacinto, Paula; Marques, Mariela; Ribeiro, João; Pais, Ana; Gervásio, Helena

    2016-01-01

    Background Bevacizumab has become standard of care as first-line treatment of metastatic colorectal cancer (mCRC), after proving increased response rates and improvement in survival outcomes. Hypertension (HTN) is a common complication of the treatment with bevacizumab and, owing to its close relation with antiangiogenic mechanism, may represent a clinical biomarker to predict the efficacy of the treatment. The aim of this study was to retrospectively evaluate if HTN grades 2 to 3 were correlated with response to treatment with bevacizumab in first line, as well as with improved progression-free survival (PFS) and overall survival (OS), in a series of patients with mCRC. Methods Retrospective evaluation of clinical records of patients with histologically proven mCRC, treated with bevacizumab as first-line treatment, between January 2008 and December 2013. Results 79 patients were evaluated. 51.9% of patients developed HTN G2-G3 during chemotherapy-bevacizumab treatment. In the group of patients who developed bevacizumab-related HTN, 73.2% showed response to treatment (complete response (CR)+ partial response (PR)) and 97.6% achieved disease control (CR, PR or stable disease) compared to 18.4% of patients with response and 63.2% with disease control in the group that did not (OR 12.08; 95% CI 4.13 to 35.29; p<0.001 responders vs non-responders; OR 20.8; 95% CI 2.56 to 168.91; p 0.005 controlled vs non controlled disease). The median OS was 28 months (22.7–33.3). Significant statistical difference was obtained in PFS between the two groups (p<0.001). In the group that developed bevacizumab-related HTN, the median OS was 33 months (25.7–40.3), and in the group that did not, it was 21 months (16.5–25.5) with no significant statistical difference between the two groups (p 0.114). Conclusions In this subset of patients, HTN G2-3 was predictive of response to treatment with bevacizumab and of PFS but not of OS. PMID:27843607

  16. 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.

  17. 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.

  18. MicroRNA profiling predicts survival in anti-EGFR treated chemorefractory metastatic colorectal cancer patients with wild-type KRAS and BRAF

    NARCIS (Netherlands)

    Mosakhani, N.; Lahti, L.M.; Borze, I.; Karjalainen-Lindsberg, M.L.; Sundström, A.; Ristamäki, R.; Osterlund, P.; Knuutila, S.; Sarhadi, V.K.

    2012-01-01

    Anti-EGFR monoclonal antibodies (anti-EGFRmAb) serve in the treatment of metastatic colorectal cancer (mCRC), but patients with a mutation in KRAS/BRAF and nearly one-half of those without the mutation fail to respond. We performed microRNA (miRNA) analysis to find miRNAs predicting anti-EGFRmAb eff

  19. Prevalence of RAS mutations and individual variation patterns among patients with metastatic colorectal cancer: A pooled analysis of randomised controlled trials

    NARCIS (Netherlands)

    Peeters, M.; Kafatos, G.; Taylor, A.; Gastanaga, V.M.; Oliner, K.S.; Hechmati, G.; Terwey, J.H.; Krieken, J.H.J.M. van

    2015-01-01

    BACKGROUND: The use of epidermal growth factor receptor inhibitors to treat metastatic colorectal cancer (mCRC) patients requires prior confirmation of tumour wild type (WT) RAS mutation status (exons 2/3/4 for KRAS or NRAS). This retrospective pooled analysis aims to robustly estimate RAS mutation

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

    DEFF Research Database (Denmark)

    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...

  1. RAS testing practices and RAS mutation prevalence among patients with metastatic colorectal cancer: results from a Europe-wide survey of pathology centres

    NARCIS (Netherlands)

    Boleij, A.; Tack, V.; Taylor, A.; Kafatos, G.; Jenkins-Anderson, S.; Tembuyser, L.; Dequeker, E.; Krieken, J.H.J.M. van

    2016-01-01

    BACKGROUND: Treatment options for patients with metastatic colorectal cancer (mCRC) include anti-epithelial growth factor therapies, which, in Europe, are indicated in patients with RAS wild-type tumours only and require prior mutation testing of "hot-spot" codons in exons 2, 3 and 4 of KRAS and

  2. Mismatch Repair Status and BRAF Mutation Status in Metastatic Colorectal Cancer Patients: A Pooled Analysis of the CAIRO, CAIRO2, COIN, and FOCUS Studies

    NARCIS (Netherlands)

    Venderbosch, S.; Nagtegaal, I.D.; Maughan, T.S.; Smith, C.G.; Cheadle, J.P.; Fisher, D.; Kaplan, R.; Quirke, P.; Seymour, M.T.; Richman, S.D.; Meijer, G.A.; Ylstra, B.; Heideman, D.A.; Haan, A.F.J. de; Punt, C.J.A.; Koopman, M.

    2014-01-01

    PURPOSE: To determine the prevalence and prognostic value of mismatch repair (MMR) status and its relation to BRAF mutation (BRAF(MT)) status in metastatic colorectal cancer (mCRC). EXPERIMENTAL DESIGN: A pooled analysis of four phase III studies in first-line treatment of mCRC (CAIRO, CAIRO2, COIN,

  3. 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

    Following the discovery that mutant KRAS is associated with resistance to anti-epidermal growth factor receptor (EGFR) antibodies, the tumours of patients with metastatic colorectal cancer are now profiled for seven KRAS mutations before receiving cetuximab or panitumumab. However, most patients ...

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

    DEFF Research Database (Denmark)

    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....

  5. 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

    DEFF Research Database (Denmark)

    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 s...

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

    NARCIS (Netherlands)

    Cohen, S.J.; Punt, C.J.A.; Iannotti, N.; Saidman, B.H.; Sabbath, K.D.; Gabrail, N.Y.; Picus, J.; Morse, M.; Mitchell, E.; Miller, M.C.; Doyle, G.V.; Tissing, H.; Terstappen, L.W.; Meropol, N.J.

    2008-01-01

    PURPOSE: 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. PATIENTS AND METHODS: In a pros

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

    DEFF Research Database (Denmark)

    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...

  8. Induction of p53-Specific Immunity by a p53 Synthetic Long Peptide Vaccine in Patients Treated for Metastatic Colorectal Cancer

    NARCIS (Netherlands)

    Speetjens, Frank M.; Kuppen, PeterJ. K.; Welters, Marij. J. P.; Essahsah, Farah; van den Brink, Anne Marie E. G. Voet; Lantrua, M. Graziella Kallenberg; Valentijn, A. Rob P. M.; Oostendorp, Jaap; Fathers, Lorraine M.; Nijman, Hans W.; Drijfhout, Jan W.; van de Velde, Cornelis J. H.; Melief, Cornelis J. M.; van der Burg, Sjoerd H.

    2009-01-01

    Purpose: The tumor-associated self-antigen p53 is commonly overexpressed in cancer, including colorectal cancer, and can serve as a target for immunotherapy. The safety and immunogenicity of a p53 synthetic long peptide (p53-SLP) vaccine were investigated in patients treated for metastatic colorecta

  9. Can perfusion CT assessment of primary colorectal adenocarcinoma blood flow at staging predict for subsequent metastatic disease? A pilot study

    Energy Technology Data Exchange (ETDEWEB)

    Goh, Vicky [Mount Vernon Hospital, Paul Strickland Scanner Centre, Northwood (United Kingdom); Halligan, Steve [University College Hospital, Department of Academic Radiology, London (United Kingdom); Wellsted, David M. [University of Hertfordshire, Health Research and Development Support Unit, Hatfield (United Kingdom); Bartram, Clive I. [St Mark' s Hospital, Intestinal Imaging Centre, Harrow (United Kingdom)

    2009-01-15

    We aimed to determine whether perfusion CT measurements at colorectal cancer staging may predict for subsequent metastatic relapse. Fifty two prospective patients underwent perfusion CT at staging to estimate tumour blood flow, blood volume, mean transit time, and permeability surface area product. Patients considered metastasis free and suitable for surgery underwent curative resection subsequently. At final analysis, a median of 48.6 months post-surgery, patients were divided into those who remained disease free, and those with subsequent metastases. Vascular parameters for these two groups were compared using t-testing, and receiver operator curve analysis was performed to determine the sensitivity and specificity of these vascular parameters for predicting metastases. Thirty seven (71%) patients underwent curative surgery; data were available for 35: 26 (74%) remained disease free; 9 (26%) recurred (8 metastatic, 1 local). Tumour blood flow differed significantly between disease-free and metastatic patients (76.0 versus 45.7 ml/min/100 g tissue; p=0.008). With blood flow <64 ml/min/100 g tissue, sensitivity and specificity (95% CI) for development of metastases were 100% (60-100%) and 73% (53-87%), respectively. Our preliminary findings suggest that primary tumour blood flow might potentially be a useful predictor warranting further study. (orig.)

  10. 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 and PI3K-AKT-mTOR pathways in colorectal cancer is uncertain, which led us to systematically review the impact of alterations in KRAS (outside of exon 2), NRAS, BRAF, PIK3CA and PTEN in relation to the clinical benefit from anti-EGFR treatment. METHODS: In total, 22 studies that include 2395 patients......, NRAS, BRAF and PIK3CA and non-functional PTEN predict resistance to anti-EGFR therapies and demonstrates that biomarker analysis beyond KRAS exon 2 should be implemented for prediction of clinical benefit from anti-EGFR antibodies in metastatic colorectal cancer....

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

    Science.gov (United States)

    Skougaard, Kristin; Nielsen, Dorte; Jensen, Benny Vittrup; Hendel, Helle Westergren

    2013-07-01

    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 and the monoclonal antibody cetuximab. From 2006 to 2009, patients with metastatic colorectal cancer were prospectively included in a phase II trial evaluating the combination of irinotecan and cetuximab every second week, as third-line treatment. (18)F-FDG PET/CT was performed between 1 and 14 d before the first treatment and after every fourth treatment cycle until progression was identified by CT with Response Evaluation Criteria in Solid Tumors (RECIST). Response evaluation with (18)F-FDG PET/CT was retrospectively performed according to both EORTC criteria and PERCIST, classifying the patients into 4 response categories: complete metabolic response (CMR), partial metabolic response (PMR), stable metabolic disease (SMD), and progressive metabolic disease (PMD). Individual best overall metabolic response (BOmR) was registered with both sets of criteria, as well as survival within response categories, and compared. A total of 61 patients and 203 PET/CT scans were eligible for response evaluation. With EORTC criteria, 38 had PMR, 16 had SMD, and 7 had PMD as their BOmR. With PERCIST, 34 had PMR, 20 had SMD, and 7 had PMD as their BOmR. None of the patients had CMR. There was agreement between EORTC criteria and PERCIST in 87% of the patients, and the corresponding κ-coefficient was 0.76. Disagreements were confined to PMR and SMD. Median overall survival (OS) in months with EORTC criteria was 14.2 in the PMR group and 7.2 in the combined SMD + PMD group. With PERCIST, it was 14.5 in the PMR group and 7.9 in the SMD + PMD group. Response evaluation with EORTC criteria and PERCIST gave similar responses and OS outcomes with good agreement on BOmR (κ-coefficient, 0.76) and

  12. Novel quality indicators for metastatic colorectal cancer management identify significant variations in these measures across treatment centers in Australia.

    Science.gov (United States)

    Turner, Natalie Heather; Wong, Hui-Li; Field, Kathryn; Wong, Rachel; Shapiro, Jeremy; Yip, Desmond; Nott, Louise; Tie, Jeanne; Kosmider, Suzanne; Tran, Ben; Desai, Jayesh; McKendrick, Joseph; Zimet, Allan; Richardson, Gary; Iddawela, Mahesh; Gibbs, Peter

    2015-09-01

    Defining multidisciplinary quality of care indicators (QCIs) for metastatic colorectal cancer (mCRC) could improve understanding of variations in routine practice care. This may identify areas of below-average performance, which could then be addressed by clinicians to improve the quality of care delivered. This study aimed to define a panel of QCIs in mCRC and, based on these QCIs, to evaluate quality of care across multiple Australian sites. A panel of clinicians with expertise in colorectal cancer defined evidence-based or best practice-based QCIs relevant to the routine multidisciplinary management of mCRC patients through structured consensus discussion. Related data were extracted from the Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry, a prospectively maintained database recording comprehensive details on consecutive mCRC patients across multiple Australian hospitals. Variations in QCIs across sites were explored. Of 13 QCIs defined, data related to 10 were reliably extracted from TRACC. Analysis of data on 1276 patients across 10 sites demonstrated low rates of screening for hereditary nonpolyposis colorectal cancer in young patients and significant variation in surveillance-detected recurrences, lung resection rates and palliative chemotherapy use. Exploratory analyses suggested correlation between liver resection rates and survival. We have defined a novel set of mCRC QCIs and have demonstrated wide variation in the quality of care of mCRC across multiple Australian sites. With further validation to confirm a direct correlation between QCI and patient outcomes, these QCIs could be applied to improve the quality of care received by all mCRC patients. © 2015 Wiley Publishing Asia Pty Ltd.

  13. 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.

  14. Biomarkers predicting resistance to epidermal growth factor receptor-targeted therapy in metastatic colorectal cancer with wild-type KRAS

    Directory of Open Access Journals (Sweden)

    Liu J

    2016-01-01

    Full Text Available Jiang Liu,* Jing Hu,* Lei Cheng, Wei Ren, Mi Yang, Baorui Liu, Li Xie, Xiaoping Qian The Comprehensive Cancer Center of Drum-Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu, People’s Republic of China *These authors contributed equally to this work Abstract: EGFR pathway is an important therapeutic target in human tumors, including metastatic colorectal cancer (mCRC. The advent of EGFR-targeted monoclonal antibodies panitumumab and cetuximab has generated promise for the treatment of mCRC and has largely improved patients’ progression-free survival (PFS and overall survival (OS. However, treatment with anti-EGFR monoclonal antibodies is only effective in a subset of mCRC patients with wild-type KRAS. This indicates that there are other factors affecting the efficacy of anti-EGFR monoclonal antibodies. Existing studies have demonstrated that among colorectal cancer patients with wild-type KRAS, harboring mutations of BRAF, PIK3CA, NRAS, or PTEN-null may demonstrate resistance to anti-EGFR-targeted therapy, and biomarkers detection can provide better-personalized treatment for mCRC patients. How to identify and reverse the secondary resistance to anti-EGFR monoclonal antibody therapy is also another great challenge to improve the anti-EGFR efficacy in wild-type KRAS mCRC patients. Finally, both of the molecular mechanisms of response and acquired resistance would be important for the directions of future research. This review focuses on how to further improve the predictive value of anti-EGFR therapies and how to also try and avoid futile treatment for wild-type KRAS colorectal cancer patients. Keywords: colorectal cancer, EGFR, BRAF, RAS, cetuximab, panitumumab

  15. Registered report: Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET.

    Science.gov (United States)

    Lesnik, Jake; Antes, Travis; Kim, Jeewon; Griner, Erin; Pedro, Luisa

    2016-01-29

    The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibility in scientific research by conducting replications of selected experiments from a number of high-profile papers in the field of cancer biology. The papers, which were published between 2010 and 2012, were selected on the basis of citations and Altmetric scores (Errington et al., 2014). This Registered Report describes the proposed replication plan of key experiments from "Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET" by Peinado and colleagues, published in Nature Medicine in 2012 (Peinado et al., 2012). The key experiments being replicated are from Figures 4E, as well as Supplementary Figures 1C and 5A. In these experiments, Peinado and colleagues show tumor exosomes enhance metastasis to bones and lungs, which is diminished by reducing Met expression in exosomes (Peinado et al., 2012). The Reproducibility Project: Cancer Biology is a collaboration between the Center for Open Science and Science Exchange and the results of the replications will be published in eLife.

  16. STRATEGIC-1: A multiple-lines, randomized, open-label GERCOR phase III study in patients with unresectable wild-type RAS metastatic colorectal cancer.

    Science.gov (United States)

    Chibaudel, Benoist; Bonnetain, Franck; Tournigand, Christophe; de Larauze, Marine Hug; de Gramont, Armand; Laurent-Puig, Pierre; Paget, Jérôme; Hadengue, Alexandra; Notelet, Dominique; Benetkiewicz, Magdalena; André, Thierry; de Gramont, Aimery

    2015-07-04

    The management of unresectable metastatic colorectal cancer (mCRC) is a comprehensive treatment strategy involving several lines of therapy, maintenance, salvage surgery, and treatment-free intervals. Besides chemotherapy (fluoropyrimidine, oxaliplatin, irinotecan), molecular-targeted agents such as anti-angiogenic agents (bevacizumab, aflibercept, regorafenib) and anti-epidermal growth factor receptor agents (cetuximab, panitumumab) have become available. Ultimately, given the increasing cost of new active compounds, new strategy trials are needed to define the optimal use and the best sequencing of these agents. Such new clinical trials require alternative endpoints that can capture the effect of several treatment lines and be measured earlier than overall survival to help shorten the duration and reduce the size and cost of trials. STRATEGIC-1 is an international, open-label, randomized, multicenter phase III trial designed to determine an optimally personalized treatment sequence of the available treatment modalities in patients with unresectable RAS wild-type mCRC. Two standard treatment strategies are compared: first-line FOLFIRI-cetuximab, followed by oxaliplatin-based second-line chemotherapy with bevacizumab (Arm A) vs. first-line OPTIMOX-bevacizumab, followed by irinotecan-based second-line chemotherapy with bevacizumab, and by an anti-epidermal growth factor receptor monoclonal antibody with or without irinotecan as third-line treatment (Arm B). The primary endpoint is duration of disease control. A total of 500 patients will be randomized in a 1:1 ratio to one of the two treatment strategies. The STRATEGIC-1 trial is designed to give global information on the therapeutic sequences in patients with unresectable RAS wild-type mCRC that in turn is likely to have a significant impact on the management of this patient population. The trial is open for inclusion since August 2013. STRATEGIC-1 is registered at Clinicaltrials.gov: NCT01910610, 23 July, 2013

  17. Cetuximab Plus Oxaliplatin May Not Be Effective Primary Treatment for Metastatic Colorectal Cancer

    Science.gov (United States)

    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.

  18. Fatal posterior revesible leukoencephalopathy syndrome associated coma induced by bevacizumab in metastatic colorectal cancer and review of literature.

    Science.gov (United States)

    Eryılmaz, Melek Karakurt; Mutlu, Hasan; Salim, Derya Kıvrak; Musri, Fatma Yalçın; Coşkun, Hasan Şenol

    2016-12-01

    Posterior reversible leukoencephalopathy syndrome (PRES) is a syndrome characterized by headache, hypertension, confusion, visual disturbance, and seizures accompanied by subcortical vasogenic edema, predominantly involving the parietal and occipital lobes. The syndrome is usually described in malignant hypertension, eclampsia, renal failure, immunosuppressive, and cytotoxic chemotherapies. Bevacizumab, a monoclonal antibody that binds to the vascular endothelial growth factor (VEGF) has been linked to PRES. We carried out review of reports documenting the occurrence of PRES in patients receiving bevacizumab. This literature review was conducted by utilizing PubMed Database. If early diagnosed, PRES is reversible. We present a case of fatal PRES-associated coma induced by bevacizumab in metastatic colorectal cancer. © The Author(s) 2015.

  19. Phase II trial of temsirolimus alone and in combination with irinotecan for KRAS mutant metastatic colorectal cancer

    DEFF Research Database (Denmark)

    Spindler, Karen-Lise Garm; Sørensen, Morten; Pallisgaard, Niels

    2013-01-01

    and plasma was 82%. All patients with tumor reduction had low levels of pKRAS. Patients with high pKRAS had a 77% risk of early progression on monotherapy compared to 43% in patients with lower levels. Multivariate survival analysis confirmed that pKRAS was a strong prognostic factor. Conclusion......Background. Patients with chemotherapy refractory metastatic colorectal cancer and KRAS mutations have no effective treatment option. The present study evaluated the efficacy of temsirolimus in chemotherapy refractory mCRC with KRAS mutations. Furthermore, we wanted to investigate if resistance...... tolerated. Thirty-eight percent achieved stable disease on monotherapy and 63% on combination therapy. Four and eight patients had a minimal response, respectively. Median overall survival was 160 days. Median time to progression was 45 and 84 days, respectively. The concordance between KRAS status in tumor...

  20. Patients’ self-reported adherence to capecitabine on XELOX treatment in metastatic colorectal cancer: findings from a retrospective cohort analysis

    Science.gov (United States)

    Kawakami, Kazuyoshi; Nakamoto, Eri; Yokokawa, Takashi; Sugita, Kazuo; Mae, Yutarou; Hagino, Akane; Suenaga, Mitsukuni; Mizunuma, Nobuyuki; Oniyama, Sayaka; Machida, Yoshiaki; Yamaguchi, Toshiharu; Hama, Toshihiro

    2015-01-01

    Background Capecitabine plus oxaliplatin (XELOX) has been established as a first-line treatment for metastatic colorectal cancer. Adherence is particularly important with capecitabine to maintain appropriate curative effect. In this study, we monitored the adherence to capecitabine on XELOX treatment and investigated which factors might decrease compliance. Methods The study included 242 consecutive patients who received XELOX treatment for metastatic colorectal cancer between October 2009 and March 2012. Adherence to capecitabine was checked by pharmacists with a patient-reported treatment diary at a pharmaceutical outpatient clinic. Adherence rate was defined as the number of times that a patient took capecitabine in a 14-day cycle/28 prescribed doses. We retrospectively surveyed median relative dose intensities of capecitabine and the factors deteriorating adherence across eight cycles from electronic patient records and examined differences in compliance rates according to age. Results The study included 144 male and 98 female patients. The overadherence rate was 1.5% (n=23). The median adherence rate was 93.5% (n=242) in the first cycle of XELOX treatment, which gradually rose to 96.1% (n=148) in the eighth cycle. The median relative dose intensity of capecitabine was 79.2%. The main factors contributing to decreased adherence to capecitabine were diarrhea (22.5%, 352 instances) and nausea/vomiting (13.8%, 215 instances). The rate of missed dose was 12.1%. Analysis of adherence issues in relation to patient age showed a trend toward worse adherence to capecitabine therapy in the group of patients aged ≥80 years (hazard ratio =3.83; 95% confidence interval 2.48–5.91, Padherence to capecitabine on XELOX treatment in clinical practice is high but adversely affected by side effects. Patients aged 80 years or more exhibit a significant decrease in compliance compared with younger patients. PMID:25914526

  1. 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.

  2. A window of opportunity phase II study of enzastaurin in chemonaive patients with asymptomatic metastatic colorectal cancer.

    Science.gov (United States)

    Glimelius, B; Lahn, M; Gawande, S; Cleverly, A; Darstein, C; Musib, L; Liu, Y; Spindler, K L; Frödin, J-E; Berglund, A; Byström, P; Qvortrup, C; Jakobsen, A; Pfeiffer, P

    2010-05-01

    Preclinically, protein kinase C and AKT activation can be inhibited by enzastaurin and reduce tumor growth of colorectal cancer cells. In asymptomatic patients with metastatic colorectal cancer (mCRC), enzastaurin activity was evaluated by measuring the 6-month progression-free survival (PFS) rate in a window study design. Chemonaive patients with asymptomatic mCRC who did not require immediate chemotherapy-induced tumor reduction received a 400-mg thrice daily loading dose of enzastaurin on day 1 of cycle 1, followed by 500 mg once daily for the remaining 28-day cycles. Progression was assessed on the basis of radiographic imaging, rise in carcinoembryonic antigen or lactate dehydrogenase (LDH) levels or by appearance of clinical symptoms. Twenty-eight patients received daily enzastaurin. The 6-month PFS rate was 28% [95% confidence interval (CI) 13%-45%] and median PFS was 1.9 months (95% CI 1.8-4.5 months). Twelve (43%) patients had stable disease with a median duration of 6.1 months. The survival rate at 20 months was 77% (95% CI 47%-92%). No grade 4 toxicity was reported and grade 3 toxic effects were observed in three patients with one patient showing probable drug-related elevation of liver transaminases. The window design in asymptomatic patients with mCRC can be safely applied to assess the activity and safety of novel cytostatic agents like enzastaurin.

  3. A paradigm shift from one-size-fits-all to tailor-made therapy for metastatic colorectal cancer.

    Science.gov (United States)

    Weinberg, Benjamin A; Marshall, John L; Hartley, Marion; Salem, Mohamed E

    2016-02-01

    Colorectal cancer is the second leading cause of cancer death in the United States. At least 50% of patients develop metastases, and most of these patients have unresectable tumors. Treatment options for metastatic colorectal cancer (mCRC) include several lines of chemotherapy, salvage surgery, maintenance therapy, and local therapy. For decades, 5-fluorouracil (5-FU) was the only chemotherapy option for patients with mCRC. This changed markedly over the last decade with the approval of irinotecan, oxaliplatin, capecitabine, humanized monoclonal antibodies that target either vascular endothelial growth factor (bevacizumab, aflibercept, and ramucirumab) or the epidermal growth factor receptor (cetuximab and panitumumab), and, most recently, regorafenib and trifluridine/tipiracil. In this review, we focus on first-line treatments for mCRC. We discuss how results from multiple clinical trials over the last 10 to 20 years confirmed the benefit of adding oxaliplatin and irinotecan to the established 5-FU chemotherapy backbone, and then further defined benefit in certain patient subgroups with the addition of mAbs. Ongoing investigations attempt to illustrate the role of newer molecular and immune therapies in the fight against mCRC. We acknowledge the tremendous advances made in first-line mCRC treatment, admit that we still have a long way to go, and highlight exciting lines of research for patients with mCRC in the burgeoning fields of precision medicine and immunotherapy.

  4. Prognosis of patients with peritoneal metastatic colorectal cancer given systemic therapy : an analysis of individual patient data from prospective randomised trials from the Analysis and Research in Cancers of the Digestive System (ARCAD) database

    OpenAIRE

    Franko, Jan; Shi, Qian; Meyers, Jeffrey P.; Maughan, Timothy S; Adams, Richard A.; Matthew T. Seymour; Saltz, Leonard; Punt, Cornelis J. A.; Koopman, Miriam; Tournigand, Christophe; Tebbutt, Niall C.; Diaz-Rubio, Eduardo; Souglakos, John; Falcone, Alfredo; Chibaudel, Benoist

    2016-01-01

    BACKGROUND: Patients with peritoneal metastatic colorectal cancer have reduced overall survival compared with patients with metastatic colorectal cancer without peritoneal involvement. Here we further investigated the effect of the number and location of metastases in patients receiving first-line systemic chemotherapy. METHODS: We analysed individual patient data for previously untreated patients enrolled in 14 phase 3 randomised trials done between 1997 and 2008. Trials were included if pro...

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

    Science.gov (United States)

    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 <5. In conclusion, by employing a sensitive device, CTC counts show good correlation with colorectal neoplasm, thus CTC may be as a simple, independent prognostic marker for the non-metastatic CRC patients who are at high risk of early recurrence.

  6. 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...

  7. OncoSurge: a strategy for improving resectability with curative intent in metastatic colorectal cancer.

    NARCIS (Netherlands)

    Poston, G.J.; Adam, R.; Alberts, S.; Curley, S.; Figueras, J.; Haller, D.; Kunstlinger, F.; Mentha, G.; Nordlinger, B.; Patt, Y.; Primrose, J.; Roh, M.; Rougier, P.; Ruers, T.J.M.; Schmoll, H.J.; Valls, C.; Vauthey, N.J.; Cornelis, M.; Kahan, J.P.

    2005-01-01

    PURPOSE: Most patients with colorectal liver metastases present to general surgeons and oncologists without a specialist interest in their management. Since treatment strategy is frequently dependent on the response to earlier treatments, our aim was to create a therapeutic decision model identifyin

  8. Review on TAS-102 development and its use for metastatic colorectal cancer.

    Science.gov (United States)

    Mota, Jose Mauricio; Fonseca, Leonardo G; Braghiroli, Maria Ignez; Hoff, Paulo M

    2016-08-01

    TAS-102 is the combination of trifluridine (TFT) with tipiracil (TPI) in a 1:0.5 molar ratio. TFT is a fluoropyrimidine that retains cytotoxic activity in 5-fluorouracil resistant cell lines. Due to TFT short half-life, early clinical development was discouraging. Thereafter, TFT was shown to be promptly degraded by thymidine phosphorylase, also known as platelet-derived endothelial cell growth factor, a pro-angiogenic protein and a poor prognosis marker in colorectal cancer. TPI is a specific antagonist of thymidine phosphorylase and led to an increase in TFT serum levels when both agents are combined. Moreover, TPI is a potential anti-angiogenic molecule and could exert antitumor actions per se. TAS-102 was tested in several Phase I studies published in the early 21st century. The best regimen was settled as 70mg/m(2)/day, q12h, orally given at days 1-5 and days 8-13, each 28days. Recently, the first Phase III trial evaluating TAS-102 in refractory colorectal cancer patients was published. The RECOURSE trial demonstrated a survival advantage of the agent over supportive care, and definitely established TAS-102 as a novel strategy in the current armamentarium against colorectal cancer. Here we review the preclinical data regarding TFT and TPI that led to the development of TAS-102, and the set of clinical data that ultimately proved that TAS-102 improved outcomes in colorectal cancer patients. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  9. BRAF V600E Mutation as a Predictive Factor of Anti-EGFR Monoclonal Antibodies Therapeutic Effects in Metastatic Colorectal Cancer:a Meta-analysis

    Institute of Scientific and Technical Information of China (English)

    Jia Wei

    2014-01-01

    Objective To investigate the correlation between BRAF V600E mutation and anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MoAbs) therapeutic effects in metastatic colorectal cancer. Methods Studies were included into meta-analysis to investigate the association between BRAF V600E mutation and clinical outcome in metastatic colorectal cancer patients treated with anti-EGFR MoAbs. Results A total of 7 studies were included in this meta-analysis. The 7 studies included 1352 patients in total, sample sizes ranged from 67 to 493. Objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were collected from included studies and were used to assess the strength of the relation. In patients with wild-type KRAS, the pooled odds ratio for ORR of mutant BRAF over wild-type BRAF was 0.27 (95%CI=0.10-0.70). BRAF mutation predicted a deterioration in PFS and OS in wild-type KRAS patients treated with anti-EGFR MoAbs (hazard ratio=2.78, 95% CI=1.62-4.76;hazard ratio=2.54, 95%CI=1.93-3.32). Conclusion BRAF V600E mutation is related to lack of response and worse survival in wild-type KRAS metastatic colorectal cancer patients treated with anti-EGFR MoAbs.

  10. Long-Lasting Tumor Response in Patients with Panitumumab Monotherapy for Chemorefractory Metastatic Colorectal Carcinoma – A Report of Two Cases

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    G. Ramadori

    2010-05-01

    Full Text Available Background: Second as well as higher-line therapies have a significant influence on progression-free and overall survival of metastatic colorectal cancer patients. However, treatment of late-stage disease remains suboptimal. Therefore, the introduction of new, effective and well-tolerated agents is of major importance. Case Reports: Here we describe the cases of 2 patients with metastatic KRAS wild-type colorectal cancer who received a fourth-line monotherapy with panitumumab after failure of 5-fluorouracil, irinotecan, oxaliplatin, and bevacizumab. Results: Both patients achieved a partial remission, and for 11.5 and 18 months, respectively, they had a stable disease with initial reduction in the tumor marker carcinoembryonic antigen. Both patients reported a good tolerability of the treatment with improved quality of life (compared to receiving combined chemotherapy. Conclusion: Panitumumab monotherapy is an effective and well tolerated treatment of metastatic colorectal cancer in extensively pretreated KRAS wild-type patients. Our data have shown a response to panitumumab monotherapy for more than 11 months.

  11. Orbital Apex Syndrome Caused by Invasive Aspergillosis as an Adverse Effect of Systemic Chemotherapy for Metastatic Colorectal Cancer: a Case Report.

    Science.gov (United States)

    Miyamoto, Yuji; Sakamoto, Yasuo; Ohuchi, Mayuko; Tokunaga, Ryuma; Shigaki, Hironobu; Kurashige, Junji; Iwatsuki, Masaaki; Baba, Yoshifumi; Yoshida, Naoya; Watanabe, Masayuki; Baba, Hideo

    2016-02-01

    Continuous therapy with cytotoxic drugs suppresses humoral immune function and may result in local infection. We present a case of orbital apex syndrome caused by Aspergillus infection during chemotherapy for metastatic colorectal cancer. A 74-year-old man with colorectal liver metastases under long-term continuous systemic chemotherapy presented with painful, progressive orbital apex syndrome. Magnetic resonance imaging disclosed a small enhancing lesion around the right ethmoid sinus. We initially diagnosed colorectal cancer metastasis and he underwent biopsy via the endoscopic endonasal transethmoid approach. However, pathological examination of the cultured specimen revealed Aspergillus fumigatus. The patient was treated with voriconazole and the orbital apex syndrome resolved after 1 month. Orbital aspergillosis is a life-threatening disease and should be listed as a differential diagnosis of uncommon local infections during continuous chemotherapy.

  12. 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.

  13. 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....

  14. Impact of Pre-Treatment Lactate Dehydrogenase Levels on Prognosis and Bevacizumab Efficacy in Patients with Metastatic Colorectal Cancer.

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    Alessandro Passardi

    Full Text Available To investigate the impact of pre-treatment lactate dehydrogenase (LDH levels on the outcome of patients with metastatic colorectal cancer treated with first-line chemotherapy with or without the anti-VEGF monoclonal antibody, bevacizumab, in a phase III prospective multicentre randomized ITACa (Italian Trial in Advanced Colorectal Cancer trial.Three hundred and seventy patients enrolled onto the ITACa first-line trial were considered for this study, 176 receiving chemotherapy (either FOLFIRI or FOLFOX plus bevacizumab and 194 receiving chemotherapy only. Pre-treatment LDH levels were evaluated to identify a potential correlation with progression-free survival (PFS, overall survival (OS and objective response rate.Information on pre-treatment LDH levels was available for 344 patients. High LDH levels were predictive of a lower median PFS (8.1 months vs. 9.2 months, p< 0.0001 and median OS (16.1 months vs. 25.2 months, p< 0.0001 in the overall population. In the chemotherapy plus bevacizumab group, median PFS was 9.1 and 9.8 months in patients with high LDH and low LDH, respectively (p= 0.073, whereas in the chemotherapy-only arm it was 6.9 and 9.1 months, respectively (p < 0.0001. In patients with high LDH, the addition of bevacizumab to chemotherapy led to a reduction in the rate of progressive disease (16.4 vs. 30.5%, p= 0.081 and to a prolonged PFS (p= 0.028.A high LDH value was confirmed as a marker of poor prognosis. Bevacizumab reduced the progressive disease rate and improved PFS in the high-LDH subgroup, making serum LDH a potentially effective an easily available and marker to select patients who benefit from bevacizumab.NCT01878422 ClinicalTrials.gov.

  15. Genetic diversity of the KIR/HLA system and outcome of patients with metastatic colorectal cancer treated with chemotherapy.

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    Valli De Re

    Full Text Available To explore genes of the killer-cell immunoglobulin-like receptor (KIR and of the HLA ligand and their relationship with the outcome of metastatic colorectal cancer (mCRC patients treated with first-line 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI.A total of 224 mCRC patients were screened for KIR/HLA typing. The determination of the KIR/HLA combinations was based upon the gene content and variants. Genetic associations with complete response (CR, time to progression (TTP and overall survival (OS were evaluated by calculating odds and hazard ratios. Multivariate modeling with prognostic covariates was also performed.For CR, the presence of KIR2DL5A, 2DS5, 2DS1, 3DS1, and KIR3DS1/HLA-Bw4-I80 was associated with increased CR rates, with median ORs ranging from 2.1 to 4.3, while the absence of KIR2DS4 and 3DL1 was associated with increased CR rates (OR 3.1. After univariate analysis, patients that underwent resective surgery of tumor, absence of KIR2DS5, and presence of KIR3DL1/HLA-Bw4-I80 showed a significant better OS (HR 1.5 to 2.8. Multivariate analysis identified as parameters independently related to OS the type of treatment (surgery; HR 2.0 and KIR3DL1/HLA-Bw4-I80 genotype (HR for T-I80 2.7 and for no functional KIR/HLA interaction 1.8. For TTP, no association with KIR/HLA genes was observed.This study, for the first time, evidences that the genotyping for KIR-HLA pairs are found predictive markers associated with complete response and improves overall survival prediction of FOLFIRI treatment response in metastatic colorectal cancer. These results suggest a role of the KIR/HLA system in patient outcome, and guide new research on the immunogenetics of mCRC through mechanistic studies and clinical validation.

  16. Early detection of poor outcome in patients with metastatic colorectal cancer: tumor kinetics evaluated by circulating tumor cells

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    Souza e Silva V

    2016-12-01

    Full Text Available Virgílio Souza e Silva,1 Ludmilla Thomé Domingos Chinen,2 Emne A Abdallah,2 Aline Damascena,2 Jociana Paludo,3 Rubens Chojniak,3 Aldo Lourenço Abbade Dettino,1 Celso Abdon Lopes de Mello,1 Vanessa S Alves,2 Marcello F Fanelli1 1Department of Clinical Oncology, 2International Research Center, 3Image Department, A. C. Camargo Cancer Center, São Paulo, Brazil Background: Colorectal cancer (CRC is the third most prevalent cancer worldwide. New prognostic markers are needed to identify patients with poorer prognosis, and circulating tumor cells (CTCs seem to be promising to accomplish this.Patients and methods: A prospective study was conducted by blood collection from patients with metastatic CRC (mCRC, three times, every 2 months in conjunction with image examinations for evaluation of therapeutic response. CTC isolation and counting were performed by Isolation by Size of Epithelial Tumor Cells (ISET.Results: A total of 54 patients with mCRC with a mean age of 57.3 years (31–82 years were included. Among all patients, 60% (n=32 were carriers of wild-type KRAS (WT KRAS tumors and 90% of them (n=29 were exposed to monoclonal antibodies along with systemic treatment. Evaluating CTC kinetics, when we compared the baseline (pretreatment CTC level (CTC1 with the level at first follow-up (CTC2, we observed that CTC1-positive patients (CTCs above the median, who became negative (CTCs below the median had a favorable evolution (n=14, with a median progression-free survival (PFS of 14.7 months. This was higher than that for patients with an unfavorable evolution (CTC1– that became CTC2+; n=13, 6.9 months; P=0.06. Patients with WT KRAS with favorable kinetics had higher PFS (14.7 months in comparison to those with WT KRAS with unfavorable kinetics (9.4 months; P=0.02. Moreover, patients whose imaging studies showed radiological progression had an increased quantification of CTCs at CTC2 compared to those without progression (P=0.04.Conclusion

  17. Prognostic value of the Glasgow Prognostic Score in metastatic colorectal cancer in the era of anti-EGFR therapies.

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    Dréanic, Johann; Maillet, Marianne; Dhooge, Marion; Mir, Olivier; Brezault, Catherine; Goldwasser, François; Chaussade, Stanislas; Coriat, Romain

    2013-01-01

    The Glasgow Prognostic Score (GPS), combination of C-reactive protein and albumin, has proven its prognostic value in metastatic colorectal cancer (mCRC) patients receiving conventional cytotoxic therapy. More recently, anti-EGFR therapies have been validated in mCRC and roll forward the patients' overall survival (OS). We aimed to evaluate the prognostic accuracy of the GPS in patients receiving anti-EGFR therapy in addition to conventional chemotherapy. From January 2007 to February 2012, consecutive mCRC patients who received 5-fluorouracil-based chemotherapy plus cetuximab were included in the present analysis. Patients were eligible for the study if they met the following criteria: advanced pathologically proven MCRC, age >18 years, adequate renal function (creatinine clearance >40 ml/min), C-reactive protein and albumin and performance status evaluation before treatment initiation. A total of 49 patients received cetuximab plus 5-fluorouracil-based chemotherapy (colon, n = 34; rectum, n = 15) and were treated with a median follow-up of 35 months (16.5-74.7). Median age was 48 years old. In addition to cetuximab, patients received oxaliplatin- (n = 34, 60%) or irinotecan (n = 15, 30%)-based chemotherapy. At time of diagnosis, 55, 29 and 16% of patients had a GPS of 0 (n = 27), 1 (n = 14) and 2 (n = 8), respectively. Fifty-five, 29 and 14 % of patients add one, two or ≥3 metastatic sites, respectively. Considering two groups (GPS = 0 and GPS ≥1), median progression-free survivals were significantly different (p = 0.0084). Median OS in the GPS 0, 1 and 2 groups were 38.2, 14 and 12.1 months, respectively (p = 0.0093). The results of the present study confirm that the GPS is still a simple and effective prognostic factor in the era of cetuximab therapy in mCRC patients.

  18. 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.

  19. TAS-102 plus bevacizumab for patients with metastatic colorectal cancer refractory to standard therapies (C-TASK FORCE): an investigator-initiated, open-label, single-arm, multicentre, phase 1/2 study.

    Science.gov (United States)

    Kuboki, Yasutoshi; Nishina, Tomohiro; Shinozaki, Eiji; Yamazaki, Kentaro; Shitara, Kohei; Okamoto, Wataru; Kajiwara, Takeshi; Matsumoto, Toshihiko; Tsushima, Takahiro; Mochizuki, Nobuo; Nomura, Shogo; Doi, Toshihiko; Sato, Akihiro; Ohtsu, Atsushi; Yoshino, Takayuki

    2017-09-01

    In patients with heavily treated metastatic colorectal cancer, TAS-102-a combination of trifluridine and tipiracil-has shown a significant overall survival benefit compared with placebo. In preclinical models, TAS-102 plus bevacizumab has shown enhanced activity against colorectal cancer xenografts compared with that for either drug alone. In this phase 1/2 study, we assessed the activity and safety of TAS-102 plus bevacizumab. We did this investigator-initiated, open-label, single-arm, multicentre, phase 1/2 trial of TAS-102 plus bevacizumab in four cancer centres in Japan. Eligible patients were aged 20 years or older; had histologically confirmed unresectable, metastatic colorectal adenocarcinoma; were refractory or intolerant to fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF therapy, and anti-EGFR therapy (for tumours with wild-type KRAS); and had no previous treatment with regorafenib. Patients had to have an Eastern Cooperative Oncology Group performance status of 0 or 1. Using a dose de-escalation design in phase 1, the recommended phase 2 dose (RP2D) was determined for TAS-102 (35 mg/m(2) given orally twice daily on days 1-5 and 8-12 in a 28-day cycle for level 1) plus bevacizumab (5 mg/kg, administered by intravenous infusion for 30 min every 2 weeks). In phase 2, patients received the RP2D. The primary endpoint was centrally assessed progression-free survival at 16 weeks, analysed in the first 21 patients to be enrolled and treated with the RP2D who had at least one imaging assessment. This study is completed and registered with the University Hospital Medical Information Network, number UMIN000012883. Between Feb 25, 2014, and July 23, 2014, we enrolled 25 patients with metastatic colorectal cancer: six patients in phase 1 and 19 patients in phase 2. The six patients who received TAS-102 at level 1 experienced no dose-limiting toxicities and this was deemed the RP2D. Nine of 21 patients who received the RP2D did not have a centrally assessed

  20. 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.

  1. [Study of circadian rhythms of activity by actometry: preliminary results in 30 patients with metastatic colorectal cancer].

    Science.gov (United States)

    Mormont, M C; De Prins, J; Lévi, F

    1996-03-01

    Activity circadian rhythms were measured non-invasively in 30 patients with metastatic colorectal cancer by wrist actigraphy, and compared with control data. Patients and control subjects were requested to wear the actigraph at home for 2 to 5 days. Control time-series exhibit high activity levels (150 to 350 counts/min) during daytime, followed by low activity levels (0 to 50 counts/min) during the night. In patients, the contrast between daytime activity and nocturnal sleep is noticeably less marked, and a wide inter-patient variability can be observed. This alteration of the rest-activity rhythm in the cancer group was statistically validated by autocorrelation test. Results from the cosinor and he maximal entropy spectral analysis must be interpreted more cautiously, since the prerequisites for these tests may not be fulfilled by actometric time-series. These results indicate that cancer patients may have altered rest-activity circadian rhythms. The significance and prognostic value of such alterations deserve further testing in a larger population. Actigraphy may provide a simple and innovative tool to study the circadian system in cancer patients.

  2. High RBM3 expression is associated with an improved survival and oxaliplatin response in patients with metastatic colorectal cancer.

    Science.gov (United States)

    Siesing, Christina; Sorbye, Halfdan; Dragomir, Anca; Pfeiffer, Per; Qvortrup, Camilla; Pontén, Fredrik; Jirström, Karin; Glimelius, Bengt; Eberhard, Jakob

    2017-01-01

    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.

  3. 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.

  4. Concordance of KRAS/BRAF Mutation Status in Metastatic Colorectal Cancer before and after Anti-EGFR Therapy

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    S. Gattenlöhner

    2009-01-01

    Full Text Available Anti-EGFR targeted therapy is a potent strategy in the treatment of metastatic colorectal cancer (mCRC but activating mutations in the KRAS gene are associated with poor response to this treatment. Therefore, KRAS mutation analysis is employed in the selection of patients for EGFR-targeted therapy and various studies have shown a high concordance between the mutation status in primary CRC and corresponding metastases. However, although development of therapy related resistance occurs also in the context of novel drugs such as tyrosine kinase-inhibitors the effect of the anti-EGFR treatment on the KRAS/BRAF mutation status itself in recurrent mCRC has not yet been clarified. Therefore, we analyzed 21 mCRCs before/after anti-EGFR therapy and found a pre-/posttherapeutic concordance of the KRAS/BRAF mutation status in 20 of the 21 cases examined. In the one discordant case, further analyses revealed that a tumor mosaicism or multiple primary tumors were present, indicating that anti-EGFR therapy has no influence on KRAS/BRAF mutation status in mCRC. Moreover, as the preselection of patients with a KRASwt genotype for anti-EGFR therapy has become a standard procedure, sample sets such ours might be the basis for future studies addressing the identification of potential anti-EGFR therapy induced genetic alterations apart from KRAS/BRAF mutations.

  5. Treatment with Antiangiogenic Drugs in Multiple Lines in Patients with Metastatic Colorectal Cancer: Meta-Analysis of Randomized Trials

    Science.gov (United States)

    Kubicka, S.; Falcone, A.; Burkholder, I.; Hacker, U. T.

    2016-01-01

    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. PMID:27656206

  6. Metastatic Tissue Proteomic Profiling Predicts 5-Year Outcomes in Patients with Colorectal Liver Metastases

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    Santiago Marfà

    2016-10-01

    Full Text Available Colorectal cancer (CRC is one of the most common cancers in the developed countries, and nearly 70% of patients with CRC develop colorectal liver metastases (CRLMs. During the last decades, several scores have been proposed to predict recurrence after CRLM resection. However, these risk scoring systems do not accurately reflect the prognosis of these patients. Therefore, this investigation was designed to identify a proteomic profile in human hepatic tumor samples to classify patients with CRLM as “mild” or “severe” based on the 5-year survival. The study was performed on 85 CRLM tumor samples. Firstly, to evaluate any distinct tumor proteomic signatures between mild and severe CRLM patients, a training group of 57 CRLM tumor samples was characterized by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry, and a classification and regression tree (CART analysis was subsequently performed. Finally, 28 CRLM tumor samples were used to confirm and validate the results obtained. Based on all the protein peaks detected in the training group, the CART analysis was generated, and four peaks were considered to be the most relevant to construct a diagnostic algorithm. Indeed, the multivariate model yielded a sensitivity of 85.7% and a specificity of 86.1%, respectively. In addition, the receiver operating characteristic (ROC curve showed an excellent diagnostic accuracy to discriminate mild from severe CRLM patients (area under the ROC: 0.903. Finally, the validation process yielded a sensitivity and specificity of 68.8% and 83.3%, respectively. We identified a proteomic profile potentially useful to determine the prognosis of CRLM patients based on the 5-year survival.

  7. The role of image-guided therapy in the management of colorectal cancer metastatic disease.

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    de Baere, Thierry; Tselikas, Lambros; Yevich, Steven; Boige, Valérie; Deschamps, Frederic; Ducreux, Michel; Goere, Diane; Nguyen, France; Malka, David

    2017-02-23

    The European Society for Medical Oncology (ESMO) have stressed that the option for treating oligometastatic disease is a strategy of local ablative therapy, the goal of which is to improve disease control. The spectrum of the local ablative therapy toolbox described by the ESMO includes surgical R0 resection, percutaneous ablation and intra-arterial therapies, the choice of treatment being left to the multidisciplinary team. Interventional therapy involving image-guided treatment offers the possibility of less invasive treatments for colorectal cancer metastases in the liver, lung and bone by preserving from toxicity distant healthy organs or even parts of the diseased organs. Oligometastases can be targeted by image-guided puncture for percutaneous ablation by delivering locally, through inserted probes, heat (radiofrequency, microwaves), extreme cold (cryoablation) or electric pulses (electroporation). Radiofrequency (RFA) is the mainstay of percutaneous ablation and provides local control rates of around 90% when metastases are small (imaging guidance. The lung provides a specific environment with excellent visibility of the target tumour, and insulation of the tumour by the healthy lung improves thermal delivery. RFA of colorectal lung metastases provides a 5-year overall survival of 56.0%, with a 91.6% control rate for metastases with a diameter <3 cm. These results are comparable to results of surgical series. Non-resectable, non-ablatable liver metastases can be targeted through their preferential arterial vascularisation with hepatic arterial infusion chemotherapy (HAIC) or selective internal radiation therapy (SIRT) with radioactive microspheres. HAIC with oxaliplatin has demonstrated an impressive response rate when patients who have previously failed intravenous oxaliplatin are rechallenged. The response rate in first-line therapy is around 90%, with conversion to surgery in roughly 40% of patients. SIRT has recently demonstrated a benefit for

  8. Correlation of Hypertension and Proteinuria with Outcome in Elderly Bevacizumab-Treated Patients with Metastatic Colorectal Cancer

    Science.gov (United States)

    Feliu, Jaime; Salud, Antonieta; Safont, Maria J.; García-Girón, Carlos; Aparicio, Jorge; Losa, Ferran; Bosch, Carlos; Escudero, Pilar; Casado, Enrique; Jorge, Monica; Bohn, Uriel; Pérez-Carrión, Ramon; Carmona, Alberto; Custodio, Ana B.; Maurel, Joan

    2015-01-01

    Background Studies suggest a relationship between hypertension and outcome in bevacizumab-treated patients with metastatic colorectal cancer (mCRC). We performed a retrospective analysis of two phase II studies (BECA and BECOX) to determine if hypertension and proteinuria predict outcome in elderly patients with mCRC treated with bevacizumab. Patients and Methods Patients ≥70 years of age received either capecitabine 1250 mg/m2 bid days 1–14 + bevacizumab 7.5 mg/kg day 1 every 21 days (BECA study) or capecitabine 1000 mg/m2 bid days 1–14 with bevacizumab 7.5 mg/kg and oxaliplatin 130 mg/m2 day 1 (BECOX study). The primary objective was to correlate hypertension and proteinuria with overall response rate (ORR), time to progression (TTP) and overall survival (OS). Secondary objectives included identification of risk factors associated with the development of hypertension and proteinuria and determining whether development of hypertension or proteinuria in the first 2 cycles was related to ORR, disease-control rate (DCR), TTP or OS. Results In total, 127 patients (median age 75.5 years) were included in the study. Hypertension correlated with DCR and OS; proteinuria correlated with ORR and DCR. Proteinuria or hypertension in the first 2 cycles did not correlate with efficacy. Risk factors for hypertension were female gender (odds ratio [OR] 0.241; P = 0.011) and more bevacizumab cycles (OR 1.112; P = 0.002); risk factors for proteinuria were diabetes (OR 3.869; P = 0.006) and more bevacizumab cycles (OR 1.181; P<0.0001). Multivariate analysis identified as having prognostic value: baseline lactate dehydrogenase, haemoglobin, number of metastatic lesions and DCR. Conclusion This analysis of two phase II studies suggests that hypertension is significantly correlated with OS but not with ORR and TTP, whereas proteinuria is correlated with ORR but not with OS and TTP. Both hypertension and proteinuria are associated with the duration of bevacizumab treatment and do

  9. Correlation of hypertension and proteinuria with outcome in elderly bevacizumab-treated patients with metastatic colorectal cancer.

    Science.gov (United States)

    Feliu, Jaime; Salud, Antonieta; Safont, Maria J; García-Girón, Carlos; Aparicio, Jorge; Losa, Ferran; Bosch, Carlos; Escudero, Pilar; Casado, Enrique; Jorge, Monica; Bohn, Uriel; Pérez-Carrión, Ramon; Carmona, Alberto; Custodio, Ana B; Maurel, Joan

    2015-01-01

    Studies suggest a relationship between hypertension and outcome in bevacizumab-treated patients with metastatic colorectal cancer (mCRC). We performed a retrospective analysis of two phase II studies (BECA and BECOX) to determine if hypertension and proteinuria predict outcome in elderly patients with mCRC treated with bevacizumab. Patients ≥ 70 years of age received either capecitabine 1250 mg/m(2) bid days 1-14 + bevacizumab 7.5 mg/kg day 1 every 21 days (BECA study) or capecitabine 1000 mg/m(2) bid days 1-14 with bevacizumab 7.5 mg/kg and oxaliplatin 130 mg/m(2) day 1 (BECOX study). The primary objective was to correlate hypertension and proteinuria with overall response rate (ORR), time to progression (TTP) and overall survival (OS). Secondary objectives included identification of risk factors associated with the development of hypertension and proteinuria and determining whether development of hypertension or proteinuria in the first 2 cycles was related to ORR, disease-control rate (DCR), TTP or OS. In total, 127 patients (median age 75.5 years) were included in the study. Hypertension correlated with DCR and OS; proteinuria correlated with ORR and DCR. Proteinuria or hypertension in the first 2 cycles did not correlate with efficacy. Risk factors for hypertension were female gender (odds ratio [OR] 0.241; P = 0.011) and more bevacizumab cycles (OR 1.112; P = 0.002); risk factors for proteinuria were diabetes (OR 3.869; P = 0.006) and more bevacizumab cycles (OR 1.181; P<0.0001). Multivariate analysis identified as having prognostic value: baseline lactate dehydrogenase, haemoglobin, number of metastatic lesions and DCR. This analysis of two phase II studies suggests that hypertension is significantly correlated with OS but not with ORR and TTP, whereas proteinuria is correlated with ORR but not with OS and TTP. Both hypertension and proteinuria are associated with the duration of bevacizumab treatment and do not represent an independent prognostic factor.

  10. Correlation of hypertension and proteinuria with outcome in elderly bevacizumab-treated patients with metastatic colorectal cancer.

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    Jaime Feliu

    Full Text Available BACKGROUND: Studies suggest a relationship between hypertension and outcome in bevacizumab-treated patients with metastatic colorectal cancer (mCRC. We performed a retrospective analysis of two phase II studies (BECA and BECOX to determine if hypertension and proteinuria predict outcome in elderly patients with mCRC treated with bevacizumab. PATIENTS AND METHODS: Patients ≥ 70 years of age received either capecitabine 1250 mg/m(2 bid days 1-14 + bevacizumab 7.5 mg/kg day 1 every 21 days (BECA study or capecitabine 1000 mg/m(2 bid days 1-14 with bevacizumab 7.5 mg/kg and oxaliplatin 130 mg/m(2 day 1 (BECOX study. The primary objective was to correlate hypertension and proteinuria with overall response rate (ORR, time to progression (TTP and overall survival (OS. Secondary objectives included identification of risk factors associated with the development of hypertension and proteinuria and determining whether development of hypertension or proteinuria in the first 2 cycles was related to ORR, disease-control rate (DCR, TTP or OS. RESULTS: In total, 127 patients (median age 75.5 years were included in the study. Hypertension correlated with DCR and OS; proteinuria correlated with ORR and DCR. Proteinuria or hypertension in the first 2 cycles did not correlate with efficacy. Risk factors for hypertension were female gender (odds ratio [OR] 0.241; P = 0.011 and more bevacizumab cycles (OR 1.112; P = 0.002; risk factors for proteinuria were diabetes (OR 3.869; P = 0.006 and more bevacizumab cycles (OR 1.181; P<0.0001. Multivariate analysis identified as having prognostic value: baseline lactate dehydrogenase, haemoglobin, number of metastatic lesions and DCR. CONCLUSION: This analysis of two phase II studies suggests that hypertension is significantly correlated with OS but not with ORR and TTP, whereas proteinuria is correlated with ORR but not with OS and TTP. Both hypertension and proteinuria are associated with the duration of bevacizumab

  11. Chemokine-Targeted Mouse Models of Human Primary and Metastatic Colorectal Cancer

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    Chen, Huanhuan Joyce; Sun, Jian; Huang, Zhiliang; Hou, Harry; Arcilla, Myra; Rakhilin, Nikolai; Joe, Daniel J.; Choi, Jiahn; Gadamsetty, Poornima; Milsom, Jeff; Nandakumar, Govind; Longman, Randy; Zhou, Xi Kathy; Edwards, Robert; Chen, Jonlin; Chen, Kai Yuan; Bu, Pengcheng; Wang, Lihua; Xu, Yitian; Munroe, Robert; Abratte, Christian; Miller, Andrew D.; Gümüş, Zeynep H.; Shuler, Michael; Nishimura, Nozomi; Edelmann, Winfried; Shen, Xiling; Lipkin, Steven M.

    2015-01-01

    Current orthotopic xenograft models of human colorectal cancer (CRC) require surgery and do not robustly form metastases in the liver, the most common site clinically. CCR9 traffics lymphocytes to intestine and colorectum. We engineered use of the chemokine receptor CCR9 in CRC cell lines and patient-derived cells to create primary gastrointestinal (GI) tumors in immunodeficient mice by tail-vein injection rather than surgery. The tumors metastasize inducibly and robustly to the liver. Metastases have higher DKK4 and NOTCH signaling levels and are more chemoresistant than paired sub-cutaneous xenografts. Using this approach, we generated 17 chemokine-targeted mouse models (CTMMs) that recapitulate the majority of common human somatic CRC mutations. We also show that primary tumors can be modeled in immunocompetent mice by microinjecting CCR9-expressing cancer cell lines into early-stage mouse blastocysts, which induces central immune tolerance. We expect that CTMMs will facilitate investigation of the biology of CRC metastasis and drug screening. PMID:26006007

  12. Molecular constituents of colorectal cancer metastatic to the liver by imaging infrared spectroscopy

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    Coe, James V.; Chen, Zhaomin; Li, Ran; Nystrom, Steven V.; Butke, Ryan; Miller, Barrie; Hitchcock, Charles L.; Allen, Heather C.; Povoski, Stephen P.; Martin, Edward W.

    2015-03-01

    Infrared (IR) imaging spectroscopy of human liver tissue slices has been used to identify and characterize liver metastasis of colorectal origin which was surgically removed from a consenting patient and frozen without formalin fixation or dehydration procedures, so that lipids and water remain in the tissues. First, a k-means clustering analysis, using metrics from the IR spectra, identified groups within the image. The groups were identified as tumor or nontumor regions by comparing to an H and E stain of the same sample after IR imaging. Then, calibrant IR spectra of protein, several fats, glycogen, and polyvinyl alcohol were isolated by differencing spectra from different regions or groups in the image space. Finally, inner products (or scores) of the IR spectra at each pixel in the image with each of the various calibrants were calculated showing how the calibrant molecules vary in tumor and nontumor regions. In this particular case, glycogen and protein changes enable separation of tumor and nontumor regions as shown with a contour plot of the glycogen scores versus the protein scores.

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

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    Yang Q

    2015-09-01

    Full Text Available Qiong Yang,1–4,* Chenxi Yin,1,3,4,* Fangxin Liao,1,3,4 Yuanyuan Huang,1,3,4 Wenzhuo He,1,3,4 Chang Jiang,1,3,4 Guifang Guo,1,3,4 Bei Zhang,1,3,4 Liangping Xia1,3,41VIP Region, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People’s Republic of China; 2Department of Oncology, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, People’s Republic of China; 3State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People’s Republic of China; 4Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, People’s Republic of China*These authors contributed equally to this workBackground: Currently available third- or later-line therapy for metastatic colorectal cancer (mCRC is limited in its efficacy, with a weak survival benefit in patients who progressed after two or more lines of standard therapy. Our retrospective study aimed to explore the value of bevacizumab plus chemotherapy in this setting.Methods: Patients with mCRC who received fluoropyrimidine, oxaliplatin, and irinotecan as first- and second-line chemotherapy were selected for inclusion. Treatment consisted of bevacizumab plus chemotherapy. Chemotherapy consisted mainly of oxaliplatin, irinotecan, and fluoropyrimidine.Results: Between February 2010 and December 2012, 35 consecutive patients with mCRC were treated with bevacizumab plus chemotherapy as a third- or later-line treatment. No complete responses, seven partial responses (20%, 22 stable disease responses (62.9%, and six progressive disease responses (17.1% were obtained, producing an objective response rate of 20% and a disease control rate of 82.9%. With a median follow-up of 11.3 months (range: 0.7–48.0 months, the median progression-free survival was 5.98 months (95% confidence interval: 4.76–7.2 months, and the median overall survival was 14.77 months (95% confidence interval: 11.45–18.1 months. In the univariate analysis

  14. Efficacy and safety of first-line chemotherapy plus bevacizumab in patients with metastatic colorectal cancer: a meta-analysis

    Institute of Scientific and Technical Information of China (English)

    Wang Ming; Zheng Xiaofeng; Ruan Xiaojiao; Ye Bailiang; Cai Long; Lin Feizhuan; Tu Jinfu

    2014-01-01

    Background What benefits and toxicities patients acquire from the use of bevacizumab combined with first-line chemotherapy remains controversial.This study was performed to evaluate the efficacy and safety of first-line chemotherapy plus bevacizumab in patients with metastatic colorectal cancer (mCRC).Methods Several databases,including PubMed,Embase,and Cochrane Library,were searched up to April 30,2013.Eligible studies were only randomized,controlled trials (RCTs) with a direct comparison between mCRC patients treated with and without bevacizumab.Overall risk ratio (RR),hazard ratio (HR),odds ratio (OR),and 95% confidence intervals (CO were calculated employing fixed or random-effects models depending on the heterogeneity of the included trials.Results Six RCTs,including 1582 patients in chemotherapy plus bevacizumab group and 1484 patients in chemotherapyalone group,were included.Overall,the addition of bevacizumab to first-line chemotherapy increased overall response rate (ORR) by 4.5%,prolonged both progression-free survival (PFS) and overall survival (OS),and increased the rate of total Grades 3 or 4 adverse events (G3/4AEs) by 6.9%.Significant differences were found in ORR (RR=1.22 (95% CI 1.01-1.46),P=0.03),PFS (HR=0.60 (95% Cl 0.47-0.77),P <0.0001),OS (HR=0.83 (95% Cl 0.70-0.97),P=0.02),and any G3/4AEs (OR=1.56 (95% Cl 1.29-1.89),P <0.00001).Conclusion Bevacizumab is a valuable addition to the current first-line chemotherapy regimens used in patients with mCRC,because of conferring a significant improvement in ORR,PFS,and OS,even though it increased adverse events.

  15. In Vivo Efficacy of Umbilical Cord Blood Stem Cell-Derived NK Cells in the Treatment of Metastatic Colorectal Cancer

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    Veluchamy, John P.; Lopez-Lastra, Silvia; Spanholtz, Jan; Bohme, Fenna; Kok, Nina; Heideman, Daniëlle A. M.; Verheul, Henk M. W.; Di Santo, James P.; de Gruijl, Tanja D.; van der Vliet, Hans J.

    2017-01-01

    Therapeutic monoclonal antibodies against the epidermal growth factor receptor (EGFR) act by inhibiting EGFR downstream signaling and by eliciting a natural killer (NK) cell-mediated antitumor response. The IgG1 mAb cetuximab has been used for treatment of RASwt metastatic colorectal cancer (mCRC) patients, showing limited efficacy. In the present study, we address the potential of adoptive NK cell therapy to overcome these limitations investigating two allogeneic NK cell products, i.e., allogeneic activated peripheral blood NK cells (A-PBNK) and umbilical cord blood stem cell-derived NK cells (UCB-NK). While cetuximab monotherapy was not effective against EGFR− RASwt, EGFR+ RASmut, and EGFR+ BRAFmut cells, A-PBNK were able to initiate lysis of EGFR+ colon cancer cells irrespective of RAS or BRAF status. Cytotoxic effects of A-PBNK (but not UCB-NK) were further potentiated significantly by coating EGFR+ colon cancer cells with cetuximab. Of note, a significantly higher cytotoxicity was induced by UCB-NK in EGFR−RASwt (42 ± 8 versus 67 ± 7%), EGFR+ RASmut (20 ± 2 versus 37 ± 6%), and EGFR+ BRAFmut (23 ± 3 versus 43 ± 7%) colon cancer cells compared to A-PBNK and equaled the cytotoxic efficacy of the combination of A-PBNK and cetuximab. The antitumor efficacy of UCB-NK cells against cetuximab-resistant human EGFR+ RASmut colon cancer cells was further confirmed in an in vivo preclinical mouse model where UCB-NK showed enhanced antitumor cytotoxicity against colon cancer independent of EGFR and RAS status. As UCB-NK have been proven safe in a recently conducted phase I clinical trial in acute myeloid leukemia, a fast translation into clinical proof of concept for mCRC could be considered. PMID:28220124

  16. Combination of NK Cells and Cetuximab to Enhance Anti-Tumor Responses in RAS Mutant Metastatic Colorectal Cancer.

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    John Pradeep Veluchamy

    Full Text Available The ability of Natural Killer (NK cells to kill tumor targets has been extensively studied in various hematological malignancies. However, NK cell therapy directed against solid tumors is still in early development. Epidermal Growth Factor Receptor (EGFR targeted therapies using monoclonal antibodies (mAbs such as cetuximab and panitumumab are widely used for the treatment of metastatic colorectal cancer (mCRC. Still, the clinical efficacy of this treatment is hampered by mutations in RAS gene, allowing tumors to escape from anti-EGFR mAb therapy. It is well established that NK cells kill tumor cells by natural cytotoxicity and can in addition be activated upon binding of IgG1 mAbs through Fc receptors (CD16/FcγRIIIa on their surface, thereby mediating antibody dependent cellular cytotoxicity (ADCC. In the current study, activated Peripheral Blood NK cells (PBNK were combined with anti-EGFR mAbs to study their effect on the killing of EGFR+/- cancer cell lines, including those with RAS mutations. In vitro cytotoxicity experiments using colon cancer primary tumors and cell lines COLO320, Caco-2, SW620, SW480 and HT-29, demonstrated that PBNK cells are cytotoxic for a range of tumor cells, regardless of EGFR, RAS or BRAF status and at low E:T ratios. Cetuximab enhanced the cytotoxic activity of NK cells on EGFR+ tumor cells (either RASwt, RASmut or BRAFmut in a CD16 dependent manner, whereas it could not increase the killing of EGFR- COLO320. Our study provides a rationale to strengthen NK cell immunotherapy through a combination with cetuximab for RAS and BRAF mutant mCRC patients.

  17. 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.

  18. The predictive and prognostic value of the Glasgow Prognostic Score in metastatic colorectal carcinoma patients receiving bevacizumab.

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    Maillet, Marianne; Dréanic, Johann; Dhooge, Marion; Mir, Olivier; Brezault, Catherine; Goldwasser, François; Chaussade, Stanislas; Coriat, Romain

    2014-11-01

    The Glasgow Prognostic Score (GPS), based on C-reactive protein and albumin levels, has shown its prognostic value in metastatic colorectal carcinoma (mCRC) patients receiving conventional cytotoxic therapy. Bevacizumab, a monoclonal antibody to vascular epidermal growth factor, improves the overall survival in mCRC. The aim of the present study was to assess the prognostic value of GPS in mCRC patients receiving antivascular epidermal growth factor therapy. From August 2005 to August 2012, consecutive patients with mCRC who received chemotherapy plus bevacizumab were eligible for the present analysis. The clinical stage, C-reactive protein, albumin and the Eastern Cooperative Oncology Group performance status were recorded at the time of initiation of bevacizumab. Patients received 5-fluorouracil-based chemotherapy plus bevacizumab in accordance with the digestive oncology multidisciplinary staff proposal and in line with the French recommendations for the treatment of mCRC. Eighty patients were eligible (colon n = 59, rectum n = 21), with a median follow-up of 14 months (range 1-58 months). Chemotherapy given with bevacizumab and 5-fluorouracil was oxaliplatin (n = 41, 51%) or irinotecan (n = 27, 34%). At baseline, 56, 31 and 13% of patients had a GPS of 0 (n = 45), 1 (n = 25) and 2 (n = 10), respectively. The median progression-free survival in these groups was 10.1, 6.5 and 5.6 months (P = 0.16), respectively. The median overall survival was 20.1, 11.4 and 6.5 months, respectively (P = 0.004). Our study confirmed the prognostic value of GPS in mCRC patients receiving chemotherapy plus bevacizumab. Given the poor survival observed in patients with an GPS of 2, studies dedicated to these patients could identify optimal treatment modalities.

  19. Human embryonic stem cells and metastatic colorectal cancer cells shared the common endogenous human microRNA-26b.

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    Ma, Yan-Lei; Zhang, Peng; Wang, Feng; Moyer, Mary Pat; Yang, Jian-Jun; Liu, Zhi-Hua; Peng, Jia-Yuan; Chen, Hong-Qi; Zhou, Yu-Kun; Liu, Wei-Jie; Qin, Huan-Long

    2011-09-01

    The increase in proliferation and the lack of differentiation of cancer cells resemble what occur in the embryonic stem cells during physiological process of embryogenesis. There are also striking similarities in the behaviour between the invasive placental cells and invasive cancer cells. In the present study, microarrays were used to analyse the global expression of microRNAs in a human embryonic stem cell line (i.e. HUES-17) and four colorectal cancer (CRC) cell lines (i.e. LoVo, SW480, HT29 and Caco-2) with different metastatic potentialities. Only the expression of miR-26b was significant decreased in HUES-17s and LoVo cells, compared with other three cell lines (P cell growth and the induction of apoptosis in LoVo cells in vitro, and the inhibition of tumour growth in vivo. Moreover, the potential targets of miR-26b was predicted by using bioinformatics, and then the predicted target genes were further validated by comparing gene expression profiles between LoVo and NCM460 cell lines. Four genes (TAF12, PTP4A1, CHFR and ALS2CR2) with intersection were found to be the targets of miR-26b. MetaCore network analysis further showed that the regulatory pathways of miR-26b were significantly associated with the invasiveness and metastasis of CRC cells. These data suggest that miR-26b might serve as a novel prognostic factor and a potential therapeutic target for CRC.

  20. Chemotherapy plus bevacizumab versus chemotherapy plus cetuximab as first-line treatment for patients with metastatic colorectal cancer

    Science.gov (United States)

    Bai, Long; Wang, Feng; Li, Zhe-zhen; Ren, Chao; Zhang, Dong-sheng; Zhao, Qi; Lu, Yun-xin; Wang, De-shen; Ju, Huai-qiang; Qiu, Miao-zhen; Wang, Zhi-qiang; Wang, Feng-hua; Xu, Rui-hua

    2016-01-01

    Abstract The present observational cohort study was designed to elucidate the efficacy and safety profile of bevacizumab or cetuximab with chemotherapy as the first-line treatment in Chinese patients with metastatic colorectal cancer (mCRC). Clinical data were collected from a single-center registry study where mCRC patients received first-line fluoropyrimidine-based chemotherapy combined with either bevacizumab (188 patients with KRAS wild-type or mutated tumors) or cetuximab (101 patients with KRAS wild-type tumors) between January 2009 and December 2013. The Kaplan–Meier method was used for survival analysis. Cox proportional hazards model was used for estimating the prognostic and predictive values of clinicopathological characteristics. No statistically significant difference was observed between the bevacizumab and cetuximab groups in terms of median progression-free survival (PFS) (10.6 vs 8.7 months, P = 0.317), median overall survival (OS) (27.7 vs 28.3 months, P = 0.525), or overall response rate (43.1% vs 53.5%, P = 0.108). For the subset of patients with peritoneal dissemination, bevacizumab-based triplet appears to be superior to cetuximab-based triplet as measured by PFS (9.6 vs 6.1 months) and OS (26.3 vs 12.7 months), but not for patients without peritoneal dissemination (PFS, 10.6 vs 9.1 months; OS, 27.9 vs 30.7 months) (all unadjusted and adjusted interaction P < 0.05). Our study suggests that bevacizumab- or cetuximab-based regimens have similar effectiveness as first-line treatment of mCRC in Chinese population. Patients with peritoneal dissemination were likely to gain more benefit from bevacizumab than cetuximab treatment. Future prospective studies are required to further confirm these results. PMID:28002313

  1. The efficacy and safety of panitumumab plus irrinotecan-based chemotherapy in the treatment of metastatic colorectal cancer

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    Chen, Qiang; Cheng, Minjing; Wang, Zhuo; Zhao, Shipeng

    2016-01-01

    Abstract Background: Panitumumab, a fully human monoclonal antibody targeting epidermal growth factor receptor, is used in combination with chemotherapy for patients with metastatic colorectal cancer (mCRC). However, the effects of panitumumab in combination with irrinotecan-based chemotherapy remain uncertain. Therefore, we conducted this meta-analysis to assess the efficacy and safety of combination treatment of panitumumab plus chemotherapy in the treatment of mCRC. Methods: By searching electronic databases (PubMed, Embase, and Web of Science), all clinical trials which assessed the effects of panitumumab plus irrinotecan-based chemotherapy in mCRC would be included. Main outcome measures included progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and adverse events. Pooled estimates were calculated by a fixed-effects model or random-effects model, according to the heterogeneity among the included studies. Results: Eleven trials with a total number of 1338 patients met the inclusion criteria and were included in this meta-analysis. The combination treatment of panitumumab and irrinotecan-based chemotherapy was associated with a median PFS of 5.83 months, OS of 11.15 months, and ORR of 33%. Subgroup analysis showed that, in the first-line and second-line treatment, the combination therapy for PFS was 9.27 and 5.01 months, for OS was 8.87 and 11.68 months, and for ORR was 61% and 26%, respectively. In the wild-type and mutant KRAS populations, the combination therapy for PFS was 5.76 and 5.27 months, for OS was 11.15 and 10.64 months, and for ORR was 37% and 18%, respectively. Moreover, combination therapy also induced an incidence of 56% treatment-related adverse events. Conclusion: Panitumumab plus irrinotecan-based chemotherapy is effective and well-tolerated in the treatment of patients with mCRC, especially in those with wild-type KRAS tumors. PMID:27977573

  2. Activation of c-Met and upregulation of CD44 expression are associated with the metastatic phenotype in the colorectal cancer liver metastasis model.

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    Victoria A Elliott

    Full Text Available BACKGROUND: Liver metastasis is the most common cause of death in patients with colorectal cancer. Despite extensive research into the biology of cancer progression, the molecular mechanisms that drive colorectal cancer metastasis are not well characterized. METHODS: HT29 LM1, HT29 LM2, HT29 LM3 cell lines were derived from the human colorectal cancer cell line HT29 following multiple rounds of in vivo selection in immunodeficient mice. RESULTS: CD44 expression, a transmembrane glycoprotein involved in cell-cell and cell-matrix adhesions, and cancer cells adhesion to endothelial cells was increased in all in vivo selected cell lines, with maximum CD44 expression and cancer cells adhesion to endothelial cells in the highly metastatic HT29 LM3 cell line. Activation of c-Met upon hepatocyte growth factor (HGF stimulation in the in vivo selected cell lines is CD44 independent. In vitro separation of CD44 high and low expression cells from HT29 LM3 cell line with FACS sorting confirmed that c-Met activation is CD44 independent upon hepatocyte growth factor stimulation. Furthermore, in vivo evaluation of CD44 low and high expressing HT29 LM3 cells demonstrated no difference in liver metastasis penetrance. CONCLUSIONS: Taken together, our findings indicate that the aggressive metastatic phenotype of in vivo selected cell lines is associated with overexpression of CD44 and activation of c-MET. We demonstrate that c-Met activation is CD44 independent upon hepatocyte growth factor stimulation and confirm that CD44 expression in HT29 LM3 cell line is not responsible for the increase in metastatic penetrance in HT29 LM3 cell line.

  3. Regorafenib as Salvage Treatment in Korean Patients with Refractory Metastatic Colorectal Cancer.

    Science.gov (United States)

    Kim, Seung Tae; Kim, Tae Won; Kim, Kyu-pyo; Kim, Tae-You; Han, Sae-Won; Lee, Ji Yun; Lim, Sung Hee; Lee, Min-Young; Kim, Haesu; Park, Young Suk

    2015-10-01

    Regorafenib, an oral multi-targeted tyrosine kinase inhibitor, is considered the new standard of care in patients with chemotherapy-refractory colorectal cancers (CRCs). However, there are no data on this drug in Korean patients. We evaluated patients who received oral regorafenib 160 mg once daily during the first 3 weeks of each 4-week cycle between August 2013 and September 2013. All patients had previously progressed fluorouracil, irinotecan, and oxaliplatin with or without biologic agents such as cetuximab or bevacizumab. Thirty-two patients were enrolled (median age, 57 years; male:female ratio, 20:12; Eastern Cooperative Oncology Group performance status [0-1:2], 31:1; colon:rectum, 21:11). The overall response rate was 3.1% and the disease control rate was 50.0% (95% confidence interval [CI]) with one partial response and 15 patients with stable disease. The median progression-free survival was 4.2 months (95% CI, 3.1 to 5.2 months) and the median overall survival has not yet been reached. The most common adverse events of grade two or higher related to regorafenib were hand-foot skin reaction (25%), mucositis (19%), abdominal pain (9%), and liver function test (LFT) abnormalities (9%). Grade 3 or 4 toxicities included LFT abnormalities (9%), abdominal pain (9%), rash (6%), anemia (3%), leukopenia (3%), neutropenic fever (3%), and fatigue (3%). There was no treatment-related death. Regorafenib appears to have promising activity and tolerable toxicity profiles in Korean patients with refractory CRC, consistent with the CORRECT trial findings.

  4. LINE-1 methylation shows little intra-patient heterogeneity in primary and synchronous metastatic colorectal cancer

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    Matsunoki Aika

    2012-12-01

    Full Text Available Abstract Background Long interspersed nucleotide element 1 (LINE-1 hypomethylation is suggested to play a role in the progression of colorectal cancer (CRC. To assess intra-patient heterogeneity of LINE-1 methylation in CRC and to understand its biological relevance in invasion and metastasis, we evaluated the LINE-1 methylation at multiple tumor sites. In addition, the influence of stromal cell content on the measurement of LINE-1 methylation in tumor tissue was analyzed. Methods Formalin-fixed paraffin-embedded primary tumor tissue was obtained from 48 CRC patients. Matched adjacent normal colon tissue, lymph node metastases and distant metastases were obtained from 12, 18 and 7 of these patients, respectively. Three different areas were microdissected from each primary tumor and included the tumor center and invasive front. Normal mucosal and stromal cells were also microdissected for comparison with the tumor cells. The microdissected samples were compared in LINE-1 methylation level measured by multicolor MethyLight assay. The assay results were also compared between microdissected and macrodissected tissue samples. Results LINE-1 methylation within primary tumors showed no significant intra-tumoral heterogeneity, with the tumor center and invasive front showing identical methylation levels. Moreover, no difference in LINE-1 methylation was observed between the primary tumor and lymph node and distant metastases from the same patient. Tumor cells showed significantly less LINE-1 methylation compared to adjacent stromal and normal mucosal epithelial cells. Consequently, LINE-1 methylation was significantly lower in microdissected samples compared to macrodissected samples. A trend for less LINE-1 methylation was also observed in more advanced stages of CRC. Conclusions LINE-1 methylation shows little intra-patient tumor heterogeneity, indicating the suitability of its use for molecular diagnosis in CRC. The methylation is relatively stable

  5. 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....

  6. Effect of First-Line Chemotherapy Combined With Cetuximab or Bevacizumab on Overall Survival in Patients With KRAS Wild-Type Advanced or Metastatic Colorectal Cancer

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    Venook, Alan P.; Niedzwiecki, Donna; Lenz, Heinz-Josef; Innocenti, Federico; Fruth, Briant; Meyerhardt, Jeffrey A.; Schrag, Deborah; Greene, Claire; O’Neil, Bert H.; Atkins, James Norman; Berry, Scott; Polite, Blase N.; O’Reilly, Eileen M.; Goldberg, Richard M.; Hochster, Howard S.; Schilsky, Richard L.; Bertagnolli, Monica M.; El-Khoueiry, Anthony B.; Watson, Peter; Benson, Al B.; Mulkerin, Daniel L.; Mayer, Robert J.; Blanke, Charles

    2017-01-01

    IMPORTANCE Combining biologic monoclonal antibodies with chemotherapeutic cytotoxic drugs provides clinical benefit to patients with advanced or metastatic colorectal cancer, but the optimal choice of the initial biologic therapy in previously untreated patients is unknown. OBJECTIVE To determine if the addition of cetuximab vsbevacizumab to the combination of leucovorin, fluorouracil, and oxaliplatin (mFOLFOX6) regimen or the combination of leucovorin, fluorouracil, and irinotecan (FOLFIRI) regimen is superior as first-line therapy in advanced or metastatic KRAS wild-type (wt) colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS Patients (≥18 years) enrolled at community and academic centers throughout the National Clinical Trials Network in the United States and Canada (November 2005-March 2012) with previously untreated advanced or metastatic colorectal cancer whose tumors were KRAS wt chose to take either the mFOLFOX6 regimen or the FOLFIRI regimen as chemotherapy and were randomized to receive either cetuximab (n = 578) or bevacizumab (n = 559). The last date of follow-up was December 15, 2015. INTERVENTIONS Cetuximab vs bevacizumab combined with either mFOLFOX6 or FOLFIRI chemotherapy regimen chosen by the treating physician and patient. MAIN OUTCOMES AND MEASURES The primary end point was overall survival. Secondary objectives included progression-free survival and overall response rate, site-reported confirmed or unconfirmed complete or partial response. RESULTS Among 1137 patients (median age, 59 years; 440 [39%] women), 1074 (94%) of patients met eligibility criteria. As of December 15, 2015, median follow-up for 263 surviving patients was 47.4 months (range, 0–110.7 months), and 82% of patients (938 of 1137) experienced disease progression. The median overall survival was 30.0 months in the cetuximab-chemotherapy group and 29.0 months in the bevacizumab-chemotherapy group with a stratified hazard ratio (HR) of 0.88 (95% CI, 0.77–1.01; P = .08). The

  7. Epidermal Growth Factor-like Domain 7 Predicts Response to First-Line Chemotherapy and Bevacizumab in Patients with Metastatic Colorectal Cancer

    DEFF Research Database (Denmark)

    Hansen, Torben Frøstrup; Nielsen, Boye Schnack; Sørensen, Flemming Brandt

    2014-01-01

    with bevacizumab, in patients with metastatic colorectal cancer (mCRC). A total of 158 patients from two different, but comparable, cohorts were included. Analyses were performed on tumor tissue from the primary tumor either based on a whole-tumor resection or an endoscopic biopsy. EGFL7 was analyzed...... = 0.049). The results showed no significant relationship between the miR126 VA and the clinical endpoints. Our study suggests a predictive value of EGFL7 in regard to first-line chemotherapy and bevacizumab in patients with mCRC and supports the mechanism of a dual blocking of the vascular endothelial...

  8. 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.

  9. 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.

  10. Methylated free-circulating HPP1 DNA is an early response marker in patients with metastatic colorectal cancer.

    Science.gov (United States)

    Herbst, Andreas; Vdovin, Nikolay; Gacesa, Sanja; Philipp, Alexander; Nagel, Dorothea; Holdt, Lesca M; Op den Winkel, Mark; Heinemann, Volker; Stieber, Petra; Graeven, Ullrich; Reinacher-Schick, Anke; Arnold, Dirk; Ricard, Ingrid; Mansmann, Ulrich; Hegewisch-Becker, Susanna; Kolligs, Frank T

    2017-05-01

    Detection of methylated free-circulating DNA (mfcDNA) for hyperplastic polyposis 1 (HPP1) in blood is correlated with a poor prognosis for patients with metastatic colorectal cancers (mCRC). Here, we analyzed the plasma levels of HPP1 mfcDNA in mCRC patients treated with a combination therapy containing a fluoropyrimidine, oxaliplatin and bevacizumab to test whether HPP1 mfcDNA is a suitable prognostic and response biomarker. From 467 patients of the prospective clinical study AIO-KRK-0207, mfcDNA was isolated from plasma samples at different time points and bisulfite-treated mfcDNA was quantified using methylation specific PCR. About 337 of 467 patients had detectable levels for HPP1 mfcDNA before start of treatment. The detection was significantly correlated with poorer overall survival (OS) (HR = 1.86; 95%CI 1.37-2.53). About 2-3 weeks after the first administration of combination chemotherapy, HPP1 mfcDNA was reduced to non-detectable levels in 167 of 337 patients. These patients showed a better OS compared with patients with continued detection of HPP1 mfcDNA (HR HPP1(sample 1: pos/ sample 2: neg) vs. HPP1(neg/neg) = 1.41; 95%CI 1.00-2.01, HPP1(neg,pos/pos) vs. HPP1(neg/neg) = 2.60; 95%CI 1.86-3.64). Receiver operating characteristic analysis demonstrated that HPP1 mfcDNA discriminates well between patients who do (not) respond to therapy according to the radiological staging after 12 or 24 weeks (AUC = 0.77 or 0.71, respectively). Detection of HPP1 mfcDNA can be used as a prognostic marker and an early marker for response (as early as 3-4 weeks after start of treatment compared with radiological staging after 12 or 24 weeks) to identify patients who will likely benefit from a combination chemotherapy with bevacizumab. © 2017 UICC.

  11. A Novel Computational Tool for Mining Real-Life Data: Application in the Metastatic Colorectal Cancer Care Setting

    Science.gov (United States)

    Siegelmann-Danieli, Nava; Farkash, Ariel; Katzir, Itzhak; Vesterman Landes, Janet; Rotem Rabinovich, Hadas; Lomnicky, Yossef; Carmeli, Boaz; Parush-Shear-Yashuv, Naama

    2016-01-01

    Background 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. Methods 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. Results 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 <0.002; notably, these patients were older). Patients who received both FP-O- and FP-I-based regimens achieved numerically longer OS vs. those who received only one of these regimens (22.1 [19.9–24.0] vs. 18.9 [15.5–21.9] months). Among patients assessed for wild-type KRAS and treated with subsequent anti-EGFR agent, OS was 25.4 months and 18.7 months for 124 treated vs. 37 non-treated patients (non-significant). Cox analysis (controlling for age and gender) identified several non-oncology parameters associated with poorer clinical outcomes including concurrent use of

  12. Comparison of PET metabolic indices for the early assessment of tumour response in metastatic colorectal cancer patients treated by polychemotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Maisonobe, Jacques-Antoine; Necib, Hatem; Buvat, Irene [IMNC UMR 8165 CNRS - Paris 7 and Paris 11 Universities, Orsay Cedex (France); Garcia, Camilo A.; Vanderlinden, Bruno; Flamen, Patrick [Universite Libre de Bruxelles, Department of Nuclear Medicine, Institut Jules Bordet, Brussels (Belgium); Hendlisz, Alain [Universite Libre de Bruxelles, Department of Gastroenterology, Institut Jules Bordet, Brussels (Belgium)

    2013-02-15

    To compare the performance of eight metabolic indices for the early assessment of tumour response in patients with metastatic colorectal cancer (mCRC) treated with chemotherapy. Forty patients with advanced mCRC underwent two FDG PET/CT scans, at baseline and on day 14 after chemotherapy initiation. For each lesion, eight metabolic indices were calculated: four standardized uptake values (SUV) without correction for the partial volume effect (PVE), two SUV with correction for PVE, a metabolic volume (MV) and a total lesion glycolysis (TLG). The relative change in each index between the two scans was calculated for each lesion. Lesions were also classified as responding and nonresponding lesions using the Response Evaluation Criteria In Solid Tumours (RECIST) 1.0 measured by contrast-enhanced CT at baseline and 6-8 weeks after starting therapy. Bland-Altman analyses were performed to compare the various indices. Based on the RECIST classification, ROC analyses were used to determine how accurately the indices predicted lesion response to therapy later seen with RECIST. RECIST showed 27 responding and 74 nonresponding lesions. Bland-Altman analyses showed that the four SUV indices uncorrected for PVE could not be used interchangeably, nor could the two SUV corrected for PVE. The areas under the ROC curves (AUC) were not significantly different between the SUV indices not corrected for PVE. The mean SUV change in a lesion better predicted lesion response without than with PVE correction. The AUC was significantly higher for SUV uncorrected for PVE than for the MV, but change in MV provided some information regarding the lesion response to therapy (AUC >0.5). In these mCRC patients, all SUV uncorrected for PVE accurately predicted the tumour response on day 14 after starting therapy as assessed 4 to 6 weeks later (i.e. 6 to 8 weeks after therapy initiation) using the RECIST criteria. Neither correcting SUV for PVE nor measuring TLG improved the assessment of tumour

  13. The prognostic role of BRAF mutation in metastatic colorectal cancer receiving anti-EGFR monoclonal antibodies: a meta-analysis.

    Directory of Open Access Journals (Sweden)

    Zi-Xu Yuan

    Full Text Available BACKGROUND: BRAF mutation has been investigated as a prognostic factor in metastatic colorectal cancer (mCRC undergoing anti-EGFR monoclonal antibodies (moAbs, but current results are still inconclusive. The aim of this meta-analysis was to evaluate the relationship between BRAF mutation status and the prognosis of mCRC patients treated with moAbs. METHODS: Eligible studies were identified by systematically searching Pubmed, the Cochrane Library, Web of Knowledge, and OVID. Risk ratio (RR for overall response rate (ORR, Hazard ratios (HRs for Progression free survival (PFS and Overall survival (OS were extracted or calculated. Prespecified subgroup analyses were conducted in KRAS wild-type and in different study types. The source of between-trial variation was explored by sensitivity analyses. Quality assessment was conducted by the Hayden's criteria. RESULTS: A total of twenty one trials including 5229 patients were identified for the meta-analysis. 343 patients displayed BRAF mutations of 4616 (7.4% patients with known BRAF status. Patients with BRAF wild-type (WT showed decreased risks of progression and death with an improved PFS(HR 0.38, 95% confidence intervals 0.29-0.51 and an improved OS (HR 0.35 [0.29-0.42], compared to BRAF mutant. In KRAS WT population, there were even larger PFS benefit (HR 0.29[0.19,0.43] and larger OS benefit (HR 0.26 [0.20,0.35] in BRAF WT. A response benefit for BRAF WT was observed (RR 0.31[0.18,0.53] in KRAS WT patients, but not observed in unselected patients (RR 0.76 [0.43-1.33]. The results were consistent in the subgroup analysis of different study types. Heterogeneity between trials decreased in the subgroup and explained by sensitivity analysis. No publication bias of ORR, PFS and OS were detected. CONCLUSIONS: The results indicate that BRAF mutant is a predictive biomarker for poor prognosis in mCRC patients undergoing anti-EGFR MoAbs therapy, especially in KRAS WT patients. Additional large prospective

  14. Prognostic signiifcance ofthe pre-chemotherapy lymphocyte-to-monocyte ratio inpatients withpreviously untreated metastatic colorectal cancer receiving FOLFOX chemotherapy

    Institute of Scientific and Technical Information of China (English)

    GuiNanLin; PanPanLiu; DongYingLiu; JieWenPeng; JianJunXiao; ZhongJunXia

    2016-01-01

    Background:As a surrogate marker of systemic inlfammation, the lymphocyte‑to‑monocyte ratio (LMR) is an independent prognostic factor for various malignancies. This study investigated the prognostic signiifcance of the pre‑chemotherapy LMR in patients with previously untreated metastatic colorectal cancer (mCRC) receiving chemotherapy. Methods:The present study included newly diagnosed mCRC patients treated between January 2005 and Decem‑ber 2013 with FOLFOX chemotherapy, speciifcally oxaliplatin 180mg/m2 on day 1, with leucovorin 400mg/m2 administered as a 2‑hour infusion before the administration of 5‑lfuorouracil 400mg/m2 as an intravenous bolus injection, and 5‑lfuorouracil 2400mg/m2 as a 46‑h infusion immediately after 5‑lfuorouracil bolus injection. The LMR was calculated as the absolute count of lymphocytes divided by the absolute count of monocytes. COX proportional hazards analysis was performed to evaluate the association of LMR with survival outcomes. Results:A total of 488 patients were included. Patients with high pre‑chemotherapy LMR experienced signiif‑cant improvements in progression‑free survival (PFS, 9.2 vs. 7.6months,P<0.001) and overall survival (OS, 19.4 vs. 16.6months,P<0.001) compared with patients with low pre‑chemotherapy LMR. Subsequent COX multivariate analysis showed that high pre‑chemotherapy LMR (≥3.11) was an independent favorable prognostic factor for PFS and OS. Additionally, patients whose LMR remained high (high–high subgroup), increased (low–high subgroup), or decreased (high–low subgroup) following chemotherapy showed better results in terms of PFS and OS than patients whose LMR remained low (low–low subgroup) after chemotherapy. Conclusions:For patients with previously untreated mCRC receiving FOLFOX chemotherapy, an elevated pre‑chem‑otherapy LMR is an independent favorable prognostic factor for PFS and OS, and changes in the LMR before and after chemotherapy seem to predict the

  15. A Novel Computational Tool for Mining Real-Life Data: Application in the Metastatic Colorectal Cancer Care Setting.

    Directory of Open Access Journals (Sweden)

    Nava Siegelmann-Danieli

    Full Text Available 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 <0.002; notably, these patients were older. Patients who received both FP-O- and FP-I-based regimens achieved numerically longer OS vs. those who received only one of these regimens (22.1 [19.9-24.0] vs. 18.9 [15.5-21.9] months. Among patients assessed for wild-type KRAS and treated with subsequent anti-EGFR agent, OS was 25.4 months and 18.7 months for 124 treated vs. 37 non-treated patients (non-significant. Cox analysis (controlling for age and gender identified several non-oncology parameters associated with poorer clinical outcomes including concurrent use of diuretics and proton

  16. UGT1A1 gene polymorphism: Impact on toxicity and efficacy of irinotecan-based regimens in metastatic colorectal cancer

    Institute of Scientific and Technical Information of China (English)

    Christoph Schulz; Volker Heinemann; Andreas Schalhorn; Nikolas Moosmann; Thomas Zwingers; Stefan Boeck; Clemens Giessen; Hans-Joachim Stemmler

    2009-01-01

    AIM: To investigate the correlation between uridine diphosphate glucuronosyl transferase 1A1 ( UGT1A1) gene polymorphisms and irinotecan-associated side effects and parameters of drug efficacy in patients with metastatic colorectal cancer (mCRC) receiving a lowdose weekly irinotecan chemotherapeutic regimen.METHODS: Genotypes were retrospectively evaluated by gene scan analysis on the ABI 310 sequencer of the TATAA box in the promoter region of the UGT1A1 gene in blood samples from 105 patients who had received 1st line irinotecan-based chemotherapy for mCRC.RESULTS: The distribution of the genotypes was as follows: wild type genotype (WT) ( 6/6) 39.0%,heterozygous genotype ( 6/7) 49.5%, and homozygous genotype ( 7/7) 9.5%. The overall response rate (OR) was similar between patients carrying the ( 6/7, 7/7) or the WT genotype ( 6/6) (44.3% vs 43.2%, P = 0.75).Neither time to progression [(TTP) 8.1 vs 8.2 mo, P = 0.97] nor overall survival [(OS) 21.2 vs 18.9 mo, P = 0.73] differed significantly in patients who carried the ( 6/6) when compared to the ( 6/7, 7/7) genotype. No significant differences in toxicity were observed: Grade 3 and 4 delayed diarrhoea [( 6/7, 7/7) vs ( 6/6); 13.0% vs 6.2%, P =0.08], treatment delays [( 6/7, 7/7) vs ( 6/6); 25.1% vs 19.3%, P = 0.24] or dose reductions [( 6/7, 7/7) vs ( 6/6); 21.5% vs 27.2%, P = 0.07].CONCLUSION: This analysis demonstrates the nonsignificant influence of the UGT1A1 gene polymorphism on efficacy and rate of irinotecan-associated toxicity in mCRC patients receiving low-dose irinotecan based chemotherapy.

  17. Lesion-based detection of early chemosensitivity using serial static FDG PET/CT in metastatic colorectal cancer

    Energy Technology Data Exchange (ETDEWEB)

    Buvat, Irene; Necib, Hatem [IMNC UMR 8165 CNRS - Paris 7 and Paris 11 Universities, Orsay cedex (France); Garcia, Camilo; Wagner, Antoine; Vanderlinden, Bruno; Flamen, Patrick [Universite Libre de Bruxelles, Nuclear Medicine Department, Institut Jules Bordet, Brussels (Belgium); Emonts, Patrick [Universite Libre de Bruxelles, Radiology Department, Institut Jules Bordet, Brussels (Belgium); Hendlisz, Alain [Universite Libre de Bruxelles, Digestive Oncology, Institut Jules Bordet, Brussels (Belgium)

    2012-10-15

    Medical oncology needs early identification of patients that are not responding to systemic therapy. {sup 18}F-Fluorodeoxyglucose (FDG) positron emission tomography (PET) performed before and early during treatment has been proposed for this purpose. However, the best way to assess the change in FDG uptake between two scans has not been identified. We studied cutoff thresholds to identify responding tumours as a function of the method used to measure tumour uptake. The study included 28 metastatic colorectal cancer (mCRC) patients who underwent 2 FDG PET/CT scans (baseline and at day 14 of the first course of polychemotherapy). For 78 tumour lesions, 4 standardized uptake value (SUV) indices were measured: maximum SUV (SUV{sub max}) and mean SUV in a region obtained using an isocontour (SUV{sub 40} {sub %}), with each of these SUV normalized either by the patient body weight (BW) or body surface area (BSA). The per cent change and absolute change in tumour uptake between the baseline and the early PET scans were measured based on these four indices. These changes were correlated to the RECIST 1.0-based response using contrast-enhanced CT at baseline and at 6-8 weeks on treatment. The 78 tumours were classified as non-responding (NRL, n = 58) and responding lesions (RL, n = 20). Receiver-operating characteristic (ROC) curves characterizing the performance in NRL/RL classification using early FDG PET uptake had areas under the curve between 0.75 and 0.84, without significant difference between the indices. The cutoff threshold in FDG uptake per cent change to get a 95 % sensitivity of RL detection depended on the way uptake was measured: -14 % (specificity of 53 %) and -22 % (specificity of 64 %) for SUV{sub max} and SUV{sub 40} {sub %}, respectively. Thresholds expressed as absolute SUV decrease instead of per cent change were less sensitive to the SUV definition: an SUV decline by 1.2 yielded a sensitivity of RL detection of 95 % for SUV{sub max} and SUV{sub 40

  18. Self-Reported Adherence to Trifluridine and Tipiracil Hydrochloride for Metastatic Colorectal Cancer: A Retrospective Cohort Study.

    Science.gov (United States)

    Sugita, Kazuo; Kawakami, Kazuyoshi; Yokokawa, Takashi; Sugisaki, Takahito; Takiguchi, Tomomi; Aoyama, Takeshi; Suzuki, Kenichi; Suenaga, Mitsukuni; Yamaguchi, Kensei; Inoue, Ayaka; Machida, Yoshiaki; Yamaguchi, Toshiharu; Hama, Toshihiro

    2016-01-01

    A novel oral agent that consists of trifluridine and tipiracil hydrochloride (TFTD) has been established as salvage-line treatment for metastatic colorectal cancer (mCRC). Adherence to TFTD is crucial to maintaining appropriate curative effects. This study sought to clarify adherence to TFTD and identify candidate factors deteriorating adherence at our institution. A total of 50 consecutive mCRC patients who received TFTD monotherapy between June 1, 2014 and July 31, 2015 were analyzed in this study. Adherence to TFTD was checked by pharmacists using a self-reported treatment diary and interviewing nonadherents at a pharmaceutical outpatient clinic. The adherence rate was defined as the number of patient intakes per 20 scheduled intakes in one cycle. We retrospectively surveyed the factors from the electronic patient record associated with reduced adherence. We measured relative dose intensity, defined as the dose intensity divided by the initial dose (each in milligrams per square meter per week). Patient characteristics were as follows: males/females, 20/30; median age, 61 years (range, 34-83 years); performance status 0/1, 37/13. Median relative dose intensity of TFTD was 91.0%. Adherence rates were 95.0% for the first cycle of TFTD, 97.3% for the second cycle, 98.0% for the third cycle, and 98.2% for the fourth cycle. Factors associated with deteriorated adherence to TFTD were nausea/vomiting/decreased appetite (27.1%, 23 instances), pain (25.9%, 22 instances), neutropenia (11.8%, 10 instances), and missed dose (4.7%, 4 instances). Increased nonadherence to TFTD was associated with Eastern Cooperative Oncology Group performance status 1, while increased TFTD adherence in the first cycle was associated with prior regimens ≥4. The high frequency of treatment-related gastrointestinal disorder is the main factor affecting adherence to TFTD. Intensive supportive care in the management of these symptoms could assist adequate adherence to TFTD in mCRC patients.

  19. The predictive value of single nucleotide polymorphisms in the VEGF system to the efficacy of first-line treatment with bevacizumab plus chemotherapy in patients with metastatic colorectal cancer : Results from the Nordic ACT trial

    DEFF Research Database (Denmark)

    Hansen, Torben Frøstrup; Christensen, René Depont; Andersen, Rikke Fredslund;

    2012-01-01

    PURPOSE: Bevacizumab and chemotherapy is a common choice for first-line treatment of metastatic colorectal cancer (mCRC). So far, no predictive markers have been identified. The aim was to investigate the possible predictive value of single nucleotide polymorphisms (SNPs) in the vascular endothel...

  20. 5-Fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6 plus sunitinib or bevacizumab as first-line treatment for metastatic colorectal cancer: a randomized Phase IIb study

    Directory of Open Access Journals (Sweden)

    Hecht JR

    2015-06-01

    Full Text Available J Randolph Hecht,1 Edith P Mitchell,2 Takayuki Yoshino,3 Manfred Welslau,4 Xun Lin,5 Edna Chow Maneval,6 Jolanda Paolini,7 Maria Jose Lechuga,7 Albrecht Kretzschmar8  1David Geffen School of Medicine at UCLA, Santa Monica, CA, 2Kimmel Cancer Center of Thomas Jefferson University, Philadelphia, PA, USA; 3National Cancer Center Hospital East, Chiba, Japan; 4Onkologische Praxis Klausmann/Welslau, Aschaffenburg, Germany; 5Pfizer Oncology, La Jolla, 6Seragon Pharmaceuticals, San Diego, CA, USA; 7Pfizer Oncology, Milan, Italy; 8Klinikum St Georg, Leipzig, Germany 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

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

    Science.gov (United States)

    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%.

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  3. Regorafenib: A novel tyrosine kinase inhibitor: A brief review of its therapeutic potential in the treatment of metastatic colorectal carcinoma and advanced gastrointestinal stromal tumors

    Directory of Open Access Journals (Sweden)

    P Thangaraju

    2015-01-01

    Full Text Available Regorafenib is a novel oral multitargeted tyrosine kinase inhibitor having both antitumor and anti-angiogenic activities. Regorafenib was recently approved by US Food and Drug Administration in February 25, 2013 in the treatment for patients with advanced gastrointestinal stromal tumor and for the treatment of patients with metastatic colorectal carcinoma after disease progression or intolerance to imatinib mesylate and sunitinib therapy. Oral regorafenib demonstrates a high level of efficacy with acceptable tolerability with the 160 mg daily for 3 weeks followed by 1 week off schedule; a continuous schedule could be of interest. Hypertension, mucositis, hand foot skin reaction, diarrhea and asthenia are the most common side-effects. Regardless of these encouraging results, studies investigating, adjuvant and neoadjuvant settings are awaited, as well as trials using regorafenib in combination with chemotherapy or other targeted therapies. Clinical trials investigating regorafenib in other tumor types are ongoing.

  4. Assessment of the topoisomerase I gene copy number as a predictive biomarker of objective response to irinotecan in metastatic colorectal cancer

    DEFF Research Database (Denmark)

    Nygård, Sune Boris; Christensen, Ib Jarle; Nielsen, Signe Lykke;

    2014-01-01

    Abstract Objective. DNA topoisomerase I is a putative biomarker of irinotecan efficacy with clinical associations previously demonstrated at the protein level. The purpose of the present study was to perform the first clinical investigation of the association between the DNA topoisomerase I gene...... (TOP1) copy number and objective response following irinotecan treatment in patients with metastatic colorectal cancer. Materials and methods. Formalin-fixed, paraffin-embedded tumor samples from 78 patients, who received irinotecan monotherapy in second line, were included. TOP1 was assessed....... Despite limitations of the study the positive associations between TOP1 and objective response suggest that further analysis in larger tumor material, preferably in a randomized setting, is highly warranted....

  5. Tissue MicroRNAs as Predictors of Outcome in Patients with Metastatic Colorectal Cancer Treated with First Line Capecitabine and Oxaliplatin with or without Bevacizumab

    DEFF Research Database (Denmark)

    Boisen, Mogens K; Dehlendorff, Christian; Linnemann, Dorte

    2014-01-01

    PURPOSE: We tested the hypothesis that expression of microRNAs (miRNAs) in cancer tissue can predict effectiveness of bevacizumab added to capecitabine and oxaliplatin (CAPEOX) in patients with metastatic colorectal cancer (mCRC). EXPERIMENTAL DESIGN: Patients with mCRC treated with first line...... CAPEOX and bevacizumab (CAPEOXBEV): screening (n = 212) and validation (n = 121) cohorts, or CAPEOX alone: control cohort (n = 127), were identified retrospectively and archival primary tumor samples were collected. Expression of 754 miRNAs was analyzed in the screening cohort using polymerase chain...... with bevacizumab effectiveness. The effects were strongest for OS. Both miRNAs showed high expression in stromal cells. Higher expression of miR-196b-5p and miR-592 predicted improved outcome regardless of bevacizumab treatment, with similar effect estimates in all three cohorts. CONCLUSIONS: We have identified...

  6. A phase II study of Epirubicin in oxaliplatin-resistant patients with metastatic colorectal cancer and TOP2A gene amplification

    DEFF Research Database (Denmark)

    Tarpgaard, Line S.; Qvortrup, Camilla; Nygård, Sune Boris

    2016-01-01

    UNLABELLED: ᅟ: The overall purpose of this study is to provide proof of concept for introducing the anthracycline epirubicin as an effective, biomarker-guided treatment for metastatic colorectal cancer (mCRC) patients who are refractory to treatment with oxaliplatin-based chemotherapy and have TOP2......A gene amplification in their tumor cells. BACKGROUND: Epirubicin is an anthracycline that targets DNA topoisomerase 2-α enzyme encoded by the TOP2A gene. It is used for treatment of several malignancies, but currently not in CRC. TOP2A gene amplifications predict improved efficacy of epirubicin...... in patients with breast cancer and thus could be an alternative option for patients with CRC and amplified TOP2A gene. We have previously analysed the frequency of TOP2A gene aberrations in CRC and found that 46.6 % of these tumors had TOP2A copy gain and 2.0 % had loss of TOP2A when compared to adjacent...

  7. Early tumour shrinkage (ETS) and depth of response (DpR) in the treatment of patients with metastatic colorectal cancer (mCRC).

    Science.gov (United States)

    Heinemann, Volker; Stintzing, Sebastian; Modest, Dominik P; Giessen-Jung, Clemens; Michl, Marlies; Mansmann, Ulrich R

    2015-09-01

    Response evaluation criteria in solid tumours (RECIST) are used to define degrees of response to anti-tumour agents. In retrospective analyses, early tumour shrinkage (ETS) has been investigated as an alternative early-on-treatment predictor of treatment efficacy with regard to progression-free and overall survival. While cut-off based analysis of ETS facilitates the categorisation of patients into responders and non-responders after a defined period of treatment, depth of response (DpR) serves as a continuous measure, which defines the nadir of tumour response. A systematic literature search for 'early tumour shrinkage' or 'tumour size decrease' in 'metastatic colorectal cancer' reported from January 2000 to July 2014 was performed. The present review summarises available data concerning ETS and DpR and evaluates their potential as predictive markers for the clinical management of patients with metastatic colorectal cancer (mCRC). A total of 10 clinical trials investigated the role of ETS as a marker of clinical outcome in patients with mCRC. In addition, DpR was investigated using the efficacy data from three of these trials. Available data show that ETS differentiates patients with high sensitivity to treatment and more favourable prognosis from a heterogeneous group of patients classified as non-ETS patients. ETS is an early indicator of the potentially achievable response. In contrast, DpR estimates the nadir of tumour response as a continuous measure, which may affect the subsequent disease history, thus translating into superior survival. The concepts of ETS and DpR offer potential as clinical end-points to aid the clinical decision making process and thus further optimise mCRC patient management in the era of tailored therapy approaches. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. 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

    Energy Technology Data Exchange (ETDEWEB)

    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.)

  9. 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.

  10. Phase I/II Trial of Labetuzumab Govitecan (Anti-CEACAM5/SN-38 Antibody-Drug Conjugate) in Patients With Refractory or Relapsing Metastatic Colorectal Cancer.

    Science.gov (United States)

    Dotan, Efrat; Cohen, Steven J; Starodub, Alexander N; Lieu, Christopher H; Messersmith, Wells A; Simpson, Pamela S; Guarino, Michael J; Marshall, John L; Goldberg, Richard M; Hecht, J Randolph; Wegener, William A; Sharkey, Robert M; Govindan, Serengulam V; Goldenberg, David M; Berlin, Jordan D

    2017-08-17

    Purpose The objectives were to evaluate dosing schedules of labetuzumab govitecan, an antibody-drug conjugate targeting carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) for tumor delivery of 7-ethyl-10-hydroxycamptothecin (SN-38), in an expanded phase II trial of patients with relapsed or refractory metastatic colorectal cancer. Patients and Methods Eligible patients with at least one prior irinotecan-containing therapy received labetuzumab govitecan once weekly at 8 and 10 mg/kg, or two times per week at 4 and 6 mg/km on weeks 1 and 2 of 3-week repeated cycles. End points were safety, response, pharmacokinetics, and immunogenicity. Results Eighty-six patients who had undergone a median of five prior therapies (range, one to 13) were each enrolled into one of the four cohorts. On the basis of Response Evaluation Criteria in Solid Tumors 1.1, 38% of these patients had a tumor as well as plasma carcinoembryonic antigen reduction from baseline after labetuzumab govitecan treatment; one patient achieved a partial response with a sustained response spanning > 2 years, whereas 42 patients had stable disease as the best overall response. Median progression-free survival and overall survival were 3.6 and 6.9 months, respectively. The major toxicities (grade ≥ 3) among all cohorts were neutropenia (16%), leukopenia (11%), anemia (9%), and diarrhea (7%). The antibody-drug conjugate's mean half-life was 16.5 hours for the four cohorts. Anti-drug/anti-antibody antibodies were not detected. The two once-weekly dose schedules, showing comparable toxicity and efficacy, were chosen for further study. Conclusion Monotherapy with labetuzumab govitecan demonstrated a manageable safety profile and therapeutic activity in heavily pretreated patients with metastatic colorectal cancer, all with prior irinotecan therapy. Further studies of labetuzumab govitecan treatment alone or in combination with other therapies in earlier settings are indicated.

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

    Directory of Open Access Journals (Sweden)

    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.

  12. Target hepatic artery regional chemotherapy and bevacizumab perfusion in liver metastatic colorectal cancer after failure of first-line or second-line systemic chemotherapy.

    Science.gov (United States)

    Chen, Hui; Zhang, Ji; Cao, Guang; Liu, Peng; Xu, Haifeng; Wang, Xiaodong; Zhu, Xu; Gao, Song; Guo, Jianhai; Zhu, Linzhong; Zhang, Pengjun

    2016-02-01

    Colorectal cancer liver metastasis (CRLM) is a refractory disease after failure of first-line or second-line chemotherapy. Bevacizumab is recommended as first-line therapy for advanced colorectal cancer, but is unproven in CRLM through the hepatic artery. We report favorable outcomes with targeted vessel regional chemotherapy (TVRC) for liver metastatic gastric cancer. TVRC with FOLFOX and bevacizumab perfusion through the hepatic artery was attempted for CRLM for efficacy and safety evaluation. In a single-institution retrospective observational study, 246 patients with CRLM after at least first-line or second-line failure of systemic chemotherapy received TVRC with FOLFOX (i.e. oxaliplatin, leucovorin, and 5-fluorouracil). Of 246 patients, 63 were enrolled into two groups: group 1 (n=30) received bevacizumab and TVRC following tumor progression during previous TVRC treatments; group 2 (n=33) received TVRC plus bevacizumab for CRLM on initiating TVRC. There were no significant differences in the median survival time (14.7 vs. 13.2 months, P=0.367), although the median time to progression was significant (3.3 vs. 5.5 months, P=0.026) between groups. No severe adverse events related to TVRC plus bevacizumab perfusion occurred. Target vessel regional chemotherapy with FOLFOX plus bevacizumab perfusion through the hepatic artery was effective and safe in CRLM. The optimal combination of TVRC and bevacizumab needs further confirmation in future phase II-III clinical trials.

  13. Meta-analysis comparing maintenance strategies with continuous therapy and complete chemotherapy-free interval strategies in the treatment of metastatic colorectal cancer.

    Science.gov (United States)

    Zhao, Lei; Wang, Jing; Li, Huihui; Che, Juanjuan; Cao, Bangwei

    2016-05-31

    There is as yet no consensus as to the best choice among the three treatment options (maintenance, complete chemotherapy-free intervals [CFIs], and continuous) for metastatic colorectal cancer (CRC). We performed a meta-analysis of six trials (N = 2, 454 patients) to compare the safety and efficacy of those three treatment strategies. Maintenance appeared to offer an advantage over CFI with respect to progression-free survival (PFS) (hazard ratio [HR]: 0.53, 95% confidence interval [CI], 0.40-0.69). PFS and overall survival (OS) were comparable between the maintenance and continuous strategies (HR: 1.18, 95% CI, 0.96-1.46; HR: 1.05, 95% CI, 0.98-1.27, respectively), as was OS between the maintenance and CFI strategies (HR: 0.84; 95% CI, 0.70-1.00). The incidence of grade 3/4 toxicity, including neutropenia, neuropathy, hand-foot syndrome and fatigue, was lower with maintenance than with continuous therapy. A maintenance regimen utilizing bevacizumab-based doublets appeared to confer a slight advantage over bevacizumab monotherapy with respect to PFS (P = 0.011). Maintenance appeared to reduce cumulative grade 3/4 toxicity as compared to the continuous strategy, while showing comparable efficacy. Bevacizumab-based doublets appeared to be of particular value in patients with metastatic CRC.

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

    Directory of Open Access Journals (Sweden)

    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.

  15. Retrospective exploratory analysis of VEGF polymorphisms in the prediction of benefit from first-line FOLFIRI plus bevacizumab in metastatic colorectal cancer

    Directory of Open Access Journals (Sweden)

    Manzoni Mariangela

    2011-06-01

    Full Text Available Abstract Background Molecular predictors of bevacizumab efficacy in colorectal cancer have not been identified yet. Specific VEGF polymorphisms may affect gene transcription and therefore indirectly influence the efficacy of bevacizumab. Methods Genomic DNA of 111 consecutive metastatic colorectal cancer patients treated with first-line FOLFIRI plus bevacizumab was obtained from blood samples. VEGF -2578 C/A, -1498 C/T, + 405 C/G, + 936 C/T polymorphisms were analyzed by means of PCR-RFLP. DNA samples from 107 patients treated with FOLFIRI alone served as historical control group. The relation of VEGF polymorphisms with PFS, evaluated through Kaplan-Meier method and log-rank test, was the primary end-point. An interaction test with a Cox model has been performed in order to demonstrate the heterogeneity of the effect of VEGF -1498 C/T polymorphism between bevacizumab-and control group. Results In the bevacizumab-group median PFS and OS of patients carrying VEGF -1498 C/C, C/T and T/T allelic variants were, respectively, 12.8, 10.5, 7.5 months (p = 0.0046, log-rank test and 27.3, 20.5, 18.6 months (p = 0.038, log-rank test. VEGF -1498 T/T genotype was associated with shorter PFS (HR = 2.13, [1.41-5.10], p = 0.0027. In the control group no significant association of VEGF -1498 C/T allelic variants and PFS or OS was found. Interaction between VEGF -1498 C/T variants and treatment effect suggested that the relation of VEGF -1498 T/T genotype with shorter PFS was caused by the effect of bevacizumab (p = 0.011. Other investigated polymorphisms did not affect the outcome. Conclusions These data suggest a possible role for VEGF -1498 C/T variants in predicting the efficacy of bevacizumab in the up-front treatment of metastatic colorectal cancer patients. A molecular tool for selecting subjects candidate to benefit from the anti-VEGF could be important for clinical practice. The retrospective and exploratory design of the present study, coupled with the

  16. Comparison of treatment outcome in metastatic colorectal cancer patients included in a clinical trial versus daily practice in The Netherlands

    NARCIS (Netherlands)

    Mol, L.; Koopman, M.; Gils, C.W. van; Ottevanger, P.B.; Punt, C.J.A.

    2013-01-01

    Abstract The external validity of trial results is a matter of debate, and no strong evidence is available to support whether a trial may have a positive or a negative effect on the outcome of patients. Methods. We compared the results of stage IV colorectal cancer patients treated within a large

  17. 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

    Directory of Open Access Journals (Sweden)

    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

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

    Directory of Open Access Journals (Sweden)

    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

  19. Surgical technique of hepatectomy for metastatic colorectal cancer by Da Vinci surgical system%机器人辅助腹腔镜结直肠癌肝转移手术中的肝切除技术

    Institute of Scientific and Technical Information of China (English)

    张煊; 胡明根; 刘荣

    2014-01-01

    目的:探讨达芬奇机器人手术系统在结直肠癌肝转移中的肝切除技术。方法回顾性分析我中心自2011年5月至2013年12月应用达芬奇机器人手术系统对4例结直肠癌肝转移患者行肝切除手术的临床资料。结果通过该系统,所有患者均成功完成手术。其中2例为单独切除肝转移瘤,2例为同期切除结肠原发灶及肝转移瘤。手术时间为210~510 min。术中失血量100~900 ml,输血1例。术后未发生并发症。术后住院时间8~15 d。结论达芬奇机器人手术系统能够安全有效地完成结直肠癌肝转移的微创外科手术。%Objective To evaluate the technique of hepatectomy for metastatic colorectal cancer by Da Vinci surgical system. Methods Between May 2011 and Dec 2013, 4 patients underwent robotic liver resection for metastatic colorectal cancer at the PLA General Hospital and were analyzed retrospectively. Results The robotic surgeries were performed successfully on all the patients. Among the 4 surgeries, 2 patients underwent synchronous resection the colorectal cancer and liver metastatic tumor and 2 patients underwent hepatectomy of liver metastatic tumor. The operative time was 210~510 min.Intraoperative blood loss ranged from 100~900 ml and blood transfusions were required in 1 patients. The postoperative course was uneventful. The postoperative hospital stay was 8 ~15 days.Conclusions The minimally invasive surgery for hepatectomy for metastatic colorectal cancer was safe and feasible when assisted by the Da Vinci surgical system. Robotics offers a new technical option for minimally invasive hepatectomy for metastatic colorectal cancer.

  20. Efficacy of trifluridine and tipiracil (TAS-102) versus placebo, with supportive care, in a randomized, controlled trial of patients with metastatic colorectal cancer from Spain: results of a subgroup analysis of the phase 3 RECOURSE trial

    OpenAIRE

    Longo-Muñoz, F.; Argiles, G.; Tabernero, J.; Cervantes, A.; Gravalos, C.; Pericay, C.; Gil-Calle, S.; Mizuguchi, H; Carrato-Mena, A.; Limón, M. L.; Garcia-Carbonero, R.

    2016-01-01

    Purpose TAS-102 is a combination of the thymidine-based nucleoside analog trifluridine and the thymidine phosphorylase inhibitor tipiracil. Efficacy and safety of TAS-102 in patients with metastatic colorectal cancer (mCRC) refractory or intolerant to standard therapies were evaluated in the phase 3 RECOURSE trial. Results of RECOURSE demonstrated significant improvement in overall survival (OS) and progression-free survival (PFS) with TAS-102 versus placebo [hazard ratio (HR) = 0.68 and 0.48...

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

    DEFF Research Database (Denmark)

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

    2015-01-01

    Circulating forms of the urokinase plasminogen activator receptor (uPAR) are associated with prognosis in patients with colorectal cancer. Preclinical studies have shown that uPAR can influence the state of phosphorylation and signalling activity of the epidermal growth factor receptor (EGFR...... 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....

  2. 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

    Directory of Open Access Journals (Sweden)

    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

  3. Efficacy and safety of addition of bevacizumab to FOLFIRI or irinotecan/bolus 5-FU/LV (IFL) in patients with metastatic colorectal cancer

    Science.gov (United States)

    Chen, Ke; Gong, Yinya; Zhang, Qi; Shen, Yanping; Zhou, Taoqi

    2016-01-01

    Abstract Recent studies have paid much attention on the safety of bevacizumab as adjuvant chemotherapy for metastatic colorectal cancer. The aim of this meta-analysis was to study the efficacy and safety of bevacizumab in combination with irinotecan, bolus followed by infusional 5-fluorouracil, and leucovorin (FOLFIRI) and, irinotecan, bolus fluorouracil, leucovorin (IFL) for patients with metastatic colorectal cancer (mCRC). An electronic search of related trials was conducted from PubMed, EMBASE, Cochrane Library databases. Risk ratio (RRs) and its 95% confidence intervals (95% CIs) were calculated by using either DerSimonian–Laird method or Mantel–Haenszel method according to the heterogeneity of included articles. The risk of mortality, therapeutic efficacy, and adverse effect were meta-analyzed. In total, 6 RCTs including 2165 participants (1109 in the treatment group, 1056 in the control group) were included in this meta-analysis. Compared with FOLFIRI-panitumumab/cetuximab, the bevacizumab addition significantly reduced the complete response (CR) rate (RR [95%CI] = 0.31[0.11, 0.89], P = 0.03) and the risk of grade 3/4 adverse event (RR [95%CI] = 0.89[0.80, 0.98], P = 0.01). Compared with FOLFIRI and IFL alone, the addition of bevacizumb significantly increased the partial response (PR) and objective response (OR) rates. Compared with IFL alone, the addition of bevacizumb significantly reduced the mortality risk of PFS (RR [95%CI] = 0.53[0.42, 0.66], P < 0.00001) and OS (RR[95%CI] = 0.70[0.60, 0.82], P < 0.00001), but increased the risk of adverse events (RR[95%CI] = 1.14[1.06, 1.21], P = 0.0002). Combination chemotherapy of bevacizumab plus FOLFIRI or IFL had a relative high efficacy and acceptable safety for treatment of mCRC. PMID:27861344

  4. Safety and Efficacy of Trifluridine/Tipiracil Monotherapy in Clinical Practice for Patients With Metastatic Colorectal Cancer: Experience at a Single Institution.

    Science.gov (United States)

    Kotani, Daisuke; Shitara, Kohei; Kawazoe, Akihito; Fukuoka, Shota; Kuboki, Yasutoshi; Bando, Hideaki; Okamoto, Wataru; Kojima, Takashi; Doi, Toshihiko; Ohtsu, Atsushi; Yoshino, Takayuki

    2016-09-01

    The combination drug TAS-102 is a novel oral nucleoside antitumor agent containing trifluridine and tipiracil hydrochloride, which prevents the degradation of trifluridine. The global phase III RECOURSE trial (Study of TAS-102 in Patients With Metastatic Colorectal Cancer Refractory to Standard Chemotherapies) demonstrated that TAS-102 prolonged the survival of patients with metastatic colorectal cancer (mCRC) whose disease progressed after standard therapies. TAS-102 was first approved in Japan in March 2014, and little is known about its safety and efficacy in clinical practice, especially for mCRC patients with previous regorafenib treatment. We investigated the safety and efficacy of TAS-102 monotherapy in clinical practice for patients with mCRC refractory to standard therapies who were treated from May 2014 to January 2015. A total of 55 patients received TAS-102. The Eastern Cooperative Oncology Group performance status was 0, 1, and 2 in 41.8%, 47.3%, and 10.9% of patients. Of the 55 patients, 32 (58.2%) had been treated with regorafenib before receiving TAS-102. The median progression-free survival and overall survival was 2.0 months and 5.3 months, respectively. Emergency hospitalization was required for 23.6% of the patients during TAS-102 treatment, although most of the events (76.9%) were disease-related. The most common grade 3 or 4 adverse events were neutropenia (41.8%), leukopenia (27.2%), anemia (23.6%), febrile neutropenia (5.5%), and fatigue (3.6%). The frequency of grade ≥ 3 events was not significantly increased among the patients who had compared with those who had not received regorafenib. The progression-free survival (median 2.1 vs. 2.0 months) and overall survival (median 6.2 vs. 4.7 months) were similar for the 2 subgroups. The safety and efficacy of TAS-102 monotherapy in clinical practice were maintained, irrespective of previous regorafenib treatment. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. Randomized study comparing full dose monotherapy (S-1 followed by irinotecan) and reduced dose combination therapy (S-1/oxaliplatin followed by S-1/irinotecan) as initial therapy for older patients with metastatic colorectal cancer: NORDIC 9.

    Science.gov (United States)

    Winther, Stine Braendegaard; Österlund, Pia; Berglund, Åke; Glimelius, Bengt; Qvortrup, Camilla; Sorbye, Halfdan; Pfeiffer, Per

    2017-08-16

    Metastatic colorectal cancer (mCRC) is a disease of older age, but there is a relative lack of knowledge about effects of chemotherapy in older patients as they are under-represented in clinical trials. Little data can guide whether the strategy in older mCRC patients should be a sequential full-dose monotherapy chemotherapy approach or a dose-reduced combination chemotherapy approach. The oral 5FU prodrug S-1 seems to have less side effects than capecitabine and should be an optimal drug for older patients, but few data are available. Improved geriatric assessments are needed to select which older patients should receive therapy. The NORDIC 9 trial is a Nordic multicenter randomized phase II study comparing full dose monotherapy (S-1 30 mg/m(2) twice daily days 1-14 every 3 weeks, followed by second line irinotecan 250-350 mg/m(2) iv day 1 every 3 weeks or 180-250 mg/m(2) iv day 1 every 2 weeks) with reduced dose combination therapy (S-1 20 mg/m(2) days 1-14 + oxaliplatin 100 mg/m(2) iv day 1 every 3 weeks, followed by second line S-1 20 mg/m(2) days 1-14 + irinotecan 180 mg/m(2) day 1 every 3 week) for older patients (≥70 years) with mCRC who are not candidates for full-dose standard combination therapy. Additional bevacizumab (7.5 mg/kg) is optional in first-line. Blood samples and tumor tissue will be collected to investigate predictive markers. Geriatric screening tools (G-8, VES-13, Timed-Up-and-Go and Handgrip strength), Charlson Comorbidty Index and quality of life (EORTC QLQ-C30) will be evaluated as predictors of efficacy and toxicity. The target sample size is 150 patients. The primary endpoint is progression-free survival and secondary endpoints are time-to-failure of strategy, overall survival, response rate, toxicity, and correlations between biomarkers, pre-treatment characteristics and geriatric assessments. The study will add knowledge on how to treat older mCRC patients who are not candidates for standard combination therapy

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

    Directory of Open Access Journals (Sweden)

    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

  7. Transcatheter arterial chemoembolization of colorectal liver metastases using degradable starch microspheres (Spherex {sup registered}). Own investigations and review to the literature; Transarterielle Chemoembolisation von Lebermetastasen kolorektaler Karzinome mit abbaubaren Staerkepartikeln (Spherex {sup registered}). Eigene Beobachtungen und Literaturuebersicht

    Energy Technology Data Exchange (ETDEWEB)

    Wasser, K. [Universitaetsklinikum Mannheim (Germany). Institut fuer Klinische Radiologie; Giebel, F. [Universitaetsklinikum Koeln (Germany). Klinik fuer Anaesthesiologie und Operative Intensivmedizin; Fischbach, R. [Universitaetsklinkum Muenster (Germany). Institut fuer Klinische Radiologie; Tesch, H. [Universitaetsklinikum Koeln (Germany). Medizinische Klinik I; Onkologische Gemeinschaftspraxis, Frankfurt (Germany); Landwehr, P. [Henriettenstiftung Hannover (Germany). Klinik fuer Diagnostische und interventionelle Radiologie

    2005-07-01

    Since two decades transarterial chemoembolization (TACE) of liver metastases has been investigated in numerous studies. However, no standardized therapeutic procedure exists so far. The present study retrospectively investigated survival, response and side effects after TACE of liver metastases in 21 patients with colorectal cancer and results are compared with previous literature. A total of 68 TACE procedures were performed. A suspension of degradable starch microspheres (DSM, Spherex {sup registered}) and Mitomycin C was applied selectively into hepatic arteries via a transfemoral approach. DSM effect a temporary arterial occlusion. Follow-up studies were performed by contrast enhanced spiral computed tomography (CT). The median survival was 13.8 months. Therapeutic response (according to WHO) was observed only in three patients. The progression free interval was 5.8 months. Patients developed a postembolization-syndrome (abdominal pain, fever, nausea) and increased transaminases in 27-43% of all interventions. A gastric ulcer occurred after four, cholecystitis after two TACE. As already shown in most previous studies, regardless of the used agents, also this investigation underlines the moderate therapeutic effect of TACE on colorectal liver metastases. So far, no significant survival benefit has been shown in the literature and the response rates are rather limited. In general, complications of TACE seem to be rare, but should not to be underestimated. Compared to TACE with long or permanent arterial occlusion, postembolization syndrome seems to be less pronounced using DSM. As TACE is rather a palliative therapeutic approach, DSM therefore might be more suited. Further studies on TACE of liver metastases should focus on to the patients' quality of life. (orig.) [German] Seit Beginn der 80er Jahre ist die transarterielle Chemoembolisation (TACE) von Lebermetastasen Gegenstand zahlreicher Studien, ohne dass sich bisher ein einheitliches Therapiekonzept

  8. Comparative Label-free LC-MS/MS Analysis of Colorectal Adenocarcinoma and Metastatic Cells Treated with 5-Fluorouracil

    OpenAIRE

    Bauer, Kerry M.; Lambert, Paul A.; Hummon, Amanda B.

    2012-01-01

    A label-free mass spectrometric strategy was used to examine the effect of 5-fluorouracil (5-FU) on the primary and metastatic colon carcinoma cell lines, SW480 and SW620, with and without treatment. 5-FU is the most common chemotherapeutic treatment for colon cancer. Pooled biological replicates were analyzed by nanoLC-MS/MS and protein quantification was determined via spectral counting. Phenotypic and proteomic changes were evident and often similar in both cell lines. The SW620 cells were...

  9. Diffusion-weighted magnetic resonance imaging predicts survival in patients with liver-predominant metastatic colorectal cancer shortly after selective internal radiation therapy

    Energy Technology Data Exchange (ETDEWEB)

    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.)

  10. Comparison of the quantification of KRAS mutations by digital PCR and E-ice-COLD-PCR in circulating-cell-free DNA from metastatic colorectal cancer patients.

    Science.gov (United States)

    Sefrioui, David; Mauger, Florence; Leclere, Laurence; Beaussire, Ludivine; Di Fiore, Frédéric; Deleuze, Jean-François; Sarafan-Vasseur, Nasrin; Tost, Jörg

    2017-02-01

    Circulating cell-free DNA (ccfDNA) bears great promise as biomarker for personalized medicine, but ccfDNA is present only at low levels in the plasma or serum of cancer patients. E-ice-COLD-PCR is a recently developed enrichment method to detect and identify mutations present at low-abundance in clinical samples. However, recent studies have shown the importance to accurately quantify low-abundance mutations as clinically important decisions will depend on certain mutation thresholds. The possibility for an enrichment method to accurately quantify the mutation levels remains a point of concern and might limit its clinical applicability. In the present study, we compared the quantification of KRAS mutations in ccfDNA from metastatic colorectal cancer patients by E-ice-COLD-PCR with two digital PCR approaches. For the quantification of mutations by E-ice-COLD-PCR, cell lines with known mutations diluted into WT genomic DNA were used for calibration. E-ice-COLD-PCR and the two digital PCR approaches showed the same range of the mutation level and were concordant for mutation levels below the clinical relevant threshold. E-ice-COLD-PCR can accurately detect and quantify low-abundant mutations in ccfDNA and has a shorter time to results making it compatible with the requirements of analyses in a clinical setting without the loss of quantitative accuracy. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  11. Age-dependent improvement in median and long-term survival in unselected population-based Nordic registries of patients with synchronous metastatic colorectal cancer.

    Science.gov (United States)

    Sorbye, H; Cvancarova, M; Qvortrup, C; Pfeiffer, P; Glimelius, B

    2013-09-01

    In metastatic colorectal cancer (mCRC) trials, median survival has increased from 6 months to above 20 months during the previous decades. Uncertainty exists in how this survival improvement has translated to the general mCRC population. Survival data from patients with synchronous mCRC were collected from the Norwegian (1980-2008), Swedish (1996-2008) and Danish (2001-09) cancer registries. A total of 29 628 patients were identified. From 1980-1985 to 2006-2008, median survival increased from 5 to 10 months for Norwegian patients. Three-year survival increased from 7% to 21% and 5-year survival from 4% to 9%. For patients 75 years of age. An increase in median and long-term survival over time was found in unselected population-based registries of patients with synchronous mCRC. The improved outcome in survival was especially seen in younger patients, raising concerns over our ability to adapt available treatment options for elderly patients.

  12. Circadian rhythm in rest and activity: a biological correlate of quality of life and a predictor of survival in patients with metastatic colorectal cancer

    Science.gov (United States)

    Innominato, Pasquale F.; Focan, Christian; Gorlia, Thierry; Moreau, Thierry; Garufi, Carlo; Waterhouse, Jim; Giacchetti, Sylvie; Coudert, Bruno; Iacobelli, Stefano; Genet, Dominique; Tampellini, Marco; Chollet, Philippe; Lentz, Marie-Ange; Mormont, Marie-Christine; Lévi, Francis; Bjarnason, Georg A.

    2009-01-01

    The rest/activity circadian rhythm (CircAct) reflects the function of the circadian timing system (CTS). In a prior single-institution study, the extent of CircAct perturbation independently predicted for survival and tumor response in 192 patients receiving chemotherapy for metastatic colorectal cancer (MCRC). Moreover, the main CircAct parameters correlated with several quality of life (HRQoL) scales. In this prospective study we attempted to extend these results to an independent cohort of chemotherapy-naïve MCRC patients participating in an international randomized phase III trial (EORTC 05963). Patients were randomized to receive chronomodulated or conventional infusion of 5-fluorouracil, leucovorin and oxaliplatin as first line treatment for MCRC. Patients from nine institutions completed the EORTC QLQ-C30, and wore a wrist-accelerometer (actigraph) for 3 days before chemotherapy delivery. Two validated parameters (I|0.25|, p<0.01). I

  13. Clinical practice guidelines for the management of metastatic colorectal cancer: a consensus statement of the Hellenic Society of Medical Oncologists (HeSMO).

    Science.gov (United States)

    Dervenis, Christos; Xynos, Evaghelos; Sotiropoulos, George; Gouvas, Nikolaos; Boukovinas, Ioannis; Agalianos, Christos; Androulakis, Nikolaos; Athanasiadis, Athanasios; Christodoulou, Christos; Chrysou, Evangelia; Emmanouilidis, Christos; Georgiou, Panagiotis; Karachaliou, Niki; Katopodi, Ourania; Kountourakis, Panteleimon; Kyriazanos, Ioannis; Makatsoris, Thomas; Papakostas, Pavlos; Papamichael, Demetris; Pechlivanides, George; Pentheroudakis, Georgios; Pilpilidis, Ioannis; Sgouros, Joseph; Tekkis, Paris; Triantopoulou, Charina; Tzardi, Maria; Vassiliou, Vassilis; Vini, Louiza; Xynogalos, Spyridon; Ziras, Nikolaos; Souglakos, John

    2016-01-01

    There is discrepancy and failure to adhere to current international guidelines for the management of metastatic colorectal cancer (CRC) in hospitals in Greece and Cyprus. The aim of the present document is to provide a consensus on the multidisciplinary management of metastastic CRC, considering both special characteristics of our Healthcare System and international guidelines. Following discussion and online communication among the members of an executive team chosen by the Hellenic Society of Medical Oncology (HeSMO), a consensus for metastastic CRC disease was developed. Statements were subjected to the Delphi methodology on two voting rounds by invited multidisciplinary international experts on CRC. Statements reaching level of agreement by ≥80% were considered as having achieved large consensus, whereas statements reaching 60-80% moderate consensus. One hundred and nine statements were developed. Ninety experts voted for those statements. The median rate of abstain per statement was 18.5% (range: 0-54%). In the end of the process, all statements achieved a large consensus. The importance of centralization, care by a multidisciplinary team, adherence to guidelines, and personalization is emphasized. R0 resection is the only intervention that may offer substantial improvement in the oncological outcomes.

  14. Comprehensive models of human primary and metastatic colorectal tumors in immunodeficient and immunocompetent mice by chemokine targeting.

    Science.gov (United States)

    Chen, Huanhuan Joyce; Sun, Jian; Huang, Zhiliang; Hou, Harry; Arcilla, Myra; Rakhilin, Nikolai; Joe, Daniel J; Choi, Jiahn; Gadamsetty, Poornima; Milsom, Jeff; Nandakumar, Govind; Longman, Randy; Zhou, Xi Kathy; Edwards, Robert; Chen, Jonlin; Chen, Kai Yuan; Bu, Pengcheng; Wang, Lihua; Xu, Yitian; Munroe, Robert; Abratte, Christian; Miller, Andrew D; Gümüş, Zeynep H; Shuler, Michael; Nishimura, Nozomi; Edelmann, Winfried; Shen, Xiling; Lipkin, Steven M

    2015-06-01

    Current orthotopic xenograft models of human colorectal cancer (CRC) require surgery and do not robustly form metastases in the liver, the most common site clinically. CCR9 traffics lymphocytes to intestine and colorectum. We engineered use of the chemokine receptor CCR9 in CRC cell lines and patient-derived cells to create primary gastrointestinal (GI) tumors in immunodeficient mice by tail-vein injection rather than surgery. The tumors metastasize inducibly and robustly to the liver. Metastases have higher DKK4 and NOTCH signaling levels and are more chemoresistant than paired subcutaneous xenografts. Using this approach, we generated 17 chemokine-targeted mouse models (CTMMs) that recapitulate the majority of common human somatic CRC mutations. We also show that primary tumors can be modeled in immunocompetent mice by microinjecting CCR9-expressing cancer cell lines into early-stage mouse blastocysts, which induces central immune tolerance. We expect that CTMMs will facilitate investigation of the biology of CRC metastasis and drug screening.

  15. 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

  16. Robust evidence for long-term survival with {sup 90}Y radioembolization in chemorefractory liver-predominant metastatic colorectal cancer

    Energy Technology Data Exchange (ETDEWEB)

    Jakobs, T.F. [Barmherzige Brueder Munich, Department of Diagnostic and Interventional Radiology, Munich (Germany); Paprottka, K.J.; Raessler, F.; Strobl, F.; Trumm, C.G.; Sommer, W.; Paprottka, P.M. [LMU - University of Munich, Department of Clinical Radiology, Munich (Germany); Lehner, S.; Ilhan, H.; Fendler, W.P. [LMU - University of Munich, Department of Nuclear Medicine, Munich (Germany)

    2017-01-15

    Our aim was to provide further evidence for the efficacy/safety of radioembolization using yttrium-90-resin microspheres for unresectable chemorefractory liver metastases from colorectal cancer (mCRC). We followed 104 consecutively treated patients until death. Overall survival (OS) was calculated from the day of the first radioembolization procedure. Response was defined by changes in tumour volume as defined by Response Evaluation Criteria in Solid Tumours (RECIST) v1.0 and/or a ≥30 % reduction in serum carcinoembryonic antigen (CEA) at 3 months. Survival varied between 23 months in patients who had a complete response to prior chemotherapy and 13 months in patients with a partial response or stable disease. Median OS also significantly improved (from 5.8 months to 17.1 months) if response durability to radioembolization extended beyond 6 months. Patients with a positive trend in CEA serum levels (≥30 % reduction) at 3 months post-radioembolization also had a survival advantage compared with those who did not: 15.0 vs 6.7 months. Radioembolization was well tolerated. Grade 3 increases in bilirubin were reported in 5.0 % of patients at 3 months postprocedure. After multiple chemotherapies, many patients still have a good performance status and are eligible for radioembolization. This single procedure can achieve meaningful survivals and is generally well tolerated. (orig.)

  17. Sinusoidal obstruction syndrome (veno-occlusive disease in a patient receiving bevacizumab for metastatic colorectal cancer: a case report

    Directory of Open Access Journals (Sweden)

    Agarwal Vijay

    2008-07-01

    Full Text Available Abstract Introduction We present the case of a patient with colon cancer who, while receiving bevacizumab, developed sinusoidal obstruction syndrome (veno-occlusive disease (SOSVOD. Certain antitumour agents such as 6-mercaptopurine and 6-thioguanine have also been reported to initiate hepatic SOSVOD in isolated cases. There have been no reports so far correlating bevacizumab with SOSVOD. Case presentation A 77-year-old man was being treated with oxaliplatin and a modified de Gramont regimen of 5-fluorouracil for metastatic colon cancer. Bevacizumab (7.5 mg/kg was added from the seventh cycle onwards. Protracted neutropenia and thrombocytopenia led to discontinuation of oxaliplatin after the ninth cycle. A computed tomography scan showed complete response and bevacizumab was continued for another 3 months, after which time the patient developed right hypochondrial pain, transudative ascites, splenomegaly and abnormal liver function tests. Upper gastrointestinal endoscopy showed oesophageal varices. Liver biopsy showed features considered to be consistent with SOSVOD. Bevacizumab was stopped and a policy of watchful waiting was adopted. He tolerated the acute damage to his liver and subsequently the ascites resolved and liver function tests normalised. Conclusion We need to be aware that bevacizumab can cause sinusoidal obstruction syndrome (veno-occlusive disease and that the occurrence of ascites should not be attributed to progressive disease without appropriate evaluation.

  18. A phase I/II study of biweekly capecitabine and irinotecan plus bevacizumab as second-line chemotherapy in patients with metastatic colorectal cancer

    Directory of Open Access Journals (Sweden)

    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

  19. 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.)

  20. Tissue microRNAs as predictors of outcome in patients with metastatic colorectal cancer treated with first line Capecitabine and Oxaliplatin with or without Bevacizumab.

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    Boisen, Mogens K; Dehlendorff, Christian; Linnemann, Dorte; Nielsen, Boye S; Larsen, Jim S; Osterlind, Kell; Nielsen, Svend E; Tarpgaard, Line S; Qvortrup, Camilla; Pfeiffer, Per; Holländer, Niels H; Keldsen, Nina; Hansen, Torben F; Jensen, Brita B; Høgdall, Estrid V S; Jensen, Benny V; Johansen, Julia S

    2014-01-01

    We tested the hypothesis that expression of microRNAs (miRNAs) in cancer tissue can predict effectiveness of bevacizumab added to capecitabine and oxaliplatin (CAPEOX) in patients with metastatic colorectal cancer (mCRC). Patients with mCRC treated with first line CAPEOX and bevacizumab (CAPEOXBEV): screening (n = 212) and validation (n = 121) cohorts, or CAPEOX alone: control cohort (n = 127), were identified retrospectively and archival primary tumor samples were collected. Expression of 754 miRNAs was analyzed in the screening cohort using polymerase chain reaction (PCR) arrays and expression levels were related to time to disease progression (TTP) and overall survival (OS). Significant miRNAs from the screening study were analyzed in all three cohorts using custom PCR arrays. In situ hybridization (ISH) was done for selected miRNAs. In the screening study, 26 miRNAs were significantly correlated with outcome in multivariate analyses. Twenty-two miRNAs were selected for further study. Higher miR-664-3p expression and lower miR-455-5p expression were predictive of improved outcome in the CAPEOXBEV cohorts and showed a significant interaction with bevacizumab effectiveness. The effects were strongest for OS. Both miRNAs showed high expression in stromal cells. Higher expression of miR-196b-5p and miR-592 predicted improved outcome regardless of bevacizumab treatment, with similar effect estimates in all three cohorts. We have identified potentially predictive miRNAs for bevacizumab effectiveness and additional miRNAs that could be related to chemotherapy effectiveness or prognosis in patients with mCRC. Our findings need further validation in large cohorts, preferably from completed randomized trials.

  1. Tissue microRNAs as predictors of outcome in patients with metastatic colorectal cancer treated with first line Capecitabine and Oxaliplatin with or without Bevacizumab.

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    Mogens K Boisen

    Full Text Available PURPOSE: We tested the hypothesis that expression of microRNAs (miRNAs in cancer tissue can predict effectiveness of bevacizumab added to capecitabine and oxaliplatin (CAPEOX in patients with metastatic colorectal cancer (mCRC. EXPERIMENTAL DESIGN: Patients with mCRC treated with first line CAPEOX and bevacizumab (CAPEOXBEV: screening (n = 212 and validation (n = 121 cohorts, or CAPEOX alone: control cohort (n = 127, were identified retrospectively and archival primary tumor samples were collected. Expression of 754 miRNAs was analyzed in the screening cohort using polymerase chain reaction (PCR arrays and expression levels were related to time to disease progression (TTP and overall survival (OS. Significant miRNAs from the screening study were analyzed in all three cohorts using custom PCR arrays. In situ hybridization (ISH was done for selected miRNAs. RESULTS: In the screening study, 26 miRNAs were significantly correlated with outcome in multivariate analyses. Twenty-two miRNAs were selected for further study. Higher miR-664-3p expression and lower miR-455-5p expression were predictive of improved outcome in the CAPEOXBEV cohorts and showed a significant interaction with bevacizumab effectiveness. The effects were strongest for OS. Both miRNAs showed high expression in stromal cells. Higher expression of miR-196b-5p and miR-592 predicted improved outcome regardless of bevacizumab treatment, with similar effect estimates in all three cohorts. CONCLUSIONS: We have identified potentially predictive miRNAs for bevacizumab effectiveness and additional miRNAs that could be related to chemotherapy effectiveness or prognosis in patients with mCRC. Our findings need further validation in large cohorts, preferably from completed randomized trials.

  2. Role of Kras status in patients with metastatic colorectal cancer receiving first-line chemotherapy plus bevacizumab: a TTD group cooperative study.

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    Díaz-Rubio, Eduardo; Gómez-España, Auxiliadora; Massutí, Bartomeu; Sastre, Javier; Reboredo, Margarita; Manzano, José Luis; Rivera, Fernando; Safont, M José; Montagut, Clara; González, Encarnación; Benavides, Manuel; Marcuello, Eugenio; Cervantes, Andrés; Martínez de Prado, Purificación; Fernández-Martos, Carlos; Arrivi, Antonio; Bando, Inmaculada; Aranda, Enrique

    2012-01-01

    In the MACRO study, patients with metastatic colorectal cancer (mCRC) were randomised to first-line treatment with 6 cycles of capecitabine and oxaliplatin (XELOX) plus bevacizumab followed by either single-agent bevacizumab or XELOX plus bevacizumab until disease progression. An additional retrospective analysis was performed to define the prognostic value of tumour KRAS status on progression-free survival (PFS), overall survival (OS) and response rates. KRAS data (tumour KRAS status and type of mutation) were collected by questionnaire from participating centres that performed KRAS analyses. These data were then cross-referenced with efficacy data for relevant patients in the MACRO study database. KRAS status was analysed in 394 of the 480 patients (82.1%) in the MACRO study. Wild-type (WT) KRAS tumours were found in 219 patients (56%) and mutant (MT) KRAS in 175 patients (44%). Median PFS was 10.9 months for patients with WT KRAS and 9.4 months for patients with MT KRAS tumours (p=0.0038; HR: 1.40; 95% CI:1.12-1.77). The difference in OS was also significant: 26.7 months versus 18.0 months for WT versus MT KRAS, respectively (p=0.0002; HR: 1.55; 95% CI: 1.23-1.96). Univariate and multivariate analyses showed that KRAS was an independent variable for both PFS and OS. Responses were observed in 126 patients (57.5%) with WT KRAS tumours and 76 patients (43.4%) with MT KRAS tumours (p=0.0054; OR: 1.77; 95% CI: 1.18-2.64). This analysis of the MACRO study suggests a prognostic role for tumour KRAS status in patients with mCRC treated with XELOX plus bevacizumab. For both PFS and OS, KRAS status was an independent factor in univariate and multivariate analyses.

  3. Role of Kras status in patients with metastatic colorectal cancer receiving first-line chemotherapy plus bevacizumab: a TTD group cooperative study.

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    Eduardo Díaz-Rubio

    Full Text Available BACKGROUND: In the MACRO study, patients with metastatic colorectal cancer (mCRC were randomised to first-line treatment with 6 cycles of capecitabine and oxaliplatin (XELOX plus bevacizumab followed by either single-agent bevacizumab or XELOX plus bevacizumab until disease progression. An additional retrospective analysis was performed to define the prognostic value of tumour KRAS status on progression-free survival (PFS, overall survival (OS and response rates. METHODOLOGY/PRINCIPAL FINDINGS: KRAS data (tumour KRAS status and type of mutation were collected by questionnaire from participating centres that performed KRAS analyses. These data were then cross-referenced with efficacy data for relevant patients in the MACRO study database. KRAS status was analysed in 394 of the 480 patients (82.1% in the MACRO study. Wild-type (WT KRAS tumours were found in 219 patients (56% and mutant (MT KRAS in 175 patients (44%. Median PFS was 10.9 months for patients with WT KRAS and 9.4 months for patients with MT KRAS tumours (p=0.0038; HR: 1.40; 95% CI:1.12-1.77. The difference in OS was also significant: 26.7 months versus 18.0 months for WT versus MT KRAS, respectively (p=0.0002; HR: 1.55; 95% CI: 1.23-1.96. Univariate and multivariate analyses showed that KRAS was an independent variable for both PFS and OS. Responses were observed in 126 patients (57.5% with WT KRAS tumours and 76 patients (43.4% with MT KRAS tumours (p=0.0054; OR: 1.77; 95% CI: 1.18-2.64. CONCLUSIONS/SIGNIFICANCE: This analysis of the MACRO study suggests a prognostic role for tumour KRAS status in patients with mCRC treated with XELOX plus bevacizumab. For both PFS and OS, KRAS status was an independent factor in univariate and multivariate analyses.

  4. An observational cohort study of bevacizumab and chemotherapy in metastatic colorectal cancer patients: safety and efficacy with analysis by age group.

    Science.gov (United States)

    Tahover, Esther; Hubert, Ayala; Temper, Mark; Salah, Azzam; Peretz, Tamar; Hamburger, Tamar; Uziely, Beatrice

    2015-03-01

    Bevacizumab improves survival when added to chemotherapy in metastatic colorectal cancer (mCRC). We assessed the safety and efficacy of bevacizumab in mCRC patients ≥70 years old (YO) vs. those plus bevacizumab were included. The primary end point was safety; secondary objectives were progression-free survival (PFS) and overall survival (OS). Data was collected retrospectively. Three-hundred eight patients (92 ≥70 YO, 216 bevacizumab-related adverse effects; all were bevacizumab in patients ≥70 YO included hypertension (37.0 %), venous thromboembolism (6.5 %), wound-healing complications (5.4 %), bleeding (7.6 %), fistula (4.3 %), arterial thromboembolism (3.3 %), congestive heart failure (2.2 %), and proteinuria (grades 1-2 only, 14.1 %). Treatment was stopped due to adverse effects in 6.0 % of older patients. Older patients had significantly more ischemic heart disease and hypertension at baseline, and were treated less with FOLFOX and more with 5FU/LV monotherapy; nevertheless, OS and PFS were similar in younger and older patients. Compared to younger patients, in older patients, rates of proteinuria (all grades 1-2) were significantly higher (14.1 vs. 5.6 %, p=0.012) and rates of treatment-related hypertension (grades 3-5) were marginally higher (37 vs. 25.9 %, p=0.053); rates of other adverse events were similar in the two groups. In our patient population, bevacizumab was safe and effective in older as well as younger patients.

  5. Targeting Colorectal Cancer Proliferation, Stemness and Metastatic Potential Using Brassicaceae Extracts Enriched in Isothiocyanates: A 3D Cell Model-Based Study

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    Lucília P. Pereira

    2017-04-01

    Full Text Available Colorectal cancer (CRC recurrence is often attributable to circulating tumor cells and/or cancer stem cells (CSCs that resist to conventional therapies and foster tumor progression. Isothiocyanates (ITCs derived from Brassicaceae vegetables have demonstrated anticancer effects in CRC, however little is known about their effect in CSCs and tumor initiation properties. Here we examined the effect of ITCs-enriched Brassicaceae extracts derived from watercress and broccoli in cell proliferation, CSC phenotype and metastasis using a previously developed three-dimensional HT29 cell model with CSC-like traits. Both extracts were phytochemically characterized and their antiproliferative effect in HT29 monolayers was explored. Next, we performed cell proliferation assays and flow cytometry analysis in HT29 spheroids treated with watercress and broccoli extracts and respective main ITCs, phenethyl isothiocyanate (PEITC and sulforaphane (SFN. Soft agar assays and relative quantitative expression analysis of stemness markers and Wnt/β-catenin signaling players were performed to evaluate the effect of these phytochemicals in stemness and metastasis. Our results showed that both Brassicaceae extracts and ITCs exert antiproliferative effects in HT29 spheroids, arresting cell cycle at G2/M, possibly due to ITC-induced DNA damage. Colony formation and expression of LGR5 and CD133 cancer stemness markers were significantly reduced. Only watercress extract and PEITC decreased ALDH1 activity in a dose-dependent manner, as well as β-catenin expression. Our research provides new insights on CRC therapy using ITC-enriched Brassicaceae extracts, specially watercress extract, to target CSCs and circulating tumor cells by impairing cell proliferation, ALDH1-mediated chemo-resistance, anoikis evasion, self-renewal and metastatic potential.

  6. MicroRNA profiling predicts survival in anti-EGFR treated chemorefractory metastatic colorectal cancer patients with wild-type KRAS and BRAF.

    Science.gov (United States)

    Mosakhani, Neda; Lahti, Leo; Borze, Ioana; Karjalainen-Lindsberg, Marja-Liisa; Sundström, Jari; Ristamäki, Raija; Osterlund, Pia; Knuutila, Sakari; Sarhadi, Virinder Kaur

    2012-11-01

    Anti-EGFR monoclonal antibodies (anti-EGFRmAb) serve in the treatment of metastatic colorectal cancer (mCRC), but patients with a mutation in KRAS/BRAF and nearly one-half of those without the mutation fail to respond. We performed microRNA (miRNA) analysis to find miRNAs predicting anti-EGFRmAb efficacy. Of the 99 mCRC patients, we studied differential miRNA expression by microarrays from primary tumors of 33 patients who had wild-type KRAS/BRAF and third- to sixth-line anti-EGFRmAb treatment, with/without irinotecan. We tested the association of each miRNA with overall survival (OS) by the Cox proportional hazards regression model. Significant miR-31* up-regulation and miR-592 down-regulation appeared in progressive disease versus disease control. miR-31* expression and down-regulation of its target genes SLC26A3 and ATN1 were verified by quantitative reverse transcriptase polymerase chain reaction. Clustering of patients based on miRNA expression revealed a significant difference in OS between patient clusters. Members of the let-7 family showed significant up-regulation in the patient cluster with poor OS. Additionally, miR-140-5p up-regulation and miR-1224-5p down-regulation were significantly associated with poor OS in both cluster analysis and the Cox proportional hazards regression model. In mCRC patients with wild-type KRAS/BRAF, miRNA profiling can efficiently predict the benefits of anti-EGFRmAb treatment. Larger series of patients are necessary for application of these miRNAs as predictive/prognostic markers.

  7. BRAF V600E mutation and resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer: a meta-analysis.

    Science.gov (United States)

    Mao, Chen; Liao, Ru-Yan; Qiu, Li-Xin; Wang, Xi-Wen; Ding, Hong; Chen, Qing

    2011-04-01

    Epidemiologic studies have evaluated the association between BRAF mutations and resistance to the treatment of anti-EGFR monoclonal antibodies (MoAb) in patients with metastatic colorectal cancer (mCRC). However, the results are still inconclusive. To derive a more precise estimation of the relationship, we performed this meta-analysis. A total of 11 studies were included in the final meta-analysis. There were seven studies for unselected mCRC patients and four studies for patients with wild type KRAS mCRC. Among unselected mCRC patients, BRAF V600E mutation was detected in 48 of 546 primary tumors (8.8%). The objective response rate (ORR) of patients with mutant BRAF was 29.2% (14/48), whereas the ORR of patients with wild-type BRAF was 33.5% (158/472).The overall RR for ORR of mutant BRAF patients over wild-type BRAF patients was 0.86 (95% CI=0.57-1.30; P=0.48). For patients with KRAS wild-type mCRC, BRAF V600E mutation was detected in 40 of 376 primary tumors (10.6%). The ORR of patients with mutant BRAF was 0.0% (0/40), whereas the ORR of patients with wild-type BRAF was 36.3% (122/336). The pooled RR of mutant BRAF patients over wild-type BRAF patients was 0.14 (95% CI=0.04-0.53; P=0.004). In conclusion, this meta-analysis provides evidence that BRAF V600E mutation is associated with lack of response in wild-type KRAS mCRC treated with anti-EGFR MoAbs. BRAF mutation may be used as an additional biomarker for the selection of mCRC patients who might benefit from anti-EGFR MoAbs therapy.

  8. Beyond KRAS mutation status: influence of KRAS copy number status and microRNAs on clinical outcome to cetuximab in metastatic colorectal cancer patients

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    Mekenkamp Leonie JM

    2012-07-01

    Full Text Available Abstract Background KRAS mutation is a negative predictive factor for treatment with anti-epidermal growth factor receptor (EGFR antibodies in metastatic colorectal cancer (mCRC. Novel predictive markers are required to further improve the selection of patients for this treatment. We assessed the influence of modification of KRAS by gene copy number aberration (CNA and microRNAs (miRNAs in correlation to clinical outcome in mCRC patients treated with cetuximab in combination with chemotherapy and bevacizumab. Methods Formalin-fixed paraffin-embedded primary tumour tissue was used from 34 mCRC patients in a phase III trial, who were selected based upon their good (n = 17 or poor (n = 17 progression-free survival (PFS upon treatment with cetuximab in combination with capecitabine, oxaliplatin, and bevacizumab. Gene copy number at the KRAS locus was assessed using high resolution genome-wide array CGH and the expression levels of 17 miRNAs targeting KRAS were determined by real-time PCR. Results Copy number loss of the KRAS locus was observed in the tumour of 5 patients who were all good responders including patients with a KRAS mutation. Copy number gains in two wild-type KRAS tumours were associated with a poor PFS. In KRAS mutated tumours increased miR-200b and decreased miR-143 expression were associated with a good PFS. In wild-type KRAS patients, miRNA expression did not correlate with PFS in a multivariate model. Conclusions Our results indicate that the assessment of KRAS CNA and miRNAs targeting KRAS might further optimize the selection of mCRC eligible for anti-EGFR therapy.

  9. Nanofluidic Digital PCR and Extended Genotyping of RAS and BRAF for Improved Selection of Metastatic Colorectal Cancer Patients for Anti-EGFR Therapies.

    Science.gov (United States)

    Azuara, Daniel; Santos, Cristina; Lopez-Doriga, Adriana; Grasselli, Julieta; Nadal, Marga; Sanjuan, Xavier; Marin, Fátima; Vidal, Joana; Montal, Robert; Moreno, Victor; Bellosillo, Beatriz; Argiles, Guillem; Elez, Elena; Dienstmann, Rodrigo; Montagut, Clara; Tabernero, Josep; Capellá, Gabriel; Salazar, Ramon

    2016-05-01

    The clinical significance of low-frequent RAS pathway-mutated alleles and the optimal sensitivity cutoff value in the prediction of response to anti-EGFR therapy in metastatic colorectal cancer (mCRC) patients remains controversial. We aimed to evaluate the added value of genotyping an extended RAS panel using a robust nanofluidic digital PCR (dPCR) approach. A panel of 34 hotspots, including RAS (KRAS and NRAS exons 2/3/4) and BRAF (V600E), was analyzed in tumor FFPE samples from 102 mCRC patients treated with anti-EGFR therapy. dPCR was compared with conventional quantitative PCR (qPCR). Response rates, progression-free survival (PFS), and overall survival (OS) were correlated to the mutational status and the mutated allele fraction. Tumor response evaluations were not available in 9 patients and were excluded for response rate analysis. Twenty-two percent of patients were positive for one mutation with qPCR (mutated alleles ranged from 2.1% to 66.6%). Analysis by dPCR increased the number of positive patients to 47%. Mutated alleles for patients only detected by dPCR ranged from 0.04% to 10.8%. An inverse correlation between the fraction of mutated alleles and radiologic response was observed. ROC analysis showed that a fraction of 1% or higher of any mutated alleles offered the best predictive value for all combinations of RAS and BRAF analysis. In addition, this threshold also optimized prediction both PFS and OS. We conclude that mutation testing using an extended gene panel, including RAS and BRAF with a threshold of 1% improved prediction of response to anti-EGFR therapy. Mol Cancer Ther; 15(5); 1106-12. ©2016 AACR.

  10. A high LDL-C to HDL-C ratio predicts poor prognosis for initially metastatic colorectal cancer patients with elevations in LDL-C.

    Science.gov (United States)

    Liao, Fangxin; He, Wenzhuo; Jiang, Chang; Yin, Chenxi; Guo, Guifang; Chen, Xuxian; Qiu, Huijuan; Rong, Yuming; Zhang, Bei; Xu, Dazhi; Xia, Liangping

    2015-01-01

    Although lipid disequilibrium has been documented for several types of cancer including colorectal cancer (CRC), it remains unknown whether lipid parameters are associated with the outcome of metastatic CRC (mCRC) patients. Here, we retrospectively examined the lipid profiles of 453 mCRC patients and investigated whether any of the lipid parameters correlated with the outcome of mCRC patients. Pretreatment serum lipids, including triglyceride, cholesterol, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), were collected in 453 initially mCRC patients. The LDL-C to HDL-C ratio (LHR) was calculated and divided into the first, second, and third tertiles. Univariate and multivariate analyses were performed to evaluate the impact of lipids on overall survival (OS) and progression-free survival (PFS). Nearly two-fifths of the patients (41.3%) exhibited elevations in LDL-C while most patients (88.3%) showed normal HDL-C levels. Decreased HDL-C (P=0.542) and increased LDL-C (P=0.023) were prognostic factors for poor OS, while triglyceride (P=0.542) and cholesterol (P=0.215) were not. Multivariate analysis revealed that LDL-C (P=0.031) was an independent prognostic factor. Triglyceride, cholesterol, HDL-C, and LDL-C did not correlate with PFS. Among patients with elevations in LDL-C levels, patients in the third tertile of the LHR had a markedly shorter median OS compared to those in the first or second tertile (P=0.012). Thus, increased LDL-C level is an independent prognostic factor for poor prognosis in mCRC patients, and a high LHR predicts poor prognosis for initially mCRC patients with elevations in LDL-C.

  11. Geriatric factors analyses from FFCD 2001-02 phase III study of first-line chemotherapy for elderly metastatic colorectal cancer patients.

    Science.gov (United States)

    Aparicio, Thomas; Gargot, Dany; Teillet, Laurent; Maillard, Emilie; Genet, Dominique; Cretin, Jacques; Locher, Christophe; Bouché, Olivier; Breysacher, Gilles; Seitz, Jean-François; Gasmi, Mohamed; Stefani, Laetitia; Ramdani, Mohamed; Lecomte, Thierry; Auby, Dominique; Faroux, Roger; Bachet, Jean-Baptiste; Lepère, Céline; Khemissa, Faiza; Sobhani, Iradj; Boulat, Olivier; Mitry, Emmanuel; Jouve, Jean-Louis

    2017-03-01

    Several predictors of metastatic colorectal cancer (mCRC) outcomes have been described. Specific geriatric characteristics could be of interest to determine prognosis. Elderly patients (75+) with previously untreated mCRC were randomly assigned to receive infusional 5-fluorouracil-based chemotherapy, either alone (FU) or in combination with irinotecan (IRI). Geriatric evaluations were included as an optional procedure. The predictive value of geriatric parameters was determined for the objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). From June 2003 to May 2010, the FFCD 2001-02 randomised trial enrolled 282 patients. A baseline geriatric evaluation was done in 123 patients; 62 allocated to the FU arm and 61 to the IRI arm. The baseline Charlson index was ≤1 in 75%, Mini-Mental State Examination was ≤27/30 in 31%, Geriatric Depression Scale was >2 in 10% and Instrumental Activities of Daily Living (IADL) was impaired in 34% of the patients. Multivariate analyses revealed that no geriatric parameter was predictive for ORR or PFS. Normal IADL was independently associated with better OS. The benefit of doublet chemotherapy on PFS differed in subgroups of patients ≤80 years, with unresected primary tumour, leucocytes >11,000 mm(3) and carcinoembryonic antigen >2N. There was a trend towards better OS in patients with normal IADL. The autonomy score was an independent predictor for OS. A trend toward a better efficacy of doublet chemotherapy in some subgroups of patients was reported and should be further explored. Copyright © 2016 Elsevier Ltd. All rights reserved.

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

    Science.gov (United States)

    Rasmussen, Mads H; Jensen, Niels F; Tarpgaard, Line S; Qvortrup, Camilla; Rømer, Maria U; Stenvang, Jan; Hansen, Tine P; Christensen, Lise L; Lindebjerg, Jan; Hansen, Flemming; Jensen, Benny V; Hansen, Torben F; Pfeiffer, Per; Brünner, Nils; Ørntoft, Torben F; Andersen, Claus L

    2013-06-01

    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 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 others, high expression of miR-625-3p, miR-181b and miR-27b to be associated with poor clinical response. In a validation cohort of 94 mCRC patients treated first-line with XELOX, high expression of miR-625-3p was confirmed to be associated with poor response (OR = 6.25, 95%CI [1.8; 21.0]). Independent 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 HCT116/oxPt (miR-625-3p, miR-181b and miR-27b) and LoVo/oxPt (miR-181b) colon cancer cell lines as compared with their isogenic parental cells. Altogether, our results suggest an association between miR-625-3p and response to first-line oxaliplatin based chemotherapy of mCRC.

  13. Preoperative prediction and prevention of intraoperative acute liver failure after major liver resection for metastatic colorectal cancer

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    A. D. Kaprin

    2016-01-01

    Full Text Available Objective: improve the results of treatment of patients with metastatic cancer of liver by reducing the risk of post-resection liver failure based on the assessment of liver functional reserve.Materials and methods. The study included 2 independent samples of patients underwent surgery for liver metastases in the department of abdominal oncology at the P. A. Herzen Moscow Oncological Research Institute. Group 1 included 47 patients: in addition to the standard treatment algorithm they underwent 13C methacetin breath test and dynamic scintigraphy of liver in the preoperative stage. Patients from the group 2 (n = 30 underwent standard clinical and laboratory examination, without preoperative evaluation of liver functional reserves; the level of total bilirubin, albumin and prothrombin time showed no decrease in liver function. Post-resection liver failure was established based on 50/50 criterion when evaluated on the 5th postoperative day.Results. The analysis of operational characteristics of functional tests showed absolute sensitivity of 13C methacetin breath test (SE ≥ 100 % and negative predictive value (–VP ≥ 100 % in case of integrated application of 2 diagnostic methods. An incidence of post-resection acute liver failure in the study group was significantly 2.2-fold lower than in the control group – 10.6 % and 23.3 %, respectively (p < 0.001.Conclusion. Combination of preoperative dynamic scintigraphy of liver with 13C methacetin breath test allows to perform comprehensive assessment of liver functional reserves, and it can greatly improve preoperative assessment and postoperative results of anatomic resections in patients with liver metastases.

  14. Creactive protein and interleukin-6 as markers of systemic inflammatory response and as prognostic factors for metastatic colorectal cancer. Data from the randomized phase III NORDIC-VII study

    DEFF Research Database (Denmark)

    Thomsen, M.; Kersten, C.; Sorbye, H.

    2015-01-01

    Background: A systemic inflammatory response (SIR) affects prognosis and treatment outcome in metastatic colorectal cancer (mCRC). The aim of the study was to explore the prognostic significance of several SIR-derived markers and the correlation between the best marker of SIR and plasma interleukin...... correlated (r = 0.661, p 60 mg/L, the different groups showed a median overall survival (OS) of 24.3, 20.6,17.1 and 12.3 months, respectively (HR = 1.34, 95% CI 1...

  15. SLCO1B1 and SLC19A1 gene variants and irinotecan-induced rapid response and survival: a prospective multicenter pharmacogenetics study of metastatic colorectal cancer.

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    Liu Huang

    Full Text Available BACKGROUND: Rapid response to chemotherapy in metastatic colorectal cancer (mCRC patients (response within 12 weeks of chemotherapy may increase the chance of complete resection and improved survival. Few molecular markers predict irinotecan-induced rapid response and survival. Single-nucleotide polymorphisms (SNPs in solute carrier genes are reported to correlate with the variable pharmacokinetics of irinotecan and folate in cancer patients. This study aims to evaluate the predictive role of 3 SNPs in mCRC patients treated with irinotecan and fluoropyrimidine-containing regimens. MATERIALS AND METHODS: Three SNPs were selected and genotyped in 137 mCRC patients from a Chinese prospective multicenter trial (NCT01282658. The chi-squared test, univariate and multivariable logistic regression model, and receiver operating characteristic analysis were used to evaluate correlations between the genotypes and rapid response. Kaplan-Meier survival analysis and Cox proportional hazard models were used to evaluate the associations between genotypes and survival outcomes. Benjamini and Hochberg False Discovery Rate correction was used in multiple testing. RESULTS: Genotype GA/AA of SNP rs2306283 of the gene SLCO1B1 and genotype GG of SNP rs1051266 of the gene SLC19A1 were associated with a higher rapid response rate (odds ratio [OR] =3.583 and 3.521, 95%CI =1.301-9.871 and 1.271-9.804, p=0.011 and p=0.013, respectively. The response rate was 70% in patients with both genotypes, compared with only 19.7% in the remaining patients (OR = 9.489, 95%CI = 2.191-41.093, Fisher's exact test p=0.002. Their significances were all maintained even after multiple testing (all p c < 0.05. The rs2306283 GA/AA genotype was also an independent prognostic factor of longer progression-free survival (PFS (hazard ratio = 0.402, 95%CI = 0.171-0.945, p=0.037. None of the SNPs predicted overall survival. CONCLUSIONS: Polymorphisms of solute carriers' may be useful to predict rapid

  16. Panitumumab Use in Metastatic Colorectal Cancer and Patterns of KRAS Testing: Results from a Europe-Wide Physician Survey and Medical Records Review.

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    Jörg Trojan

    Full Text Available From 2008-2013, the European indication for panitumumab required that patients' tumor KRAS exon 2 mutation status was known prior to starting treatment. To evaluate physician awareness of panitumumab prescribing information and how physicians prescribe panitumumab in patients with metastatic colorectal cancer (mCRC, two European multi-country, cross-sectional, observational studies were initiated in 2012: a physician survey and a medical records review. The first two out of three planned rounds for each study are reported.The primary objective in the physician survey was to estimate the prevalence of KRAS testing, and in the medical records review, it was to evaluate the effect of test results on patterns of panitumumab use. The medical records review study also included a pathologists' survey.In the physician survey, nearly all oncologists (299/301 were aware of the correct panitumumab indication and the need to test patients' tumor KRAS status before treatment with panitumumab. Nearly all oncologists (283/301 had in the past 6 months of clinical practice administered panitumumab correctly to mCRC patients with wild-type KRAS status. In the medical records review, 97.5% of participating oncologists (77/79 conducted a KRAS test for all of their patients prior to prescribing panitumumab. Four patients (1.3% did not have tumor KRAS mutation status tested prior to starting panitumumab treatment. Approximately one-quarter of patients (85/306 were treated with panitumumab and concurrent oxaliplatin-containing chemotherapy; of these, 83/85 had confirmed wild-type KRAS status prior to starting panitumumab treatment. All 56 referred laboratories that participated used a Conformité Européenne-marked or otherwise validated KRAS detection method, and nearly all (55/56 participated in a quality assurance scheme.There was a high level of knowledge amongst oncologists around panitumumab prescribing information and the need to test and confirm patients

  17. EGFR gene copy number as a predictive biomarker for the treatment of metastatic colorectal cancer with anti-EGFR monoclonal antibodies: a meta-analysis

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    Yang Zu-Yao

    2012-08-01

    Full Text Available Abstract Background Epidermal growth factor receptor gene copy number (EGFR GCN has been heavily investigated as a potential predictive biomarker for the treatment of metastatic colorectal cancer (mCRC with anti-EGFR monoclonal antibodies (MAbs. The objective of this study was to systematically review current evidences on this issue. Methods PubMed, EMBASE, The Cochrane Library, Chinese Biomedical Literature Database, Wanfang Data, and the conference abstracts of American Society of Clinical Oncology and European Society of Medical Oncology were comprehensively searched. Studies that reported the objective response rate (ORR, progression-free survival, and/or overall survival of mCRC patients treated with anti-EGFR MAbs, stratified by EGFR GCN status, were included. The effect measures for binary outcome (response and time-to-event outcomes (progression-free survival and overall survival were risk difference and hazard ratio, respectively. Statistical heterogeneity among the studies was assessed by the Cochran’s Q-test and the I2 statistic. If appropriate, a quantitative synthesis of data from different studies would be conducted with a random-effects model. Results Nineteen eligible studies were identified. The criteria for increased EGFR GCN (GCN+ were highly inconsistent across different studies. The prevalence of GCN + ranged from 6.9% to 88.9%, and the difference in ORR between patients with GCN + and those with non-increased EGFR GCN (GCN- varied from −28% to 84%. Because of the significant heterogeneity, no quantitative synthesis of data was performed. There was a general trend towards higher ORR in patients with GCN+. The difference in ORRs between patients with GCN + and those with GCN- was even greater in KRAS wild-type patients, while in KRAS mutated patients the difference often did not exist. Almost all patients with EGFR amplification responded to the treatment. However, the prevalence of EGFR amplification was

  18. Experience with S-1 in older Caucasian patients with metastatic colorectal cancer (mCRC): Findings from an observational chart review.

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    Winther, Stine Braendegaard; Zubcevic, Kanita; Qvortrup, Camilla; Vestermark, Lene Weber; Jensen, Helle Anita; Krogh, Merete; Sorbye, Halfdan; Pfeiffer, Per

    2016-07-01

    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. 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. From June 2012 to December 2014, 71 older patients received ≥1 cycle of either S-1 (n = 9), SOx (n = 44) or IRIS (n = 18) for mCRC. Median age was 76 years and most patients had a WHO performance status of 0 (32%) or 1 (56%). All patients were evaluable for response and safety. In the SOx group, 18 (41%) and 20 patients (45%) had partial response (PR) and stable disease (SD), respectively (disease control rate 86%). Median progression-free survival (PFS) was 8.5 months and median overall survival (OS) was 18.5 months. In the S-1 group (median age 82 years), PR was 22%, median PFS 6.4 months and median OS 15.8 months. In the IRIS group, PR was 28%, median PFS 7.8 months and the median OS 16.5 months. In general, therapy was well tolerated; main non-hematological toxicities were fatigue and diarrhea. S-1 monotherapy, SOx and IRIS were well tolerated for older patients with mCRC and could become alternative regimens in older mCRC patients. These regimens are now further evaluated in the randomized ongoing NORDIC9 trial.

  19. A phase II study of Epirubicin in oxaliplatin-resistant patients with metastatic colorectal cancer and TOP2A gene amplification.

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    Tarpgaard, Line S; Qvortrup, Camilla; Nygård, Sune B; Nielsen, Signe L; Andersen, Diana R; Jensen, Niels Frank; Stenvang, Jan; Detlefsen, Sönke; Brünner, Nils; Pfeiffer, Per

    2016-02-11

    The overall purpose of this study is to provide proof of concept for introducing the anthracycline epirubicin as an effective, biomarker-guided treatment for metastatic colorectal cancer (mCRC) patients who are refractory to treatment with oxaliplatin-based chemotherapy and have TOP2A gene amplification in their tumor cells. Epirubicin is an anthracycline that targets DNA topoisomerase 2-α enzyme encoded by the TOP2A gene. It is used for treatment of several malignancies, but currently not in CRC. TOP2A gene amplifications predict improved efficacy of epirubicin in patients with breast cancer and thus could be an alternative option for patients with CRC and amplified TOP2A gene. We have previously analysed the frequency of TOP2A gene aberrations in CRC and found that 46.6% of these tumors had TOP2A copy gain and 2.0% had loss of TOP2A when compared to adjacent normal tissue. The TOP2A gene is located on chromosome 17 and when the TOP2A/CEN-17 ratio was applied to identify tumors with gene loss or amplifications, 10.5% had a ratio ≥ 1.5 consistent with gene amplification and 2.6% had a ratio ≤ 0.8 suggesting gene deletions. Based on these observations and the knowledge gained from treatment of breast cancer patients, we have initiated a prospective clinical, phase II protocol using epirubicin (90 mg/m2 iv q 3 weeks) in mCRC patients, who are refractory to treatment with oxaliplatin. The study is an open label, single arm, phase II study, investigating the efficacy of epirubicin in patients with oxaliplatin refractory mCRC and with a cancer cell TOP2A/CEN-17 ratio ≥ 1.5. TOP2A gene amplification measured by fluorescence in situ hybridization. A total of 25 evaluable patients (15 + 10 in two steps) will be included (Simon's two-stage minimax design). Every nine weeks, response is measured by computed tomography imaging and evaluated according to RECIST 1.1. The primary end-point of the study is progression-free survival. Eudract no. 2013-001648-79.

  20. Uracil/ftorafur/leucovorin combined with irinotecan (TEGAFIRI) or oxaliplatin (TEGAFOX) as first-line treatment for metastatic colorectal cancer patients: results of randomised phase II study

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    Bajetta, E; Di Bartolomeo, M; Buzzoni, R; Mariani, L; Zilembo, N; Ferrario, E; Lo Vullo, S; Aitini, E; Isa, L; Barone, C; Jacobelli, S; Recaldin, E; Pinotti, G; Iop, A

    2007-01-01

    This randomised phase II study evaluates the safety and efficacy profile of uracil/tegafur/leucovorin combined with irinotecan (TEGAFIRI) or with oxaliplatin (TEGAFOX). One hundred and forty-three patients with measurable, non-resectable metastatic colorectal cancer were randomised in a multicentre study to receive TEGAFIRI (UFT 250 mg m−2 day days 1–14, LV 90 mg day days 1–14, irinotecan 240 mg m−2 day 1; q21) or TEGAFOX (UFT 250 mg m−2 day days 1–14, LV 90 mg day days 1–14, oxaliplatin 120 mg m−2 day 1; q21). Among 143 randomised patients, 141 were analysed (68 received TEGAFIRI and 73 TEGAFOX). The main characteristics of the two arms were well balanced. The most common grade 3–4 treatment-related adverse events were neutropenia (13% of cases with TEGAFIRI; 1% in the TEGAFOX group). Diarrhoea was prevalent in the TEGAFIRI arm (16%) vs TEGAFOX (4%). Six complete remission (CR) and 19 partial remission (PR) were recorded in the TEGAFIRI arm (odds ratio (OR): 41.7; 95% confidence limit (CL), 29.1–55.1%), and six CR and 22 PR were recorded in the TEGAFOX group, (OR: 38.9; 95% CL, 27.6–51.1). At a median time follow-up of 17 months (intequartile (IQ) range 12–23), a median survival probability of 20 and 19 months was obtained in the TEGAFIRI and TEGAFOX groups, respectively. Median time to progression was 8 months for both groups. TEGAFIRI and TEGAFOX are both effective and tolerable first-line therapies in MCRC patients. The employment of UFT/LV given in doublet combination is interesting and the presented data appear comparable to equivalent infusion regimens described in the literature. The safety profile of the two combinations also allows an evaluation with other biological agents such as monoclonal antibodies. PMID:17245343

  1. Predictive value of VEGF gene polymorphisms for metastatic colorectal cancer patients receiving first-line treatment including fluorouracil, irinotecan, and bevacizumab.

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    Formica, Vincenzo; Palmirotta, Raffaele; Del Monte, Girolamo; Savonarola, Annalisa; Ludovici, Giorgia; De Marchis, Maria Laura; Grenga, Italia; Schirru, Michele; Guadagni, Fiorella; Roselli, Mario

    2011-02-01

    The aim of this study is to evaluate the influence of germline vascular endothelial growth factor (VEGF) gene polymorphisms (VGPs) on the efficacy of the anti-VEGF antibody bevacizumab (Bev) in metastatic colorectal cancer (MCRC) patients. Forty MCRC patients eligible for a first-line therapy were enrolled in this prospective trial and treated with FOLinate/Fluorouracil/Irinotecan (FOLFIRI) + Bev (male/female = 22:18, age (median) = 61 years). Eight VGPs within the promoter/5'UTR region were evaluated in patient blood samples. Primary endpoint was association between VGPs and median progression-free survival (mPFS). Overall radiological response rate (ORR), overall survival (OS), and toxicity were assessed as secondary outcomes. VGPs -2578, -1512, -1451, -1411, and -460 were in complete linkage disequilibrium and therefore analyzed as haplotype (two variants: Haplo1: A-18 bp insertion-T-4G-C and Haplo2: C-18 bp deletion-C-5G-T, respectively). Seventeen patients Haplo2/Haplo2 had significantly shorter mPFS compared to 23 patients Haplo1/Haplo1 or Haplo1/Haplo2 (mPFS, 9 vs. 15.4 months, respectively, p = 0.02; hazard ratio (HR), 2.64). Also, VGPs -152 (G/G vs. G/A + A/A) and -1154 (G/G vs. G/A + A/A) were significantly associated with PFS (mPFS, 8.9 vs. 15.4 months, p = 0.007; HR, 3.53 and 9.8 vs. 16 months, p = 0.03, HR, 2.32, respectively). In the multivariate analysis including also biochemical variables known to influence prognosis, VGP -1154 retained an independent predictive value for mPFS (G/G over G/A + A/A = HR, 4.43; p = 0.02). With regard to ORR, only VGP -634 was significantly associated with response (G/G vs. G/C + C/C = 64% vs. 14%, p = 0.03). No significant influence on OS and toxicity by the investigated VGPs was observed. Although these data need to be confirmed in larger trials, investigation of germline VGPs may help identify patients who are more sensitive to anti-VEGF agents.

  2. Initial LDH level can predict the survival benefit from bevacizumab in the first-line setting in Chinese patients with metastatic colorectal cancer

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    Yin CX

    2014-08-01

    Full Text Available Chenxi Yin,1,2,* Chang Jiang,1,2,* Fangxin Liao,1,2 Yuming Rong,1,2 Xiuyu Cai,1,2 Guifang Guo,1,2 Huijuan Qiu,1,2 Xuxian Chen,1,2 Bei Zhang,1,2 Wenzhuo He,1,2 Liangping Xia1,2 1State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer, Medicine, 2VIP Region, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People’s Republic of China *These authors contributed equally to this paper Background: Markers to predict the efficacy of bevacizumab treatment have been not fully validated in most cancers, including metastatic colorectal cancer (mCRC. The aim of this study was to investigate the potential role of lactate dehydrogenase (LDH in predicting the survival benefit from first-line bevacizumab treatment, in Chinese patients with mCRC. Methods: All the patients were diagnosed with mCRC at the Sun Yat-sen University Cancer Center from 2003 to 2013. The study group and the control group were classified by receiving bevacizumab or not. The serum LDH value of all the patients had been detected before the first-line treatment. The primary end point was progression-free survival (PFS. Results: The median PFS of the study and the control group (patients who received bevacizumab or not was 11.3 and 9.1 months, respectively (P=0.004. In the control group, the median PFS of the high LDH level and the low LDH level groups was 6.9 and 10.2 months, respectively (P<0.001. However, in the study group, the corresponding median PFS was 9.9 and 11.9 months, respectively (P=0.145. In addition, for the low LDH level group, the median PFS was 11.9 and 10.2 months for patients who received bevacizumab or not, respectively (P=0.066; however, the median PFS of patients receiving bevacizumab or not was significantly different in the high LDH level group (9.9 and 6.9 months, respectively (P=0.012. Conclusion: The addition of bevacizumab in the first-line treatment setting could improve the

  3. Chemotherapy induced neutropenia at 1-month mark is a predictor of overall survival in patients receiving TAS-102 for refractory metastatic colorectal cancer: a cohort study.

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    Kasi, Pashtoon M; Kotani, Daisuke; Cecchini, Michael; Shitara, Kohei; Ohtsu, Atsushi; Ramanathan, Ramesh K; Hochster, Howard S; Grothey, Axel; Yoshino, Takayuki

    2016-07-13

    TAS-102 (trifluridine and tipiracil hydrochloride; a novel combination oral nucleoside anti-tumor agent) has recently received regulatory approval for patients with refractory metastatic colorectal cancer (mCRC). Internal review of data at a single-institution showed a trend towards better overall survival (OS) for patients who experienced chemotherapy-induced neutropenia at 1-month (CIN-1-month). To explore this finding further, a cohort study was designed based on outcome data from three centers in United States and one from Japan. CIN-1-month after starting TAS-102 was defined by the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03 as a neutrophil count decrease of ≥ grade 2 (absolute neutrophil count < 1500/mm(3)). Patients had confirmed mCRC that was refractory to standard therapies. Patient demographics and clinical characteristics were compared between patients with CIN-1-month (CIN-1-month positive) versus those who did not have CIN-1-month (CIN-1-month negative); with the median progression-free survival (PFS) and OS were calculated using the Kaplan-Meier method, and differences evaluated using the Log-rank test. Our cohort study had a total of 149 patients with data regarding their neutrophil assessment at 1-month mark. Patients who developed ≥ grade 2 CIN-1-month had a both longer PFS (median 3.0 months versus 2.4 months; Log-rank P-value = 0.01), as well as OS (14.0 versus 5.6 months; Log-rank P-value < 0.0001). Only CIN-1-month (adjusted HR: 0.21 (95 % CI: 0.11-0.38) and higher baseline CEA levels (adjusted HR: 2.00 (95 % CI: 1.22-3.35) were noted to be independent predictors of OS. Furthermore, the CIN-1-month was noted to be a statistically significantly predictor of OS over a wide range of cutoffs. Our observations are novel and hypothesis generating. Neutropenia after starting TAS-102 was associated with better prognosis in patients with refractory mCRC. It can be postulated that the dosage of TAS

  4. Danish Colorectal Cancer Group Database

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    Ingeholm P

    2016-10-01

    Full Text Available Peter Ingeholm,1,2 Ismail Gögenur,1,3 Lene H Iversen1,4 1Danish Colorectal Cancer Group Database, Copenhagen, 2Department of Pathology, Herlev University Hospital, Herlev, 3Department of Surgery, Roskilde University Hospital, Roskilde, 4Department of Surgery P, Aarhus University Hospital, Aarhus C, Denmark Aim of database: 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. Study population: All Danish patients with newly diagnosed colorectal cancer who are either diagnosed or treated in a surgical department of a public Danish hospital. Main variables: 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. Descriptive data: 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 <2% since 2013. Conclusion: The database is a national population-based clinical database with high patient and data completeness for the perioperative period

  5. Maintenance Therapy With Cetuximab Every Second Week in the First-Line Treatment of Metastatic Colorectal Cancer: The NORDIC-7.5 Study by the Nordic Colorectal Cancer Biomodulation Group.

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    Pfeiffer, Per; Sorbye, Hafdan; Qvortrup, Camilla; Karlberg, Mia; Kersten, Christian; Vistisen, Kirsten; Lindh, Birgitta; Bjerregaard, Jon Kroll; Glimelius, Bengt

    2015-09-01

    In the NORDIC-7.5 trial, how cetuximab might safely and conveniently be added to an intermittent treatment strategy in patients with prospectively selected Kirsten rat sarcoma viral oncogene homolog wild type (KRASwt) metastatic colorectal cancer (mCRC) was investigated. Patients were treated in a multicenter phase II trial with cetuximab in combination with the Nordic bolus FLOX (oxaliplatin, 5-fluorouracil, and folinic acid) for 4 months followed by maintenance cetuximab. Patients had KRASwt, nonresectable mCRC, no previous chemotherapy, and Eastern Cooperative Group performance status of 0 to 2. Patients received 8 courses of Nordic FLOX (oxaliplatin 85 mg/m(2) over 1 hour on day 1, and 5-fluorouracil 500 mg/m(2) as a bolus injection, followed 30 minutes later with bolus folinic acid 60 mg/m(2) on days 1 and 2). Cetuximab was administered every 2 weeks at a dose of 500 mg/m(2) for 16 weeks followed by cetuximab as maintenance therapy until disease progression. Between July 2008 and September 2010, 152 KRASwt patients were included. The response rate was 62% (95% confidence interval [CI], 54%-69%), median progression-free survival was 8.0 months (95% CI, 7.5-8.9) and median overall survival was 23.2 (95% CI, 18.1-27.4) months. Twenty-one patients (14%) had later R0-resection of metastasis. FLOX with cetuximab was reintroduced in 47 of 85 patients (55%). The most common Grade 3/4 nonhematologic adverse events were diarrhea in 14 patients (9%), skin rash in 13 patients (9%), infection without neutropenia in 11 patients (7%), and fatigue in 11 patients (7%). In a prospectively selected KRASwt population, biweekly cetuximab was safely integrated in an intermittent chemotherapy strategy and might have added to a longer chemotherapy-free interval. However, the combination of biweekly cetuximab with chemotherapy needs to be validated in trials using FOLFOX (oxaliplatin, fluorouracil, and leucovorin) or FOLFIRI (irinotecan, fluorouracil, and leucovorin). Copyright

  6. Combined immunohistochemistry of β-catenin, cytokeratin 7, and cytokeratin 20 is useful in discriminating primary lung adenocarcinomas from metastatic colorectal cancer

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    Tokumoto Noriaki

    2006-02-01

    Full Text Available Abstract Background It is important to discriminate between primary and secondary lung cancer. However, often, the discriminating diagnosis of primary lung acinar adenocarcinoma and lung metastasis of colorectal cancer based on morphological and pathological findings is difficult. The purpose of this study was to evaluate the clinical usefulness of immunohistochemistry of β-catenin, cytokeratin (CK 7, and CK20 for the discriminating diagnosis of lung cancer. Methods We performed immunohistochemistry of β-catenin, CK7, and CK20 in 19 lung metastasis of colorectal cancer samples, 10 corresponding primary colorectal cancer samples and 11 primary lung acinar adenocarcinoma samples and compared the levels of accuracy of the discriminating diagnosis by using antibodies against these antigens. Results Positive staining of β-catenin was observed in all the lung metastasis of colorectal cancer samples as well as in the primary colorectal cancer samples but in none of the primary lung acinar adenocarcinoma samples. Positive staining of CK7 was observed in 90.9% of the primary lung acinar adenocarcinoma samples and in 5.3% of the lung metastasis of colorectal cancer samples, but in none of the primary colorectal cancer samples. Positive staining of CK20 was observed in all the primary colorectal cancer samples and in 84.2% of the lung metastasis of colorectal cancer samples, but in none of the primary lung acinar adenocarcinoma samples. Conclusion Combined immunohistochemistry of β-catenin, CK7, and CK20 is useful for making a discriminating diagnosis between lung metastasis of colorectal cancer and primary lung acinar adenocarcinoma. This method will enable accurate diagnosis of a lung tumor and will be useful for selecting appropriate therapeutic strategies, including chemotherapeutic agents and operation methods.

  7. 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.

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    De Roock, Wendy; Claes, Bart; Bernasconi, David; De Schutter, Jef; Biesmans, Bart; Fountzilas, George; Kalogeras, Konstantine T; Kotoula, Vassiliki; Papamichael, Demetris; Laurent-Puig, Pierre; Penault-Llorca, Frédérique; Rougier, Philippe; Vincenzi, Bruno; Santini, Daniele; Tonini, Giuseppe; Cappuzzo, Federico; Frattini, Milo; Molinari, Francesca; Saletti, Piercarlo; De Dosso, Sara; Martini, Miriam; Bardelli, Alberto; Siena, Salvatore; Sartore-Bianchi, Andrea; Tabernero, Josep; Macarulla, Teresa; Di Fiore, Frédéric; Gangloff, Alice Oden; Ciardiello, Fortunato; Pfeiffer, Per; Qvortrup, Camilla; Hansen, Tine Plato; Van Cutsem, Eric; Piessevaux, Hubert; Lambrechts, Diether; Delorenzi, Mauro; Tejpar, Sabine

    2010-08-01

    Following the discovery that mutant KRAS is associated with resistance to anti-epidermal growth factor receptor (EGFR) antibodies, the tumours of patients with metastatic colorectal cancer are now profiled for seven KRAS mutations before receiving cetuximab or panitumumab. However, most patients 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-KRAS selection era. 1022 tumour DNA samples (73 from fresh-frozen and 949 from formalin-fixed, paraffin-embedded tissue) from patients treated with cetuximab between 2001 and 2008 were gathered from 11 centres in seven European countries. 773 primary tumour samples had sufficient quality DNA and were included in mutation frequency analyses; mass spectrometry genotyping of tumour samples for KRAS, BRAF, NRAS, and PIK3CA was done centrally. We analysed objective response, progression-free survival (PFS), and overall survival in molecularly defined subgroups of the 649 chemotherapy-refractory patients treated with cetuximab plus chemotherapy. 40.0% (299/747) of the tumours harboured a KRAS mutation, 14.5% (108/743) harboured a PIK3CA mutation (of which 68.5% [74/108] were located in exon 9 and 20.4% [22/108] in exon 20), 4.7% (36/761) harboured a BRAF mutation, and 2.6% (17/644) harboured an NRAS mutation. KRAS mutants did not derive benefit compared with wild types, with a response rate of 6.7% (17/253) versus 35.8% (126/352; odds ratio [OR] 0.13, 95% CI 0.07-0.22; p<0.0001), a median PFS of 12 weeks versus 24 weeks (hazard ratio [HR] 1.98, 1.66-2.36; p<0.0001), and a median overall survival of 32 weeks versus 50 weeks (1.75, 1.47-2.09; p<0.0001). In KRAS wild types, carriers of BRAF and NRAS mutations had a significantly lower response rate than did BRAF and NRAS wild types

  8. Chemotherapy of metastatic colon cancer

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    M. Yu. Fedyanin

    2012-01-01

    Full Text Available Colorectal cancer is one of the leading causes of cancer incidence and mortality. In 2008 inRussian Federation55 719 new cases of colorectal cancer were diagnosed and 37 911 patients died of this disease. A significant progress was achieved in metastatic colorectal cancer treatment during the last decades. A lot of treatment options became available: from 5-fluoruracil monotherapy to combined treatment treatment schemes including surgery. A group of patients with isolated liver metastases was distinguished, who can achieve 5-year survival rate of 40 % after systemic treatment and surgery. Today, based on clinical data and molecular analysis, we come close to individualized treatment of this patient group. In this literature review results of metastatic colorectal cancer chemotherapy are being analyzed and rational treatment tactic is proposed based on therapy goals. 

  9. Maintenance strategies after first-line oxaliplatin plus fluoropyrimidine plus bevacizumab for patients with metastatic colorectal cancer (AIO 0207): a randomised, non-inferiority, open-label, phase 3 trial.

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    Hegewisch-Becker, Susanna; Graeven, Ullrich; Lerchenmüller, Christian A; Killing, Birgitta; Depenbusch, Reinhard; Steffens, Claus-Christoph; Al-Batran, Salah-Eddin; Lange, Thoralf; Dietrich, Georg; Stoehlmacher, Jan; Tannapfel, Andrea; Reinacher-Schick, Anke; Quidde, Julia; Trarbach, Tanja; Hinke, Axel; Schmoll, Hans-Joachim; Arnold, Dirk

    2015-10-01

    The definition of a best maintenance strategy following combination chemotherapy plus bevacizumab in metastatic colorectal cancer is unclear. We investigated whether no continuation of therapy or bevacizumab alone are non-inferior to fluoropyrimidine plus bevacizumab, following induction treatment with a fluoropyrimidine plus oxaliplatin plus bevacizumab. In this open-label, non-inferiority, randomised phase 3 trial, we included patients aged 18 years or older with histologically confirmed, previously untreated metastatic colorectal cancer, Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, adequate bone marrow, liver, and renal function, no pre-existing neuropathy greater than grade 1, and measurable disease, from 55 hospitals and 51 private practices in Germany. After 24 weeks of induction therapy with either fluorouracil plus leucovorin plus oxaliplatin or capecitabine plus oxaliplatin, both with bevacizumab, patients without disease progression were randomly assigned centrally by fax (1:1:1) to standard maintenance treatment with a fluoropyrimidine plus bevacizumab, bevacizumab alone, or no treatment. Both patients and investigators were aware of treatment assignment. Stratification criteria were response status, termination of oxaliplatin, previous adjuvant treatment with oxaliplatin, and ECOG performance status. At first progression, re-induction with all drugs of the induction treatment was a planned part of the protocol. Time to failure of strategy was the primary endpoint, defined as time from randomisation to second progression after maintenance (and if applicable re-induction), death, or initiation of further treatment including a new drug. Time to failure of strategy was equivalent to time to first progression for patients who did not receive re-induction (for any reason). The boundary for assessment of non-inferiority was upper limit of the one-sided 98·8% CI 1·43. Analyses were done by intention to treat. The study has completed

  10. Clinical utility of KRAS status in circulating plasma DNA compared to archival tumour tissue from patients with metastatic colorectal cancer treated with anti-epidermal growth factor receptor therapy

    DEFF Research Database (Denmark)

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

    2015-01-01

    by an in-house qPCR method. Results are presented according to REMARK. RESULTS: One-hundred-and-forty patients were included. Thirty-four percent had detectable KRAS mutations in the tumour, compared to 23% in plasma. KRAS detection in archival tumour tissue showed no correlation to survival, whereas...... in patients from metastatic colorectal cancer (mCRC) prior to anti-epidermal growth factor receptor (anti-EGFR) therapy. Secondly, we investigated the concentration of total cfDNA in relation to clinical outcome. PATIENTS AND METHODS: Patients were resistant to 5-FU, oxaliplatin and irinotecan and treated......BACKGROUND: Circulating cell-free DNA (cfDNA) in plasma is a mixture of DNA from malignant and normal cells, and can be used as a liquid biopsy to detect and quantify tumour specific mutations e.g. KRAS. We investigated the clinical value of KRAS mutations when detected in plasma compared to tumour...

  11. 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

    micro array (TMA) (42%) had worse prognostic factors and inferior survival (all patients; 7m vs 11m, chemotherapy-treated;12m vs 17m). The 92 patients (21%) with BRAF mutation had a poor prognosis regardless of microsatellite instability, but receipt of 1-2nd chemotherapy was similar to wildtype BRAF...... 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 TMA 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...

  12. 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.

    Science.gov (United States)

    Martinez, Micaela; Ono, Nadia; Planutiene, Marina; Planutis, Kestutis; Nelson, Edward L; Holcombe, Randall F

    2012-01-23

    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. 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 (+). 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 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 of the immune system for cancer patients receiving cytotoxic therapy. ClinicalTrials.gov: NCT00257322.

  13. 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.

    Science.gov (United States)

    Sorbye, Halfdan; Dragomir, Anca; Sundström, Magnus; Pfeiffer, Per; Thunberg, Ulf; Bergfors, Monica; Aasebø, Kristine; Eide, Geir Egil; Ponten, Fredrik; Qvortrup, Camilla; Glimelius, Bengt

    2015-01-01

    RAS and BRAF mutations impact treatment and prognosis of metastatic colorectal cancer patients (mCRC), but the knowledge is based on trial patients usually not representative for the general cancer population. Patient characteristics, treatment and efficacy according to KRAS, BRAF and MSI status 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 micro array (TMA) (42%) had worse prognostic factors and inferior survival (all patients; 7m vs 11m, chemotherapy-treated;12m vs 17m). The 92 patients (21%) with BRAF mutation had a poor prognosis regardless of microsatellite instability, but receipt of 1-2nd chemotherapy was similar to wildtype BRAF 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 <75 years in good PS. TMA availability, BRAF mutation and KRAS mutation were all independent prognostic factors for survival. The observed 21% BRAF mutation incidence is higher than the previously and repeatedly reported incidence of 5-12% in mCRC. Screening for BRAF mutations before selection of treatment is relevant for many patients, especially outside clinical trials. A BRAF mutation only partly explained the very poor prognosis of many mCRC 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 studies and implies that we lack information on the biologically worst mCRC cases. Lack of available tissue is an important underexposed issue which introduces sample bias, and this should

  14. 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.

    Science.gov (United States)

    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

    2017-09-11

    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 tipiracil could result in increased overall survival compared with placebo, but there is 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 the two drugs in adjusted analysis using propensity score, regorafenib showed favorable survival in patients aged tipiracil was favored in patients aged ≥65 years in the subgroup analysis. © 2017 The Authors The Oncologist published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

  15. 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

    Energy Technology Data Exchange (ETDEWEB)

    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.)

  16. CT引导射频消融治疗结直肠癌肝转移的应用价值%Application value of CT-guided radiofreguency ablation on metastatic liver carciaoma caused by colorectal cancer

    Institute of Scientific and Technical Information of China (English)

    李德周; 赵玉东; 赵玉鑫

    2014-01-01

    Objective To investigate the indications,therapeutic regimen and effects of CT-guided radio frequency ablation(RFA) in the treatment of metastatic liver carciaoma caused by colorectal cancer.Methods Fifty-six patients(124 lesions)clinically and pathologically diagnosed with metastatic liver carciaoma caused by colorectal cancer scheduled for RFA were included into this study.The average diameter of the tumors was (3.5 ± 1.4)cm,tumors with diameter≥4 cm accounting for 32.3% (40/124 leisions),single tumor accounting for 32.1% (18 leisions).All patients were examined by contrasted enhanced CT examination,the indications of RFA were made according to leision numbers,size,shape,infiltration range,location and relations with the surrounding structures.All the 56 patients were treated by conventional CT-guided percutanous RFA.The effects were evaluated by contrasted enhanced CT examination during the 1 to 4 months follow-up.Results According to the results of contrasted enhanced CT examination,56 patients (124 lesions) were given RFA staging treatment and expanding ablationtreatment.Tumor deactivation rate was 93.5% (116/124 lesions),local recurrence rate was 8.0% (10/124 lesions),and new metastasis rate was 39.3% (20/56 cases).Conclusions CT-guided radio frequency ablation is an important supplementary method for the treatment of metastatic liver carciaoma caused by colorectal cancer,enhanced CT examination can provide reference for indications selection and treatment scheme made of metastatic liver carciaoma.%目的 探讨CT引导下射频消融(RFA)治疗结直肠癌肝转移的适应证、治疗方案及疗效.方法 选择56例(124个病灶)经临床及病理确诊为结直肠癌肝转移并拟行RFA者纳入本研究.肿瘤平均直径为(3.5±1.4)cm,直径≥4 cm肿瘤占32.3%(40/124病灶),单发肿瘤占32.1%(18例).所有患者均行增强CT检查,根据病灶数目、大小、形态、浸润范围、位置、与周围结构关

  17. Prognostic importance of circulating epidermal growth factor-like domain 7 in patients with metastatic colorectal cancer treated with chemotherapy and bevacizumab

    DEFF Research Database (Denmark)

    Hansen, Torben Frøstrup; Andersen, Rikke Fredslund; Aalund Olsen, Dorte

    2017-01-01

    High tumor expression of epidermal growth factor-like domain 7 (EGFL7) has been associated with a poor prognosis in colorectal cancer. The aim of the current study was to investigate the possible prognostic impact of circulating EGFL7 (cir-EGFL7), combined with single nucleotide polymorphism (SNP...

  18. CytoTrack Analysis Reveals Low Presence of Circulating Tumor Cells in the Perioperative Period in Patients with Non-metastatic Colorectal Cancer

    DEFF Research Database (Denmark)

    Gogenur, Mikail; Hillig, Thore; Gogenur, Ismail

    2017-01-01

    of circulating tumor cells and Union for International Cancer Control (UICC) stage and if surgery itself results in the release of circulating tumor cells. PATIENTS AND METHODS: A prospective study was conducted including patients with colorectal cancer UICC stage I-III who underwent minimally-invasive surgery...

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

    DEFF Research Database (Denmark)

    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 patie...

  20. 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

  1. Prophylaxis against colorectal cancer

    DEFF Research Database (Denmark)

    Bülow, Steffen; Kronborg, O

    1996-01-01

    Colorectal cancer is diagnosed in more than 3000 people every year in Denmark, with a population of 5 million, and 2000 die from this disease every year. The aetiology of the disease is complex, but an increasing number of cancers have been related to genetics and Denmark is contributing...... with a well-established register of familial adenomatous polyposis and a recently founded register for hereditary nonpolyposis colorectal cancer, both with major international relationships. The Danish tradition of epidemiology and clinical trials has also been demonstrated in population screening trials...... for colorectal cancer in average-risk persons as well as high-risk groups with precursors of the disease. The present review places Danish contributions within the prophylaxis of colorectal cancer during the last decade in an international context....

  2. Prophylaxis against colorectal cancer

    DEFF Research Database (Denmark)

    Bülow, Steffen; Kronborg, O

    1996-01-01

    Colorectal cancer is diagnosed in more than 3000 people every year in Denmark, with a population of 5 million, and 2000 die from this disease every year. The aetiology of the disease is complex, but an increasing number of cancers have been related to genetics and Denmark is contributing...... with a well-established register of familial adenomatous polyposis and a recently founded register for hereditary nonpolyposis colorectal cancer, both with major international relationships. The Danish tradition of epidemiology and clinical trials has also been demonstrated in population screening trials...... for colorectal cancer in average-risk persons as well as high-risk groups with precursors of the disease. The present review places Danish contributions within the prophylaxis of colorectal cancer during the last decade in an international context....

  3. Protocol for Combined Analysis of FOXFIRE, SIRFLOX, and FOXFIRE-Global Randomized Phase III Trials of Chemotherapy +/- Selective Internal Radiation Therapy as First-Line Treatment for Patients With Metastatic Colorectal Cancer.

    Science.gov (United States)

    Virdee, Pradeep S; Moschandreas, Joanna; Gebski, Val; Love, Sharon B; Francis, E Anne; Wasan, Harpreet S; van Hazel, Guy; Gibbs, Peter; Sharma, Ricky A

    2017-03-28

    In colorectal cancer (CRC), unresectable liver metastases are associated with a poor prognosis. The FOXFIRE (an open-label randomized phase III trial of 5-fluorouracil, oxaliplatin, and folinic acid +/- interventional radioembolization as first-line treatment for patients with unresectable liver-only or liver-predominant metastatic colorectal cancer), SIRFLOX (randomized comparative study of FOLFOX6m plus SIR-Spheres microspheres versus FOLFOX6m alone as first-line treatment in patients with nonresectable liver metastases from primary colorectal carcinoma), and FOXFIRE-Global (assessment of overall survival of FOLFOX6m plus SIR-Spheres microspheres versus FOLFOX6m alone as first-line treatment in patients with nonresectable liver metastases from primary colorectal carcinoma in a randomized clinical study) clinical trials were designed to evaluate the efficacy and safety of combining first-line chemotherapy with selective internal radiation therapy (SIRT) using yttrium-90 resin microspheres, also called transarterial radioembolization. The aim of this analysis is to prospectively combine clinical data from 3 trials to allow adequate power to evaluate the impact of chemotherapy with SIRT on overall survival. Eligible patients are adults with histologically confirmed CRC and unequivocal evidence of liver metastases which are not treatable by surgical resection or local ablation with curative intent at the time of study entry. Patients may also have limited extrahepatic metastases. Final analysis will take place when all participants have been followed up for a minimum of 2 years. Efficacy and safety estimates derived using individual participant data (IPD) from SIRFLOX, FOXFIRE, and FOXFIRE-Global will be pooled using 2-stage prospective meta-analysis. Secondary outcome measures include progression-free survival (PFS), liver-specific PFS, health-related quality of life, response rate, resection rate, and adverse event profile. The large study population will

  4. A prospective observational study to examine the relationship between quality of life and adverse events of first-line chemotherapy plus cetuximab in patients with KRAS wild-type unresectable metastatic colorectal cancer: QUACK Trial.

    Science.gov (United States)

    Ooki, Akira; Ando, Masahiko; Sakamoto, Junichi; Sato, Atushi; Fujii, Hirofumi; Yamaguchi, Kensei

    2014-04-01

    We have planned a multicentre prospective study to examine the relative impact of the efficacy and adverse events of cetuximab plus first-line chemotherapy on the quality of life in Japanese patients with KRAS wild-type unresectable colorectal cancer. The Dermatology Life Quality Index and the European Organization for Research Treatment of Cancer Quality of Life Questionnaire Core 30 will be used to assess dermatology-specific and health-related quality of life. The severity of adverse events will be assessed by using the National Cancer Institute Common Terminology Criteria for adverse Events ver. 4.0. The endpoints will be the following associations: adverse events, including skin toxicity and quality of life; efficacy and skin toxicity; efficacy and quality of life; and skin-related quality of life and health-related quality of life. A total of 140 patients are considered to be appropriate for inclusion in this study. The results of this study will provide more information to both patients and physicians regarding the practical use of cetuximab and its impact on quality of life in patients with unresectable colorectal cancer in Japan. This study was registered at the University Hospital Medical Information Network Clinical Trial Registry as UMIN000010985.

  5. 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

    Directory of Open Access Journals (Sweden)

    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

  6. 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.

    Directory of Open Access Journals (Sweden)

    Halfdan Sorbye

    Full Text Available RAS and BRAF mutations impact treatment and prognosis of metastatic colorectal cancer patients (mCRC, but the knowledge is based on trial patients usually not representative for the general cancer population. Patient characteristics, treatment and efficacy according to KRAS, BRAF and MSI status 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 micro array (TMA (42% had worse prognostic factors and inferior survival (all patients; 7m vs 11m, chemotherapy-treated;12m vs 17m. The 92 patients (21% with BRAF mutation had a poor prognosis regardless of microsatellite instability, but receipt of 1-2nd chemotherapy was similar to wildtype BRAF 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 <75 years in good PS. TMA availability, BRAF mutation and KRAS mutation were all independent prognostic factors for survival. The observed 21% BRAF mutation incidence is higher than the previously and repeatedly reported incidence of 5-12% in mCRC. Screening for BRAF mutations before selection of treatment is relevant for many patients, especially outside clinical trials. A BRAF mutation only partly explained the very poor prognosis of many mCRC 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 studies and implies that we lack information on the biologically worst mCRC cases. Lack of available tissue is an important underexposed issue which introduces sample bias, and

  7. Research progress in treatment of metastatic colorectal cancer with EGFR monoclonal antibody%EGFR单抗治疗转移性结直肠癌的研究进展

    Institute of Scientific and Technical Information of China (English)

    李晓佳; 韩宇; 黄鹏; 李燕京; 白玉贤

    2013-01-01

    Epidermal growth factor receptor(EGFR) monoclonal antibody is increasingly important in the treatment of metastatic colorectal cancer. Monoclonal antibody, especially, cetuximab and panitumumab have a high efficiency opposed to the uselessness of chemotherapy. In this paper, we provide several clinical trials to explored that either first-line or second-line and preoperative chemotherapy, EGFR monoclonal antibody in combination with chemotherapy maybe superior to anti-EGFR monoclonal alone to extend survival for patient with metastatic colorectal cancer. In order to improve the curative effect, the bio-maker researches is necessary for individualized treatment, such as EGFR GCN and KRAS, BRAF, PIK3CAin the downstream of the EGFR signal pathway. The aim of this paper is to introduce the research progress about the EGFR monoclonal antibody.%目前随着晚期结直肠癌分子生物学研究的不断深入,表皮生长因子受体(EGFR)单抗在转移性结直肠癌的治疗中变得尤为重要,尤其是西妥昔单抗和帕尼单抗,在标准化疗方案失败的患者中具有很高的疗效。大量临床试验表明,在晚期结直肠癌的治疗中,无论一线、二线抑或是转化化疗,标准化疗方案联合EGFR单抗靶向药物治疗的疗效均优于单纯化疗。为了进一步筛检EGFR单抗疗效的有效性,对相关基因研究的结果为此提供了依据,例如 EGFR 基因拷贝量的多少,及其下游通路的 KRAS,BRAF, PIK3CA基因的状态等。本文结合最新报道,就EGFR单抗治疗转移性结直肠癌的疗效及预测因子做一综述。

  8. 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....

  9. [Cost-effectiveness Analysis of Panitumumab Plus mFOLFOX6 Compared to Bevacizumab Plus mFOLFOX6 for First-line Treatment of Patients with Wild-type RAS Metastatic Colorectal Cancer--Czech Republic Model Adaptation].

    Science.gov (United States)

    Fínek, J; Skoupá, J; Jandová, P

    2015-01-01

    Pharmacoeconomic assessments are a part of the decision process not only during reimbursement setting, but in clinical practice as well. The presented cost-effectiveness analysis assesses panitumumab+mFOLFOX6 vs. bevacizumab+mFOLFOX6 in 1st line treatment of patients with wildtype RAS metastatic colorectal cancer (mCRC) in the Czech environment. The adaptation of a Markov model considers the healthcare perspective; clinical data (efficacy, healthcare utilization and adverse events) are derived from a head-to-head comparison (PEAK study). Health states included in the model: progression free on treatment, progression (with/ without active treatment), resection of metastases, disease-free after successful resection and death. Actual reimbursement levels were used to estimate costs, published literature to estimate duration of 2nd line treatment. The analysis assumes a lifetime horizon; uncertainty was limited by performing one-way and probabilistic sensitivity analyses. Analysis outcomes are life-years gained (LYG) and quality-adjusted life-years (QALYs). Panitumumab+mFOLFOX6 is more effective and more costly in 1st line patients with wildtype RAS mCRC. Incremental costs per QALY are 837,270 CZK, per LYG 615,022 CZK; however, below the willingness-to-pay threshold applied in the Czech Republic. Panitumumab+mFOLFOX6 is cost-effective in 1st line treatment of patients with wildtype RAS mCRC compared to bevacizumab+mFOLFOX6 in the Czech setting.

  10. First-line XELOX plus bevacizumab followed by XELOX plus bevacizumab or single-agent bevacizumab as maintenance therapy in patients with metastatic colorectal cancer: the phase III MACRO TTD study.

    Science.gov (United States)

    Díaz-Rubio, Eduardo; Gómez-España, Auxiliadora; Massutí, Bartomeu; Sastre, Javier; Abad, Albert; Valladares, Manuel; Rivera, Fernando; Safont, Maria J; Martínez de Prado, Purificación; Gallén, Manuel; González, Encarnación; Marcuello, Eugenio; Benavides, Manuel; Fernández-Martos, Carlos; Losa, Ferrán; Escudero, Pilar; Arrivi, Antonio; Cervantes, Andrés; Dueñas, Rosario; López-Ladrón, Amelia; Lacasta, Adelaida; Llanos, Marta; Tabernero, Jose M; Antón, Antonio; Aranda, Enrique

    2012-01-01

    The aim of this phase III trial was to compare the efficacy and safety of bevacizumab alone with those of bevacizumab and capecitabine plus oxaliplatin (XELOX) as maintenance treatment following induction chemotherapy with XELOX plus bevacizumab in the first-line treatment of patients with metastatic colorectal cancer (mCRC). Patients were randomly assigned to receive six cycles of bevacizumab, capecitabine, and oxaliplatin every 3 weeks followed by XELOX plus bevacizumab or bevacizumab alone until progression. The primary endpoint was the progression-free survival (PFS) interval; secondary endpoints were the overall survival (OS) time, objective response rate (RR), time to response, duration of response, and safety. The intent-to-treat population comprised 480 patients (XELOX plus bevacizumab, n = 239; bevacizumab, n = 241); there were no significant differences in baseline characteristics. The median follow-up was 29.0 months (range, 0-53.2 months). There were no statistically significant differences in the median PFS or OS times or in the RR between the two arms. The most common grade 3 or 4 toxicities in the XELOX plus bevacizumab versus bevacizumab arms were diarrhea, hand-foot syndrome, and neuropathy. Although the noninferiority of bevacizumab versus XELOX plus bevacizumab cannot be confirmed, we can reliably exclude a median PFS detriment >3 weeks. This study suggests that maintenance therapy with single-agent bevacizumab may be an appropriate option following induction XELOX plus bevacizumab in mCRC patients.

  11. 转移性结直肠癌西妥昔单抗治疗的疗效及安全性%The Efficacy and Safety of Cetuximab in the Treatment for Metastatic Colorectal Cancer

    Institute of Scientific and Technical Information of China (English)

    应杰儿; 刘碧霞; 钟海均; 徐琦; 张沂平; 朱利明; 杨云山

    2012-01-01

    [Purpose] To investigate the efficacy and safety of cetuximab in the treatment for K-ras wild-type metastatic colorectal cancer. [Methods] The efficacy and toxicity of cetuximab alone(l case) or combined (33 cases) chemotherapy in 34 cases with K-ras wild-type advanced colorectal cancer were analyzed. [Results] All the 34 patients were assessable for efficacy and toxicity. Of the whole group,the response rate (RR) was 41.2%,with the median progression-free survival (mPFS) 6.5 months,the median survival 16.9 months. Of 7 cases as the first-line treatment,RR was 57.1% ,mPFS, 7.2 months and median survival, 21.4 months. Of 21 cases as second-line treatment,RR was 38.1%,mPFS, 6.9 months and the median survival,15.7 months. Of 6 cases as third-line treatment or above,RR was 33.3%.The most common toxicities were skin toxicity and bone marrow suppression,however most of them were grade I ?U .[Conclusion] In the K-ras wild-type Chinese patients with metastatic colorectal cancer,cetuximab combined chemotherapy as first line, second-line and multi-line treatment have showed a good objective response and disease control,and the toxicities are tolerable.%[目的]观察西妥昔单抗对K-ras野生型转移性结直肠癌的疗效和不良反应.[方法]对34例接受西妥昔单抗单药(1例)或联合化疗(33例)治疗的K-ras野生型转移性结直肠癌患者进行疗效及不良反应分析.[结果]34例患者均可评价疗效及不良反应.全组有效率41.2%,中位无进展生存时间6.5个月,中位生存时间16.9个月.7例一线治疗患者有效率57.1%,中位无进展生存时间7.2个月,中位生存时间21.4个月.21例二线治疗患者,有效率38.1%,中位无进展生存时间6.9个月,中位生存时间15.7个月.6例三线或三线以上患者,有效率33.3%.最常见的不良反应为皮肤毒性,其次骨髓抑制,大多为Ⅰ~Ⅱ度.[结论]国人K-ras野生型转移性结直肠癌患者中,两妥昔单抗联合化疗在一线、二线

  12. Performance and cost efficiency of KRAS mutation testing for metastatic colorectal cancer in routine diagnosis: the MOKAECM study, a nationwide experience.

    Directory of Open Access Journals (Sweden)

    Hélène Blons

    Full Text Available PURPOSE: Rapid advances in the understanding of cancer biology have transformed drug development thus leading to the approval of targeted therapies and to the development of molecular tests to select patients that will respond to treatments. KRAS status has emerged as a negative predictor of clinical benefit from anti-EGFR antibodies in colorectal cancer, and anti-EGFR antibodies use was limited to KRAS wild type tumors. In order to ensure wide access to tumor molecular profiling, the French National Cancer Institute (INCa has set up a national network of 28 regional molecular genetics centers. Concurrently, a nationwide external quality assessment for KRAS testing (MOKAECM was granted to analyze reproducibility and costs. METHODS: 96 cell-line DNAs and 24 DNA samples from paraffin embedded tumor tissues were sent to 40 French laboratories. A total of 5448 KRAS results were collected and analyzed and a micro-costing study was performed on sites for 5 common methods by an independent team of health economists. RESULTS: This work provided a baseline picture of the accuracy and reliability of KRAS analysis in routine testing conditions at a nationwide level. Inter-laboratory Kappa values were >0.8 for KRAS results despite differences detection methods and the use of in-house technologies. Specificity was excellent with only one false positive in 1128 FFPE data, and sensitivity was higher for targeted techniques as compared to Sanger sequencing based methods that were dependent upon local expertise. Estimated reagent costs per patient ranged from €5.5 to €19.0. CONCLUSION: The INCa has set-up a network of public laboratories dedicated to molecular oncology tests. Our results showed almost perfect agreements in KRAS testing at a nationwide level despite different testing methods ensuring a cost-effective equal access to personalized colorectal cancer treatment.

  13. Effect of BRAF V600E mutation on tumor response of anti-EGFR monoclonal antibodies for first-line metastatic colorectal cancer treatment: a meta-analysis of randomized studies.

    Science.gov (United States)

    Cui, Dandan; Cao, Dan; Yang, Yu; Qiu, Meng; Huang, Ying; Yi, Cheng

    2014-03-01

    Anti-EGFR monoclonal antibodies (anti-EGFR MoAbs) in metastatic colorectal cancer (mCRC) treatment are still not effective in all patients. This study aimed to evaluate the relationship between BRAF V600E mutation and the tumor response of anti-EGFR MoAbs for first-line treatment in mCRC patients. We searched the MEDLINE and EMBASE databases, using the key words that included colorectal cancer, cetuximab, panitumumab, and BRAF mutation and retrieved 445 articles. Among them four were included in the systematic review. Relative risks (RRs) with 95% confidence intervals (CI) for response rate were calculated. BRAF mutation carriers had worse ORR than non-carriers in mCRC patients with KRAS wild-type in first-line treatment whether adding anti-EGFR MoAb to chemotherapy or not (RR = 0.43, [95% CI 0.16-0.75]; RR = 0.38, [95% CI 0.20-0.73]). But in the unselected patients whose KRAS mutation were unknown, BRAF mutation carriers had similar ORR whether adding cetuximab to chemotherapy or not (RR = 0.45, [95% CI 0.18-1.09]; RR = 0.57, [95% CI 0.15-2.23]). In BRAF mutation carriers adding anti-EGFR MoAb to chemotherapy was similar to chemotherapy alone whether in patients with wild-type KRAS or unselected patients (RR = 1.61, [95% CI 0.57-4.47]; RR = 0.71, [95% CI 0.18-2.77]). But in the BRAF mutation non-carriers, adding anti-EGFR MoAb produced a clear benefit in response rate than chemotherapy alone and this advantage was restricted to KRAS wild-type patients (RR = 1.48, [95% CI 1.28-1.71]). BRAF mutation decreases tumor response in first-line treatment whether cetuximab was given or not in patients with KRAS wild-type, and anti-EGFR MoAb produces a clear benefit in response rate in patients with BRAF and KRAS wild-type.

  14. Erlotinib and Cetuximab With or Without Bevacizumab in Treating Patients With Metastatic or Unresectable Kidney, Colorectal, Head and Neck, Pancreatic, or Non-Small Cell Lung Cancer

    Science.gov (United States)

    2014-06-10

    Metastatic Squamous Neck Cancer With Occult Primary Squamous Cell Carcinoma; Recurrent Adenoid Cystic Carcinoma of the Oral Cavity; Recurrent Basal Cell Carcinoma of the Lip; Recurrent Colon Cancer; Recurrent Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Recurrent Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Recurrent Lymphoepithelioma of the Nasopharynx; Recurrent Lymphoepithelioma of the Oropharynx; Recurrent Metastatic Squamous Neck Cancer With Occult Primary; Recurrent Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Recurrent Mucoepidermoid Carcinoma of the Oral Cavity; Recurrent Non-small Cell Lung Cancer; Recurrent Pancreatic Cancer; Recurrent Rectal Cancer; Recurrent Salivary Gland Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Verrucous Carcinoma of the Larynx; Recurrent Verrucous Carcinoma of the Oral Cavity; Stage III Adenoid Cystic Carcinoma of the Oral Cavity; Stage III Basal Cell Carcinoma of the Lip; Stage III Colon Cancer; Stage III Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Stage III Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Stage III Lymphoepithelioma of the Nasopharynx; Stage III Lymphoepithelioma of the Oropharynx; Stage III Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Stage III Mucoepidermoid Carcinoma of the Oral Cavity; Stage III Pancreatic Cancer; Stage III Rectal Cancer; Stage III Salivary Gland Cancer; Stage III Squamous Cell Carcinoma of the Hypopharynx; Stage III Squamous Cell Carcinoma of the Larynx; Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage III Squamous Cell Carcinoma of the Nasopharynx

  15. Phase I/II study of azacitidine and capecitabine/oxaliplatin (CAPOX) in refractory CIMP-high metastatic colorectal cancer: evaluation of circulating methylated vimentin

    Science.gov (United States)

    Overman, Michael J.; Morris, Van; Moinova, Helen; Manyam, Ganiraju; Ensor, Joe; Lee, Michael S.; Eng, Cathy; Kee, Bryan; Fogelman, David; Shroff, Rachna T.; LaFramboise, Thomas; Mazard, Thibault; Feng, Tian; Hamilton, Stanley; Broom, Bradley; Lutterbaugh, James; Issa, Jean-Pierre; Markowitz, Sanford D.; Kopetz, Scott

    2016-01-01

    Purpose Hypermethylation of promoter CpG islands (CIMP) has been strongly implicated in chemotherapy resistance and is implicated in the pathogenesis of a subset of colorectal cancers (CRCs) termed CIMP-high. Experimental Design This phase I/II study in CRC (phase II portion restricted to CIMP-high CRC), treated fluoropyrimidine/oxaliplatin refractory patients with azacitidine (75 mg/m2/day subcutaneously D1-5) and CAPOX (capecitibine and oxaliplatin) every three weeks. Results Twenty-six patients (pts) were enrolled in this study: 15 pts (12 treated at MTD) in phase I and 11 pts in phase II. No dose limiting toxicities were observed. A total of 14 pts were CIMP-high. No responses were seen. CIMP-high status did not correlate with efficacy endpoints [stable disease (SD) or progression-free survival (PFS)] or baseline vimentin methylation level. Changes in vimentin methylation over time did not correlate with efficacy outcomes. Baseline methylated vimentin correlated with tumor volume (P<0.001) and higher levels of baseline methylation correlated with the obtainment of stable disease (P=0.04). Conclusions Azacitidine and CAPOX were well tolerated with high rates of stable disease in CIMP-high pts, but no objective responses. Serum methylated vimentin may be associated with benefit from a regimen including a hypomethylation agent, although this study is not able to separate a potential prognostic or predictive role for the biomarker. PMID:27542211

  16. COLORECTAL-CARCINOMA - AN UPDATE

    NARCIS (Netherlands)

    SINNIGE, HAM; MULDER, NH

    1991-01-01

    During the last decade important advances have occurred in the fields of understanding genesis, molecular biology, detection of "precancerous data", intervention, and metastatic behaviour of colorectal cancer. An important step forward has been made in adjuvant therapy. Better understanding of 5-flu

  17. Subgroup analysis in RAISE: a randomized, double-blind phase III study of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) plus ramucirumab or placebo in patients with metastatic colorectal carcinoma progression†

    Science.gov (United States)

    Obermannová, R.; Van Cutsem, E.; Yoshino, T.; Bodoky, G.; Prausová, J.; Garcia-Carbonero, R.; Ciuleanu, T.; Garcia Alfonso, P.; Portnoy, D.; Cohn, A.; Yamazaki, K.; Clingan, P.; Lonardi, S.; Kim, T. W.; Yang, L.; Nasroulah, F.; Tabernero, J.

    2016-01-01

    Background The RAISE phase III clinical trial demonstrated that ramucirumab + FOLFIRI improved overall survival (OS) [hazard ratio (HR) = 0.844, P = 0.0219] and progression-free survival (PFS) (HR = 0.793, P compared with placebo + FOLFIRI for second-line metastatic colorectal carcinoma (mCRC) patients previously treated with first-line bevacizumab, oxaliplatin, and a fluoropyrimidine. Since some patient or disease characteristics could be associated with differential efficacy or safety, prespecified subgroup analyses were undertaken. This report focuses on three of the most relevant ones: KRAS status (wild-type versus mutant), age (Cox proportional hazards model. Treatment-by-subgroup interaction was tested to determine whether treatment effect was consistent between subgroup pairs. Results Patients with both wild-type and mutant KRAS benefited from ramucirumab + FOLFIRI treatment over placebo + FOLFIRI (interaction P = 0.526); although numerically, wild-type KRAS patients benefited more (wild-type KRAS: median OS = 14.4 versus 11.9 months, HR = 0.82, P = 0.049; mutant KRAS: median OS = 12.7 versus 11.3 months, HR = 0.89, P = 0.263). Patients with both longer and shorter first-line TTP benefited from ramucirumab (interaction P = 0.9434), although TTP Conclusions These analyses revealed similar efficacy and safety among patient subgroups with differing KRAS mutation status, longer or shorter first-line TTP, and age. Ramucirumab is a beneficial addition to second-line FOLFIRI treatment for a wide range of patients with mCRC. Trial registration ClinicalTrials.gov, NCT01183780 PMID:27573561

  18. Observational study on quality of life, safety, and effectiveness of first-line cetuximab plus chemotherapy in KRAS wild-type metastatic colorectal cancer patients: the ObservEr Study.

    Science.gov (United States)

    Pinto, Carmine; Di Fabio, Francesca; Rosati, Gerardo; Lolli, Ivan R; Ruggeri, Enzo M; Ciuffreda, Libero; Ferrari, Daris; Lo Re, Giovanni; Rosti, Giovanni; Tralongo, Paolo; Ferrara, Raimondo; Alabiso, Oscar; Chiara, Silvana; Ianniello, Giovanni P; Frassoldati, Antonio; Bilancia, Domenico; Campanella, Giovanna A; Signorelli, Carlo; Racca, Patrizia; Benincasa, Elena; Stroppolo, Maria Elena; Di Costanzo, Francesco

    2016-11-01

    Cetuximab improves efficacy when added to chemotherapy for metastatic colorectal cancer (mCRC). Effective management of skin reactions from cetuximab improves quality of life (QoL), and treatment compliance in clinical trials. No data are available from real-world settings. The ObservEr observational, multicenter, prospective study evaluated QoL, the incidence of skin reactions, and management of chemotherapy plus cetuximab in first-line for mCRC. The primary endpoint was QoL measured with the Dermatology Life Quality Index (DLQI) and EORTC QLQ-C30. Secondary endpoints were the incidence of skin and serious adverse events, median overall and progression-free survival, tumor response, and resection rates. Between May 2011 and November 2012, 228 patients with KRASwt mCRC were enrolled at 28 Italian centers, 225 evaluable, median age 65 years. QoL did not change during treatment and was not affected by the choice of prophylactic or reactive skin management. The incidence of cetuximab-specific grade ≥3 skin reactions was 14%, with no grade 4/5 events. Skin reactions correlated with survival (P = 0.016), and their incidence was influenced by chemotherapy regimen (oxaliplatin vs. irinotecan-Incidence rate ratio [IRR] 1.72, P < 0.0001) and gender (male vs. female-IRR 1.38, P = 0.0008). Compliance at first postbaseline evaluation was 97.75%. Median overall survival was 23.6 months, median progression-free survival 8.3 months. Cetuximab plus chemotherapy did not compromise QoL in the routine clinical setting when patients receive close monitoring plus prophylactic or reactive management of skin reactions. We observed the same correlation between overall survival (OS) and skin reactions reported in controlled clinical trials, also in this setting.

  19. Cetuximab in combination with irinotecan/5-fluorouracil/folinic acid (FOLFIRI in the initial treatment of metastatic colorectal cancer: a multicentre two-part phase I/II study

    Directory of Open Access Journals (Sweden)

    Cals Laurent

    2009-04-01

    Full Text Available Abstract Background This study was designed to investigate the efficacy and safety of the epidermal growth factor receptor (EGFR inhibitor cetuximab combined with irinotecan, folinic acid (FA and two different doses of infusional 5-fluorouracil (5-FU in the first-line treatment of EGFR-detectable metastatic colorectal cancer. Methods The 5-FU dose was selected on the basis of dose-limiting toxicities (DLTs during part I of the study. Patients received cetuximab (400 mg/m2 initial dose and 250 mg/m2/week thereafter and every 2 weeks irinotecan (180 mg/m2, FA (400 mg/m2 and 5-FU (either low dose [LD], 300 mg/m2 bolus plus 2,000 mg/m2 46-hour infusion, n = 7; or, high-dose [HD], 400 mg/m2 bolus plus 2,400 mg/m2; n = 45. Results Only two DLTs occurred in the HD group, and HD 5-FU was selected for use in part II. Apart from rash, commonly observed grade 3/4 adverse events such as leucopenia, diarrhoea, vomiting and asthenia occurred within the expected range for FOLFIRI. Among 52 patients, the overall response rate was 48%. Median progression-free survival (PFS was 8.6 months (counting all reported progressions and the median overall survival was 22.4 months. Treatment facilitated the resection of initially unresectable metastases in fourteen patients (27%: of these, 10 patients (71% had no residual tumour after surgery, and these resections hindered the estimation of PFS. Conclusion The combination of cetuximab and FOLFIRI was active and well tolerated in this setting. Initially unresectable metastases became resectable in one-quarter of patients, with a high number of complete resections, and these promising results formed the basis for the investigation of FOLFIRI with and without cetuximab in the phase III CRYSTAL trial.

  20. Expression profiling of blood samples from an SU5416 Phase III metastatic colorectal cancer clinical trial: a novel strategy for biomarker identification

    Directory of Open Access Journals (Sweden)

    Smolich Beverly D

    2003-02-01

    Full Text Available Abstract Background Microarray-based gene expression profiling is a powerful approach for the identification of molecular biomarkers of disease, particularly in human cancers. Utility of this approach to measure responses to therapy is less well established, in part due to challenges in obtaining serial biopsies. Identification of suitable surrogate tissues will help minimize limitations imposed by those challenges. This study describes an approach used to identify gene expression changes that might serve as surrogate biomarkers of drug activity. Methods Expression profiling using microarrays was applied to peripheral blood mononuclear cell (PBMC samples obtained from patients with advanced colorectal cancer participating in a Phase III clinical trial. The PBMC samples were harvested pre-treatment and at the end of the first 6-week cycle from patients receiving standard of care chemotherapy or standard of care plus SU5416, a vascular endothelial growth factor (VEGF receptor tyrosine kinase (RTK inhibitor. Results from matched pairs of PBMC samples from 23 patients were queried for expression changes that consistently correlated with SU5416 administration. Results Thirteen transcripts met this selection criterion; six were further tested by quantitative RT-PCR analysis of 62 additional samples from this trial and a second SU5416 Phase III trial of similar design. This method confirmed four of these transcripts (CD24, lactoferrin, lipocalin 2, and MMP-9 as potential biomarkers of drug treatment. Discriminant analysis showed that expression profiles of these 4 transcripts could be used to classify patients by treatment arm in a predictive fashion. Conclusions These results establish a foundation for the further exploration of peripheral blood cells as a surrogate system for biomarker analyses in clinical oncology studies.

  1. Predictive Value of Early Tumor Shrinkage and Density Reduction of Lung Metastases in Patients With Metastatic Colorectal Cancer Treated With Regorafenib.

    Science.gov (United States)

    Vanwynsberghe, Hannes; Verbeke, Xander; Coolen, Johan; Van Cutsem, Eric

    2017-03-29

    The benefit of regorafenib in colorectal cancer is not very pronounced. At present, there is lack of predictive biological or radiological markers. We studied if density reduction or small changes in size of lung metastases could be a predictive marker. We retrospectively measured density in size of lung metastases of all patients included in the CORRECT and CONSIGN trials at our center. Contrast-enhanced CT scan at baseline and at week 8 were compared. Data of progressive-free survival and overall survival were collected from the CORRECT and CONSIGN trials. A significant difference in progressive-free survival was seen in 3 groups: response or stable disease in size (5.36 vs. 3.96 months), response in density (6.03 vs. 2.72 months), and response in corrected density (6.14 vs. 3.08 months). No difference was seen for response in size versus stable disease or progressive disease in size. For overall survival, a difference was observed in the same 3 groups: response or stable disease in size (9.89 vs. 6.44 months), response in density (9.59 vs. 7.04 months), and response in corrected density (9.09 vs. 7.16 months). No difference was seen for response in size versus stable disease or progressive disease in size. Density reduction in lung metastases might be a good predictive parameter to predict outcome for regorafenib. Early tumor progression might be a negative predictive factor. If further validated, density reduction and early tumor progression might be useful to ameliorate the cost-benefit of regorafenib. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Prophylaxis against colorectal cancer

    DEFF Research Database (Denmark)

    Bülow, Steffen; Kronborg, O

    1996-01-01

    Colorectal cancer is diagnosed in more than 3000 people every year in Denmark, with a population of 5 million, and 2000 die from this disease every year. The aetiology of the disease is complex, but an increasing number of cancers have been related to genetics and Denmark is contributing with a w...... for colorectal cancer in average-risk persons as well as high-risk groups with precursors of the disease. The present review places Danish contributions within the prophylaxis of colorectal cancer during the last decade in an international context.......Colorectal cancer is diagnosed in more than 3000 people every year in Denmark, with a population of 5 million, and 2000 die from this disease every year. The aetiology of the disease is complex, but an increasing number of cancers have been related to genetics and Denmark is contributing...... with a well-established register of familial adenomatous polyposis and a recently founded register for hereditary nonpolyposis colorectal cancer, both with major international relationships. The Danish tradition of epidemiology and clinical trials has also been demonstrated in population screening trials...

  3. 伊立替康联合卡培他滨治疗转移性结直肠癌的临床研究%Study of Irinotecan plus Capecitabine combination in the treatment of patients with metastatic colorectal cancer

    Institute of Scientific and Technical Information of China (English)

    罗秦英; 罗敏娜; 唐露; 魏友霞; 赵新汉

    2013-01-01

    Objective To investigate the efficacy,the side effects and the survival of the combination of Irinotecan and Capecitabine in patients with metastatic colorectal cancer (MCRC).Methods 135 patients (median age 57 years)with histologic or cytologic confirmnation of metastatic colorectal cancer received Irinotecan 350 mg/m2 intravenously on day 1 for 90 minutes and Capecitabine 1000 mg/m2 orally twice daily on days 1 to 14 in a 21-day treatment cycle as palliative chemotherapy.Each patient was received at least six cycles.Results The complete response rate(CR) was 0% (0/135).The partial response rate (PR) was 46.7% (63/135),stable disease (SD) rate was 31.1% (42/135),and disease progression (PD) rate was 22.2% (30/135).The overall rate (CR + PR) was 46.7% and the clinical benefit rate(RR + SD) was 77.8%.The main toxicities were leukopenia(48.9%),nausea and vomiting(44.4%),diarrhea (64.4%)and hand-foot syndrome (28.9%).No grade 4 events from the entire cohort was found.The median progression-free survival was 10 months (95% CI 6.8-13.1 months),and median overall survival was 18 months (95% CI 16.5-19.5 months).The 1-year,2-year and 3-year survival rates were 57.8%,31.1% and 21.5% respectively.High Karnofsky performance status,single metastatic lesion and response to the regimen indicated respectively good prognosis.Conclusion It was demonstrated that Irinotecan plus Capecitabine regimen was efficient and tolerable in MCRC.The regimen improve the survival moderately and merits further study.%目的 探讨伊立替康(CPT-11)联合卡培他滨治疗转移性结直肠癌的近期疗效、毒性反应及生存状况.方法 135例病理学证实的转移性结直肠腺癌患者接受了伊立替康350 mg/m2,静脉滴注90 min,第1天;卡培他滨1000 mg/m2,第1~14天,2次/d,口服;每3周为一周期,至少6周期方案治疗.评价近期疗效、毒副反应,并进行随访观察生存情况.结果 全组135例患者疗效及

  4. What Is Colorectal Cancer?

    Science.gov (United States)

    ... Research? Colorectal Cancer About Colorectal Cancer What Is Colorectal Cancer? Colorectal cancer is a cancer that starts in ... and spread, see What Is Cancer? How does colorectal cancer start? Most colorectal cancers begin as a growth ...

  5. Cost-effectiveness analysis of panitumumab plus mFOLFOX6 compared with bevacizumab plus mFOLFOX6 for first-line treatment of patients with wild-type RAS metastatic colorectal cancer.

    Science.gov (United States)

    Graham, Christopher N; Hechmati, Guy; Hjelmgren, Jonas; de Liège, Frédérique; Lanier, Julie; Knox, Hediyyih; Barber, Beth

    2014-11-01

    To investigate the cost-effectiveness of panitumumab plus mFOLFOX6 (oxaliplatin, 5-fluorouracil and leucovorin) compared with bevacizumab plus mFOLFOX6 in first-line treatment of patients with wild-type RAS metastatic colorectal cancer (mCRC). A semi-Markov model was constructed from a French health collective perspective, with health states related to first-line treatment (progression-free), disease progression with and without subsequent active treatment, resection of metastases, disease-free after successful resection and death. Parametric survival analyses of patient-level progression-free and overall survival data from the only head-to-head clinical trial of panitumumab and bevacizumab (PEAK) were performed to estimate transitions to disease progression and death. Additional data from PEAK informed the amount of each drug consumed, duration of therapy, subsequent therapy use, and toxicities related to mCRC treatment. Literature and French public data sources were used to estimate unit costs associated with treatment and duration of subsequent active therapies. Utility weights were calculated from patient-level data from panitumumab trials in the first-, second- and third-line settings. A life-time perspective was applied. Scenario, one-way, and probabilistic sensitivity analyses were performed. Based on a head-to-head clinical trial that demonstrates better efficacy outcomes for patients with wild-type RAS mCRC who receive panitumumab plus mFOLFOX6 versus bevacizumab plus mFOLFOX6, the incremental cost per life-year gained was estimated to be €26,918, and the incremental cost per quality-adjusted life year (QALY) gained was estimated to be €36,577. Sensitivity analyses indicate the model is robust to alternative parameters and assumptions. The incremental cost per QALY gained indicates that panitumumab plus mFOLFOX6 represents good value for money in comparison to bevacizumab plus mFOLFOX6 and, with a willingness-to-pay ranging from €40,000 to €60

  6. Analysis of PTEN, BRAF and PI3K status for determination of benefit from cetuximab therapy in metastatic colorectal cancer patients refractory to chemotherapy with wild-type KRAS.

    Science.gov (United States)

    Tural, Deniz; Batur, Sebnem; Erdamar, Sibel; Akar, Emre; Kepil, Nuray; Mandel, Nil Molinas; Serdengeçti, Süheyla

    2014-02-01

    We investigated predictive values of BRAF, PI3K and PTEN in cetuximab responses in KRAS wild-type (+) chemotherapy refractory, metastatic colorectal cancer (CRC) patients. Primary tumour tissues of 41 KRAS wild-type mCRC patients receiving cetuximab-based chemotherapy were investigated for PI3K, PTEN, KRAS and BRAF mutations. Progression-free survival (PFS) and overall survival (OS) periods were calculated with Kaplan-Meier method and the Cox proportional hazards model was used. PTEN and PI3K expressions were 63 and 42 %, respectively. BRAF mutation was observed as 9.8 % among patients. Tumours with BRAF mutation had statistically lower response rates (RR) for cetuximab-based treatment than tumours with BRAF wild type (0 vs. 58 %, p = 0.02). PTEN expressing tumours had statistically higher RR for cetuximab-based treatment than tumours with PTEN loss (42 vs. 12 %, p = 0.04). PI3K expression had worse significant effect on cetuximab RR than PI3K non-expressed tumours (15 vs. 44 %, p = 0.023). Median PFS was significantly longer in patients with PTEN expression (14 months) than in patients with PTEN loss (5 months) (HR, 0.4; p = 0.028). Median PFS was significantly longer in patients with PI3K non-expression (15.2 months) than in patients with PI3K expression (4.1 months) (HR, 0.31; p = 0.001). Significant difference in PFS and OS between patients with BRAF mutated and BRAF wild-type tumours was not detected. However, patients with PTEN expression had significantly longer OS (15.1 months) than patients with PTEN loss tumour (9.9 months) (HR, 0.34; p = 0.008). Patients without PI3K expression had significantly longer OS (18.2 months) than patients with PI3K expression (10.1 months) (HR, 0.27; p = 0.001). Multivariate analyses revealed that PTEN expression (HR, 0.48; p = 0.02) and absence of PI3K expression (HR, 0.2; p = 0.001) were independent prognostic factors for increased PFS. Similarly, PTEN overexpression (HR, 0.62; p = 0.03) and absence of PI3K expression (HR, 0

  7. First-line single-agent panitumumab in frail elderly patients with wild-type KRAS metastatic colorectal cancer and poor prognostic factors: A phase II study of the Spanish Cooperative Group for the Treatment of Digestive Tumours.

    Science.gov (United States)

    Sastre, J; Massuti, B; Pulido, G; Guillén-Ponce, C; Benavides, M; Manzano, J L; Reboredo, M; Rivera, F; Grávalos, C; Safont, M J; Martínez Villacampa, M; Llovet, P; Dotor, E; Díaz-Rubio, E; Aranda, E

    2015-07-01

    Frail elderly patients with metastatic colorectal cancer (mCRC) are not candidates for chemotherapy. Monotherapy with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies may be an option for these patients with few systemic toxic effects. Single-arm, multicentre, phase II trial including patients ⩾ 70y ears with wild-type (WT) KRAS (exon 2) mCRC, Eastern Cooperative Oncology Group (ECOG) status ⩽ 3, KPC (Köhne Prognostic Classification)--defined intermediate or high risk status, frailty and/or ineligibility for chemotherapy. Patients received panitumumab until progression or unacceptable toxicity. The primary end-point was progression free survival (PFS) rate at 6 months. The study included 33 patients (intention-to-treat (ITT) population). Median age: 81 years; sex: 66.7% male; high-risk KPC status: 45.4%. Median treatment duration was 14 weeks and 6-month PFS rate was 36.4% (95% confidence interval (CI): 20.0-52.8). The objective response rate: 9.1% (95% CI: 0-18.9) (all partial responses), and there were 18 stable diseases (54.5%). Median PFS was 4.3 months (95% CI: 2.8-6.4) and median overall survival (OS) was 7.1 months (95% CI: 5.0-12.3). There were no deaths or grade 4-5 adverse events (AEs) related to panitumumab and the most common grade 3-related AE was rash acneiform (15.2%). A significant association between clinical response and RAS status was observed (P=0.037). In the WT RAS subgroup (WT exons 2, 3, and 4 of KRAS and NRAS, N = 15), 6-month PFS rate was 53.3% (95% CI: 30.1-75.2) and median PFS and OS were 7.9 and 12.3 months, respectively. Single-agent panitumumab is active and well tolerated and may be a therapeutic option for high-risk frail elderly patients with WT RAS tumours considered not candidates for chemotherapy (clinicaltrials.gov identifier NCT01126112). Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. Evaluation of efficacy and safety of modified infusion of fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFOXIRI in treatment of metastatic colorectal cancer: a retrospective study of 21 cases

    Directory of Open Access Journals (Sweden)

    Xi-cheng WANG

    2016-04-01

    Full Text Available Objective  To evaluate the safety and preliminary efficacy of mFOLFOXIRI (the combination of irinotecan, oxaliplatin and 5-fluorouracil with reducing dosages in first-line treatment for Chinese patients with unresectable metastatic colorectal cancer (mCRC. Methods  A total of 21 patients received mFOLFOXIRI treatment: irinotecan 150mg/m2 on day 1, oxaliplatin 85mg/m2 on day 1, leucovorin 200mg/m2 on day 1, and 5-fluorouracil (5-FU 2800mg/m2 in a 48-h continuous infusion starting on day 1. The regimen was repeated every 2 weeks. Result  All the 21 patients were evaluated for efficacy of the aforesaid therapeutic regimen, and the incidence of toxic effects. No death occurred in association with the treatment. The total rate of grade 3 to 4 adverse events was 42.9% (9/21 including 38.1% (8 cases with grade 3 neutropenia and 4.8% (1 case suffering from grade 3 anemia. One of 21 patients (4.8% showed grade 4 neutropenia accompanied by fever. The delivered relative dose intensity of irinotecan, oxaliplatin and 5-FU during the entire treatment course were 93.4%, 98.5% and 97.6%, respectively of planned dosage. In the intention-to-treat analysis for treatment activity, 14 patients showed remission, 6 stability, and 1 with progression of the disease. The overall response rate was 66.7%, and the disease control rate was 95.2%. Three patients (15.8% with residual liver metastases were radically resected after mFOLFOXIRI chemotherapy. Conclusions  This mFOLFOXIRI project has manageable toxicity and is well tolerated in Chinese patients. The safety profile appears to be improved compared with standard FOLFOXIRI regimen. In addition, the antitumor activity and preliminary efficacy seem to be maintained. DOI: 10.11855/j.issn.0577-7402.2016.03.15

  9. Efficacy of trifluridine and tipiracil (TAS-102) versus placebo, with supportive care, in a randomized, controlled trial of patients with metastatic colorectal cancer from Spain: results of a subgroup analysis of the phase 3 RECOURSE trial.

    Science.gov (United States)

    Longo-Muñoz, F; Argiles, G; Tabernero, J; Cervantes, A; Gravalos, C; Pericay, C; Gil-Calle, S; Mizuguchi, H; Carrato-Mena, A; Limón, M L; Garcia-Carbonero, R

    2017-02-01

    TAS-102 is a combination of the thymidine-based nucleoside analog trifluridine and the thymidine phosphorylase inhibitor tipiracil. Efficacy and safety of TAS-102 in patients with metastatic colorectal cancer (mCRC) refractory or intolerant to standard therapies were evaluated in the phase 3 RECOURSE trial. Results of RECOURSE demonstrated significant improvement in overall survival (OS) and progression-free survival (PFS) with TAS-102 versus placebo [hazard ratio (HR) = 0.68 and 0.48 for OS and PFS, respectively; both P analysis evaluates efficacy and safety of TAS-102 in the RECOURSE Spanish subgroup. Primary and key secondary endpoints were evaluated in a post hoc analysis of the RECOURSE Spanish subgroup, using univariate and multivariate analyses. Safety and tolerability were reported with descriptive statistics. The RECOURSE Spanish subgroup included 112 patients (mean age 61 years, 62 % male). Median OS was 6.8 months in the TAS-102 group (n = 80) versus 4.6 months in the placebo group (n = 32) [HR = 0.47; 95 % confidence interval (CI): 0.28-0.78; P = 0.0032). Median PFS was 2.0 months in the TAS-102 group and 1.7 months in the placebo group (HR = 0.47; 95 % CI: 0.30-0.74; P = 0.001). Eighty (100 %) TAS-102 versus 31 (96.9 %) placebo patients had adverse events (AEs). The most common drug-related ≥Grade 3 AE was neutropenia (40 % TAS-102 versus 0 % placebo). There was 1 (1.3 %) case of febrile neutropenia in the TAS-102 group versus none in the placebo group. In the RECOURSE Spanish subgroup, TAS-102 was associated with significantly improved OS and PFS versus placebo, consistent with the overall RECOURSE population. No new safety signals were identified. CLINICALTRIALS. NCT01607957.

  10. Danish Colorectal Cancer Group Database

    DEFF Research Database (Denmark)

    Ingeholm, Peter; Gögenur, Ismail; Iversen, Lene H

    2016-01-01

    , and other pathological risk factors. DESCRIPTIVE DATA: 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......-term survivals since it started in 2001 for both patients with colon and rectal cancers.......AIM OF DATABASE: 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. STUDY POPULATION: All Danish patients with newly diagnosed colorectal cancer who are either diagnosed...

  11. Colorectal Cancer

    Science.gov (United States)

    ... rectum are part of the large intestine. Colorectal cancer occurs when tumors form in the lining of ... men and women. The risk of developing colorectal cancer rises after age 50. You're also more ...

  12. Registered partnerships

    CERN Multimedia

    Staff Association

    2015-01-01

    In recent decades, family patterns have changed significantly. National laws have taken these changes into account, recognizing new forms of unions, different to heterosexual marriage. Indeed, recently some countries have given the possibility to same-sex couples to enter into various forms of unions. Staff regulations of international organizations are not directly affected by national laws, but in the context of diversity policies, the lack of recognition of these new forms of unions, may appear to discriminate based on sexual orientation and to limit the freedom of choosing marital status. A study by the International Service for Remunerations and Pensions (iSRP) of the OECD in January 2015 (PROS Report (1015) 04) shows that in comparison with other international organizations, CERN offers the least favorable social conditions for its Staff with in a registered partnership. As part of the Five-year review in 2015, it is important that CERN aligns itself with the practice of these other organizations...

  13. Synchronous resections of primary colorectal tumor and liver metastasis by laparoscopic approach

    OpenAIRE

    2013-01-01

    Liver metastasis of colorectal cancer is common. Resection of solitary tumors of primary and metastatic colorectal cancer can have a favorable outcome. Open resection of primary colorectal tumor and liver metastasis in one operation or in separate operations is currently common practice. Reports have shown that synchronous resections do not jeopardize short or long-term surgical outcomes and that this is a safe and effective approach in open surgery. The development of laparoscopic colorectal...

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

    Science.gov (United States)

    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.

  15. 贝伐单抗联合化疗一线治疗转移性结直肠癌的Meta分析%Bevacizumab Combined with Chemotherapy as First-line Therapy for Metastatic Colorectal Cancer: A Meta-analysis

    Institute of Scientific and Technical Information of China (English)

    曲颜丽; 王海峰; 唐勇

    2014-01-01

    目的 评价贝伐单抗(bevacizumab,BEV)联合化疗一线治疗转移性结直肠癌(metastatic colorectal cancer,mCRC)的有效性和安全性.方法 通过The Cochrane Library、PubMed、EMBASE和中国生物医学文献数据库(CBM)、中国期刊全文数据库(CNKI)、维普数据库(VIP)、万方数据库等检索有关BEV联合化疗一线治疗mCRC的随机对照试验(randomized control trial,RCT);主要研究指标是无进展生存时间(progression free survival,PFS)和总生存时间(overall survival,OS),次要研究指标包括有效率(objective response rate,ORR)和不良反应;采用相对危险度(relative risk,RR)和风险比(hazard ratios,HR)为效应量,各效应量以95%置信区间(95%CI)表示,Stata 11.0统计软件进行Meta分析.结果 共纳入9项RCT,共3 930例mCRC患者,Meta分析结果显示,与单纯化疗相比,贝伐单抗(bevacizumb,BEV)联合化疗可以降低疾病进展风险(HR=0.62,P<0.0001,95%CI:0.64~0.74)和疾病死亡风险(HR=0.84,P<0.001,95%CI:0.73~0.95),提高mCRC的ORR(RR=0.80,P<0.001,95%CI:0.60~0.93).亚组分析显示BEV联合双药方案可降低疾病进展风险(HR=0.68,P<0.001,95%CI:0.46~0.89),但并没有降低疾病死亡风险(HR=0.85,P=0.068,95%CI:0.68~1.03);BEV联合氟尿嘧啶类单药降低疾病进展风险(HR=0.56,P<0.001,95%CI:0.47~0.64)和疾病死亡风险(HR=0.83,P<0.001,95%CI:0.68~0.97).在不良反应方面,BEV联合化疗没有增加治疗相关死亡率(RR=0.97,P=0.91,95%CI:0.62~1.54);增加BEV相关不良反应发生率.结论 BEV联合化疗一线治疗能提高mCRC患者PFS、OS和RR.BEV联合不同化疗方案所带来生存获益大小不同.虽然BEV相关不良反应增加,但是可控的.

  16. Cytomorphology of Circulating Colorectal Tumor Cells: A Small Case Series

    Directory of Open Access Journals (Sweden)

    Dena Marrinucci

    2010-01-01

    Full Text Available Several methodologies exist to enumerate circulating tumor cells (CTCs from the blood of cancer patients; however, most methodologies lack high-resolution imaging, and thus, little is known about the cytomorphologic features of these cells. In this study of metastatic colorectal cancer patients, we used immunofluorescent staining with fiber-optic array scanning technology to identify CTCs, with subsequent Wright-Giemsa and Papanicolau staining. The CTCs were compared to the corresponding primary and metastatic tumors. The colorectal CTCs showed marked intrapatient pleomorphism. In comparison to the corresponding tissue biopsies, cells from all sites showed similar pleomorphism, demonstrating that colorectal CTCs retain the pleomorphism present in regions of solid growth. They also often retain particular cytomorphologic features present in the patient's primary and/or metastatic tumor tissue. This study provides an initial analysis of the cytomorphologic features of circulating colon cancer cells, providing a foundation for further investigation into the significance and metastatic potential of CTCs.

  17. MicroRNA regulation network in colorectal cancer metastasis

    Institute of Scientific and Technical Information of China (English)

    Jiao-Jiao; Zhou; Shu; Zheng; Li-Feng; Sun; Lei; Zheng

    2014-01-01

    Colorectal cancer is the third most common cancer worldwide. Metastasis is a major cause of colorectal cancer-related death. Mechanisms of metastasis remain largely obscure. MicroRNA is one of the most important epigenetic regulators by targeting mRNAs posttranscriptionally. Accumulated evidence has supported its significant role in the metastasis of colorectal cancer, including epithelial-mesenchymal transition and angiogenesis. Dissecting microRNAome potentially identifies specific microRNAs as biomarkers of colorectal cancer metastasis. Better understanding of the complex network of microRNAs in colorectal cancer metastasis provide new insights in the biological process of metastasis and in the potential targets for colorectal cancer therapies and for diagnosis of recurrent and metastatic colorectal cancer.

  18. Bevacizumab safety in Japanese patients with colorectal cancer.

    Science.gov (United States)

    Hatake, Kiyohiko; Doi, Toshihiko; Uetake, Hiroyuki; Takahashi, Yoichiro; Ishihara, Yumi; Shirao, Kuniaki

    2016-03-01

    Bevacizumab (Avastin(®)) was approved in Japan in April 2007 for patients with advanced or metastatic colorectal cancer. To address the limited clinical experience in Japanese patients, a post-approval surveillance study was undertaken in bevacizumab-treated patients in Japan. Bevacizumab (5 or 10 mg/kg every 2 weeks) was administered with chemotherapy; patients were observed for 26 weeks from initiation of treatment. The primary objective was to investigate the incidence of adverse drug reactions, particularly those of interest for bevacizumab. Univariate and multivariate analyses were performed to identify potential risk factors for adverse drug reactions. In total, 2712 patients were registered and 2696 patients were included in the safety analysis. Hypertension (13.1%), hemorrhage (10.5%) and proteinuria (4.5%) were the most common adverse drug reaction. The incidences of serious adverse drug reactions were low: gastrointestinal perforation occurred in 0.9% of patients, hemorrhage in 1.3%, arterial thromboembolic events in 0.3%, venous thromboembolic events in 1.3% and wound-healing complications in 0.4%. The incidence of bevacizumab-specific adverse drug reactions was not influenced by the bevacizumab dose. Multivariate analyses identified risk factors for the following adverse drug reactions: hypertension (prior/concurrent hypertension); tumor-associated bleeding (performance status, prior/concomitant anticoagulant or nonsteroidal anti-inflammatory drug use); proteinuria (sex, performance status, prior/concurrent diabetes and proteinuria); gastrointestinal perforation (primary tumor in situ, concurrent nonsteroidal anti-inflammatory drug use); venous thromboembolic event (treatment stage, port insertion). The safety profile of bevacizumab-containing regimens in this Japanese population was comparable with studies performed in Western countries. Bevacizumab is generally well tolerated in Japanese patients with advanced or metastatic colorectal cancer. © The

  19. Expression of CCR7, L-selectin, CD44v6 and MMP9 in colorectal cancer and their relative with lymphatic metastatic%大肠癌中CCR7、L-selectin、CD44v6和MMP9表达及其与淋巴转移的关系

    Institute of Scientific and Technical Information of China (English)

    武欣; 李坤; 张凡; 刘军超; 林媛媛; 金春亭

    2013-01-01

    目的 探讨CC趋化因子受体7(CCR7)、L-selectin、CD44v6和MMP9在大肠癌组织中的表达及其与大肠癌淋巴转移的关系.方法 采用免疫组化PV 9000两步法检测104例大肠癌组织(大肠癌组)、55例癌旁正常组织(癌旁组)和34例转移灶组织(转移组)中CCR7和L-selectin、CD44v6和MMP9的表达.结果 大肠癌组、转移组中CCR7、L-selectin、CD44v6和MMP9阳性率明显高于癌旁组(P<0.05),有淋巴结转移者明显高于无转移者(P<0.05);CCR7与L-selectin、MMP9表达呈正相关(P<0.05);CD44v6与L-selectin、MMP9表达相关;L-selectin与MMP9的表达呈正相关.结论 CCR7、L-selectin、CD44v6和MMP9在大肠癌中的表达与大肠癌的发生、淋巴转移有关,它们可能共同参与了大肠癌发生及淋巴结转移过程.%Purpose To investigate the expression of chemokine receptor 7 ( CCR7 ), adhesion molecule L-selectin, CD44v6 and MMP9 in human colorectal carcinoma, and analyze their correlation with lymph node metastasis. Methods The expression of CCR7, L-selectin, CD44v6 and MMP9 were tested by immunohistochemical method in 104 cases of colorectal carcinoma specimens ( colorectal carcinoma group ), 55 cases of normal intestinal mucosa adjacent to carcinoma ( adjacent group ) and 34 cases of metastatic tumor tissue ( metastasis group). Results The positive rate of CCR7, L-selectin, CD44v6 and MMP9 expression in the colorectal carcinoma group and metastatic tumor tissue were significantly higher than that in adjacent group and metastasis group ( P < 0. 05 ). The expression of CCR7, L-selectin, CD44v6 and MMP9 in the tissue with lymph node metastasis was significantly higher than that in the tissue without lymph node metastasis ( P <0. 05 ). There was significantly positive correlation between expression of CCR7 and L-selectin, CCR7 and MMP9, CD44v6 and L-selectin, CD44v6 and MMP9, L-selectin and MMP9 ( P < 0. 05 ). Conclusions The expression of CCR7, L-selectin, CD44v6 and MMP9 are closely

  20. Bio markers and Anti-EGFR therapies for Krads wild-type tumors in metastatic colorectal cancer patients; Biomarcadores y terapeutica ANTI-EGFR en el cancer colorrectal metastasico en pacientes con K-Ras no mutado

    Energy Technology Data Exchange (ETDEWEB)

    Diaz Rubio Garcia, E.

    2009-07-01

    The natural history of metastasis colorectal cancer has being clearly modified in terms of response rate, time to progression and overall survival, once the anti-EGFR 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.

  1. Cardiac Recurrence in a Patient with Long-Term Survival from Metastatic Colon Cancer

    Directory of Open Access Journals (Sweden)

    Annabelle Butler

    2012-04-01

    Full Text Available Metastatic colorectal cancer represents a major health problem in the US and worldwide. Forty percent of patients undergoing resection of the primary tumor will experience relapse. In this brief review, we describe a case of a woman with metastatic disease and long-term survival culminating with an unusual myocardial recurrence. Over three decades, a multimodality approach has evolved to allow for long-term survival in selected patients with metastatic colorectal cancer. In this case report, the role of multiple aggressive surgical resections is emphasized.

  2. High prevalence of advanced colorectal neoplasia in the Thai population: a prospective screening colonoscopy of 1,404 cases.

    Science.gov (United States)

    Siripongpreeda, Bunchorn; Mahidol, Chulabhorn; Dusitanond, Navara; Sriprayoon, Tassanee; Muyphuag, Bunlung; Sricharunrat, Thaniya; Teerayatanakul, Narongchai; Chaiwong, Watanya; Worasawate, Wipra; Sattayarungsee, Prassanee; Sangthongdee, Juthamas; Prarom, Jirapa; Sornsamdang, Gaidganok; Soonklang, Kamonwan; Wittayasak, Kasiruck; Auewarakul, Chirayu U

    2016-08-23

    Increasing morbidity and mortality from colorectal cancer is evident in recent years in the developing Asian nations. Particularly in Thailand and most neighbouring low-income countries, screening colonoscopy is not yet recommended nor implemented at the national policy level. Screening colonoscopy was offered to 1,500 healthy volunteers aged 50-65 years old who were registered into the program between July 2009 and June 2010. Biopsy and surgery was performed depending on the identified lesions. Fecal immunochemical tests (FIT) were additionally performed for comparison with colonoscopy. There were 1,404 participants who underwent colonoscopy. The mean age of the cohort was 56.9 ± 4.2 years and 69.4 % were females. About 30 % (411 cases) of all colonoscopies had abnormal colonoscopic findings, and of these, 256 cases had adenomatous polyps. High risk adenomas (villous or tubulovillous or high grade dysplasia or size > 1 cm or > 3 adenomatous polyps) were found in 98 cases (7 %), low risk adenoma in 158 cases (11.3 %), and hyperplastic polyps in 119 cases (8.5 %). Eighteen cases (1.3 %) had colorectal cancer and 90 % of them (16 cases) were non-metastatic including five stage 0 cases, seven stage I cases, and four stage IIA cases. Only two cases had metastasis: one to regional lymph nodes (stage IIIB) and another to other organs (stage IVA). The most common cancer site was the distal intestine including rectum (7 cases, 38.9 %) and sigmoid colon (7 cases, 38.9 %). Ten colorectal cancer cases had positive FIT whereas 8 colorectal cancer cases were FIT-negative. The sensitivity and specificity of FIT was 55.6 % and 96.2 %, respectively, while the positive predictive value was 16.4 % and negative predictive value was 99.4 %. The overall survival of colorectal cancer cases at 5-year was 83.3 %. High prevalence of colorectal cancer and high-risk adenoma was found in the Thai population aged 50-65 years old by screening colonoscopy. FIT was

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

    Energy Technology Data Exchange (ETDEWEB)

    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

  4. Can we accurately report PTEN status in advanced colorectal cancer?

    OpenAIRE

    Hocking, Christopher; Hardingham, Jennifer E.; Broadbridge, Vy; Wrin, Joe; Townsend, Amanda R; Tebbutt, Niall; Cooper, John; Ruszkiewicz, Andrew; Lee, Chee; Price, Timothy J.

    2014-01-01

    Background Loss of phosphatase and tensin homologue (PTEN) function evaluated by loss of PTEN protein expression on immunohistochemistry (IHC) has been reported as both prognostic in metastatic colorectal cancer and predictive of response to anti-EGFR monoclonal antibodies although results remain uncertain. Difficulties in the methodological assessment of PTEN are likely to be a major contributor to recent conflicting results. Methods We assessed loss of PTEN function in 51 colorectal cancer ...

  5. Prognostic Significance of Peritoneal Metastasis in Stage IV Colorectal Cancer Patients With R0 Resection: A Multicenter, Retrospective Study.

    Science.gov (United States)

    Arakawa, Keiichi; Kawai, Kazushige; Ishihara, Soichiro; Hata, Keisuke; Nozawa, Hiroaki; Oba, Koji; Sugihara, Kenichi; Watanabe, Toshiaki

    2017-10-01

    Stage IV colorectal cancer encompasses various clinical conditions. The differences in prognosis after surgery between different metastatic organs have not been fully investigated. This study aimed to assess prognostic significance in peritoneal metastasis in R0 resected stage IV colorectal cancer. We conducted a multicenter retrospective study of patients with R0 resected stage IV colorectal cancer; they were categorized into 3 groups according to the number and location of metastatic organs, including single-organ metastasis in the peritoneum, single-organ metastasis at sites except the peritoneum, and multiple-organ metastases. This study used data accumulated by the Japanese Study Group for Postoperative Follow-Up of Colorectal Cancer. A total of 1133 patients with R0 resected stage IV colorectal cancer were registered retrospectively between 1997 and 2007 in 20 referral hospitals. Cancer-specific survival rates between the groups were measured. The median cancer-specific survival of the single-organ metastasis in the peritoneum group was considerably shorter than that of the single-organ metastasis at a site other than the peritoneum group and was almost comparable to that of the multiple-organ metastases group (3.41 years, 6.20 years, and 2.99 years). In a multivariate analysis of cancer-specific survival, peritoneal dissemination was confirmed as an independent prognostic factor of survival. The median postrecurrence survival of single-organ metastasis in the peritoneum group was considerably shorter than that of the single-organ metastasis at a site other than the peritoneum group. Approximately half of the patients who experienced recurrence of single-organ metastasis in the peritoneum experienced peritoneal recurrence. This was a retrospective, population-based study that requires a prospective design to validate its conclusions. Peritoneal metastasis of colorectal cancer frequently recurred in the peritoneum even after R0 resection. The cancer

  6. Pulmonary nodules and metastases in colorectal cancer

    DEFF Research Database (Denmark)

    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...

  7. Capecitabine and bevacizumab in heavily pre-treated patients with advanced colorectal cancer

    DEFF Research Database (Denmark)

    Larsen, Finn Ole; Boisen, Mogens Karsbøl; Fromm, Anne-Lene Gunge

    2012-01-01

    No standard treatment exists for patients with metastatic colorectal cancer who have progressed after treatment with 5-fluorouracil (5-FU), oxaliplatin, irinotecan and an anti-EGFR antibody. The efficacy and safety of bevacizumab and capecitabine in heavily pre-treated patients with metastatic...

  8. Metastatic Cancer to the Larynx: A Case Report and Update.

    Science.gov (United States)

    Zenga, Joseph; Mehrad, Mitra; Bradley, Joseph P

    2016-11-01

    The aim of this study was to describe a case of colorectal carcinoma metastatic to the larynx and provide a review of the current literature. A case report with chart review was performed. A review of the current literature was performed by systematically searching PubMed, OVID, CINAHL Plus, and EMBASE. In 1988, a comprehensive literature review identified melanoma as the most common neoplasm to exhibit laryngeal involvement. Since that study, 41 subsequent cases have been reported, and among these, colorectal adenocarcinoma was the most frequent distant primary (24%). In 25 (58%) cases, curative surgery was attempted, but only 4 patients remained disease-free at last follow up. We report the history of a 52-year-old man who presented with rectal adenocarcinoma metastatic to his larynx 4 years after definitive treatment of the primary site. In patients with a laryngeal mass and a history of colorectal cancer, or those at high risk of having an occult colorectal primary, metastatic spread to the larynx must always be considered. Although secondary laryngeal metastasis portends a poor prognosis, for the select patient, surgical intervention can provide long-term disease control. Copyright © 2016 The Voice Foundation. Published by Elsevier Inc. All rights reserved.

  9. National Register Historic Districts

    Data.gov (United States)

    Iowa State University GIS Support and Research Facility — The National Register Historic District layer is a shape file showing the boundaries of Historic Districts that are listed on the National Register of Historic Places.

  10. Cytomorphology of Circulating Colorectal Tumor Cells:A Small Case Series

    Science.gov (United States)

    Marrinucci, Dena; Bethel, Kelly; Lazar, Daniel; Fisher, Jennifer; Huynh, Edward; Clark, Peter; Bruce, Richard; Nieva, Jorge; Kuhn, Peter

    2010-01-01

    Several methodologies exist to enumerate circulating tumor cells (CTCs) from the blood of cancer patients; however, most methodologies lack high-resolution imaging, and thus, little is known about the cytomorphologic features of these cells. In this study of metastatic colorectal cancer patients, we used immunofluorescent staining with fiber-optic array scanning technology to identify CTCs, with subsequent Wright-Giemsa and Papanicolau staining. The CTCs were compared to the corresponding primary and metastatic tumors. The colorectal CTCs showed marked intrapatient pleomorphism. In comparison to the corresponding tissue biopsies, cells from all sites showed similar pleomorphism, demonstrating that colorectal CTCs retain the pleomorphism present in regions of solid growth. They also often retain particular cytomorphologic features present in the patient's primary and/or metastatic tumor tissue. This study provides an initial analysis of the cytomorphologic features of circulating colon cancer cells, providing a foundation for further investigation into the significance and metastatic potential of CTCs. PMID:20111743

  11. Peptide Vaccine Therapy in Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    Shi-Yu Yang

    2012-08-01

    Full Text Available Colorectal cancer is the third most common cause of cancer-related deaths and the second most prevalent (after breast cancer in the western world. High metastatic relapse rates and severe side effects associated with the adjuvant treatment have urged oncologists and clinicians to find a novel, less toxic therapeutic strategy. Considering the limited success of the past clinical trials involving peptide vaccine therapy to treat colorectal cancer, it is necessary to revise our knowledge of the immune system and its potential use in tackling cancer. This review presents the efforts of the scientific community in the development of peptide vaccine therapy for colorectal cancer. We review recent clinical trials and the strategies for immunologic monitoring of responses to peptide vaccine therapy. We also discuss the mechanisms underlying the therapy and potential molecular targets in colon cancer.

  12. Tests for Colorectal Cancer

    Science.gov (United States)

    ... Cancer Early Detection, Diagnosis, and Staging Tests for Colorectal Cancer Colorectal cancer is often found after symptoms appear, ... Report: Colon Pathology. Imaging tests to look for colorectal cancer Imaging tests use sound waves, x-rays, magnetic ...

  13. The microenvironment of liver metastases from Colorectal adenocarcinoma

    DEFF Research Database (Denmark)

    Eefsen, Rikke Løvendahl

    Colorectal adenocarcinoma (CRC) is the third most frequent cancer type worldwide and the third leading cause of cancer related death. During the course of the disease about 50% of patients are diagnosed with metastatic CRC (mCRC). The 5-year survival for patients who undergo a hepatic resection i...

  14. Randomised trial comparing three different schedules of infusional 5FU and raltitrexed alone as first-line therapy in metastatic colorectal cancer. Final results of the Fédération Francophone de Cancérologie Digestive (FFCD) 9601 trial.

    Science.gov (United States)

    Ducreux, M; Bouche, O; Pignon, J P; Mousseau, M; Raoul, J L; Cassan, P; Leduc, B; Berger, C; Dunant, A; Fournet, J; Bedenne, L

    2006-01-01

    LV5FU2 with high-dose leucovorin (LV), weekly infusional 5-fluorouracil (5FU) (AIO schedule) and raltitrexed have been demonstrated to be active agents in first-line treatment of colorectal cancer. We performed a 4-arm randomised trial to compare (1) a low-dose intravenous bolus of LV (20 mg/m2), followed by an intravenous bolus of 5FU (400 mg/m2), followed by a 22-hour continuous infusion of 5FU (600 mg/m2) on day 1 and day 2/2 weeks (ldLV5FU2 arm), (2) a weekly continuous infusion of high-dose 5FU (2.6 g/m2/week) for 6 weeks followed by a rest week (HD-FU arm) and (3) raltitrexed (Tomudex arm; 3 mg/m2/3 weeks) to standard LV5FU2. From 1997 to 2001, 294 patients were included. The 4 arms were well balanced for sex ratio, age, WHO performance status, the primary tumour site and prior adjuvant chemotherapy. Treatment was stopped due to low accrual. Two toxicity-related deaths were observed in the Tomudex arm. The treatments gave rise to different rates of grade 3-4 neutropenia (3, 4, 11 and 14% of the patients in the LV5FU2, ldLV5FU2, HD-FU and Tomudex arms, respectively, p = 0.028), leucopenia and vomiting. At least one episode of grade 3-4 toxicity was observed in 27, 25, 38 and 47% of the patients in the LV5FU2, ldLV5FU2, HD-FU and Tomudex arms, respectively (p = 0.016). An objective response was observed in 28, 21, 22 and 10% of the patients in the LV5FU2, ldLV5FU2, HD-FU and Tomudex arms, respectively (p = 0.04). Progression-free survival (PFS) of the patients in the Tomudex arm was statistically lower compared to that of patients treated with LV5FU2 or ldLV5FU2 (combined group; p = 0.013, log rank test). In conclusion, Tomudex is more toxic and yields shorter PFS than infusional 5FU. Despite the early closure of the study and the lack of power of the comparison, it seems that ldLV5FU2 could be considered as an active, easier and less expensive option for the treatment of metastatic colorectal cancer compared to classic LV5FU2 or weekly HD-FU.

  15. Is obesity an advantage in patients with colorectal cancer?

    Science.gov (United States)

    Kasi, Pashtoon Murtaza; Zafar, S Yousuf; Grothey, Axel

    2015-01-01

    Obesity/higher BMI appears to be important determinants in the development of colon cancer as well as in predicting outcomes in the adjuvant setting in these patients. These associations seem to be stronger for men and tend to be 'J-shaped', with worse outcomes in both lower and upper BMI categories than in the middle categories. How this factors in the metastatic setting is less clear. A recent pooled analysis of patients with metastatic colorectal cancer receiving bevacizumab in the first-line setting observed that patients with the lowest BMI had the lowest median overall survival. An incremental BMI increase of 5 kg/m(2) led to actually a decrease in the risk of death (hazard ratio, 0.911 [95% CI, 0.879-0.944]). The observed association does not necessarily mean that obesity is an advantage for patients with metastatic colorectal cancer. More likely, it is conceivable that, in patients with metastatic colorectal cancer with a lower BMI, the effects of cancer-related cachexia may be more deleterious than the potential adverse events related to a higher BMI. In patients already diagnosed with metastatic disease, studying how body weight affects tumor biology and treatment-related decisions are important considerations.

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

    Directory of Open Access Journals (Sweden)

    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.

  17. The Danish Twin Register

    DEFF Research Database (Denmark)

    Kyvik, K O; Christensen, Kaare; Skytthe, A;

    1996-01-01

    BACKGROUND: Population based twin registers represent a valuable tool for genetic epidemiological research, since twin studies aim at separating the effect of genes and environment for complex traits. The Danish Twin Register's history, size, ascertainment and completeness of data, as well as data...... accessibility and availability are described. RESULTS: The Danish Twin Register comprises 14,051 twin pairs born 1870-1930, representing all twins surviving to age six years, and 20,888 twin pairs born 1953-1982, representing 75% of those born 1953-1967 and 95% of those born 1968-1982. The birth cohorts 1931......-1952 og 1983-1993 are being ascertained at the moment. The register is available for research given certain conditions are fulfilled. CONCLUSION: This register will in a few years be the most comprehensive twin register in the world. It is a very valuable Danish research resource....

  18. The Danish Twin Register

    DEFF Research Database (Denmark)

    Kyvik, K O; Christensen, Kaare; Skytthe, A

    1996-01-01

    BACKGROUND: Population based twin registers represent a valuable tool for genetic epidemiological research, since twin studies aim at separating the effect of genes and environment for complex traits. The Danish Twin Register's history, size, ascertainment and completeness of data, as well as data...... accessibility and availability are described. RESULTS: The Danish Twin Register comprises 14,051 twin pairs born 1870-1930, representing all twins surviving to age six years, and 20,888 twin pairs born 1953-1982, representing 75% of those born 1953-1967 and 95% of those born 1968-1982. The birth cohorts 1931......-1952 og 1983-1993 are being ascertained at the moment. The register is available for research given certain conditions are fulfilled. CONCLUSION: This register will in a few years be the most comprehensive twin register in the world. It is a very valuable Danish research resource....

  19. Tiam1 gene expression and its significance in colorectal carcinoma

    Institute of Scientific and Technical Information of China (English)

    Li Liu; De-Hua Wu; Yan-Qing Ding

    2005-01-01

    AIM: To explore the expression of Tiam1 gene in colorectal carcinoma and its correlation with tumor metastasis.METHODS: Expressions of Tiam1 gene in 8 colorectal carcinoma cell lines were detected by reverse transcriptasepolymerase chain reaction. In vitro invasiveness was determined by means of Matrigel invasion assay. The correlation of Tiam1 expression with the invasive ability was also analyzed.RESULTS: Tiam1 gene was highly expressed in LoVo and SW620, which were established from metastatic colorectal carcinomas in comparison with LS174T, SW480, HCT116,LST, HRT-18 and Hee8693, which were established from primary colorectal carcinomas. In vitro cell invasivion demonstrated that LoVo and SW620 had a higher invasive ability than LS174T, SW480, HCT116, LST, HRT-18 and Hee8693. The expression of Tiam1 gene was highly related to the metastatic potential of colorectal carcinoma cells.CONCLUSION: Tiam1 gene may play an important role in invasion and metastasis of colorectal carcinoma and is a metastasis-related gene.

  20. Arthroplasty register for Germany

    Directory of Open Access Journals (Sweden)

    Hagen, Anja

    2009-10-01

    Full Text Available Scientific background: The annual number of joint replacement operations in Germany is high. The introduction of an arthroplasty register promises an important contribution to the improvement of the quality of patient’s care. Research questions: The presented report addresses the questions on organization and functioning, benefits and cost-benefits as well as on legal, ethical and social aspects of the arthroplasty registers. Methods: A systematic literature search was conducted in September 2008 in the medical databases MEDLINE, EMBASE etc. and was complemented with a hand search. Documents describing arthroplasty registers and/or their relevance as well as papers on legal, ethical and social aspects of such registers were included in the evaluation. The most important information was extracted and analysed. Results: Data concerning 30 arthroplasty registers in 19 countries as well as one international arthroplasty register were identified. Most of the arthroplasty registers are maintained by national orthopedic societies, others by health authorities or by their cooperation. Mostly, registries are financially supported by governments and rarely by other sources.The participation of the orthopedists in the data collection process of the arthroplasty registry is voluntary in most countries. The consent of the patients is usually required. The unique patient identification is ensured in nearly all registers.Each data set consists of patient and clinic identification numbers, data on diagnosis, the performed intervention, the operation date and implanted prostheses. The use of clinical scores, patient-reported questionnaires and radiological documentation is rare. Methods for data documentation and transfer are paper form, electronic entry as well as scanning of the data using bar codes. The data are mostly being checked for their completeness and validity. Most registers offer results of the data evaluation to the treating orthopedists and

  1. Liver resection in metastatic colorectal cancer: a multidisciplinary approach Resección hepática por metástasis de cáncer colorrectal: una visión multidisciplinar

    Directory of Open Access Journals (Sweden)

    J. F. Noguera Aguilar

    2005-11-01

    Full Text Available Aim: to analyze qualitative short-time results of a new program for multidisciplinary liver evaluation in complex cases of liver metastasis from colorectal cancer. Patients and methods: 40 clinical consecutive evaluations with liver metastasis assessed for major liver resection by a multidisplinary specialist committee. Complementary explorations performed included CT and ultrasounds, and MRI or PET for doubtful cases. Liver resection was made in a single operation or two-stage hepatectomy, or combined with other techniques. Results: postoperative mortality at 30 days was 4%. Complications occurred in 28%, with surgical wound infection being most frequent (20%; 16.6% of resections were transfused, with a mean volume of 1000 ml. Two patients needed reoperation -one for an intraperitoneal abscess and one for bile-duct stenosis. Percentage of global relapse was 36%, with 26% of relapses out of the liver. Actuarial survival at one year follow-up was 90%, and 82% at two years; 64% of patients remain free of disease two years after the operation. Conclusions: programs for liver resection for colorectal cancer metastasis may be implemented by multidisciplinary teams of recent setup. There is a need to evaluate own results and then compare them with a standard of quality previously reported.Objetivo: valorar los resultados cualitativos a corto y medio plazo de un programa de reciente implantación de evaluación hepática multidisciplinar de casos complejos de metástasis hepáticas de cáncer colorrectal. Pacientes y métodos: cuarenta evaluaciones clínicas consecutivas de pacientes con metástasis hepáticas de cáncer colorrectal valorados para resección hepática mayor, realizadas por un comité multidisciplinar de especialistas. Las exploraciones complementarias practicadas fueron TAC trifásica y ecografía intraoperatoria, junto a RMN y/o PET en casos de dudas. La resección hepática se podía realizar como gesto único o bien en dos tiempos y

  2. HLA-G 3'UTR Polymorphisms Predict Drug-Induced G3-4 Toxicity Related to Folinic Acid/5-Fluorouracil/Oxaliplatin (FOLFOX4) Chemotherapy in Non-Metastatic Colorectal Cancer.

    Science.gov (United States)

    Garziera, Marica; Virdone, Saverio; De Mattia, Elena; Scarabel, Lucia; Cecchin, Erika; Polesel, Jerry; D'Andrea, Mario; Pella, Nicoletta; Buonadonna, Angela; Favaretto, Adolfo; Toffoli, Giuseppe

    2017-06-27

    Polymorphisms in drug-metabolizing enzymes might not completely explain inter-individual differences in toxicity profiles of patients with colorectal cancer (CRC) that receive folinic acid/5-fluorouracil/oxaliplatin (FOLFOX4). Recent data indicate that the immune system could contribute to FOLFOX4 outcomes. In light of the immune inhibitory nature of human leukocyte antigen-G (HLA-G), a non-classical major histocompatibility complex (MHC) class I molecule, we aimed to identify novel genomic markers of grades 3 and 4 (G3-4) toxicity related to FOLFOX4 therapy in patients with CRC. We retrospectively analyzed data for 144 patients with stages II-III CRC to identify HLA-G 3' untranslated region (3'UTR) polymorphisms and related haplotypes and evaluate their impact on the risk of developing G3-4 toxicities (i.e., neutropenia, hematological/non-hematological toxicity, neurotoxicity) with logistic regression. The rs1610696-G/G polymorphism was associated with increased risk of G3-4 neutropenia (OR = 3.76, p = 0.015) and neurotoxicity (OR = 8.78, p = 0.016); rs371194629-Ins/Ins was associated with increased risk of neurotoxicity (OR = 5.49, p = 0.027). HLA-G 3'UTR-2, which contains rs1610696-G/G and rs371194629-Ins/Ins polymorphisms, was associated with increased risk of G3-4 neutropenia (OR = 3.92, p = 0.017) and neurotoxicity (OR = 11.29, p = 0.009). A bootstrap analysis confirmed the predictive value of rs1610696 and rs371194629, but the UTR-2 haplotype was validated only for neurotoxicity. This exploratory study identified new HLA-G 3'UTR polymorphisms/haplotypes as potential predictive markers of G3-4 toxicities in CRC.

  3. Time to Definitive Health-Related Quality of Life Score Deterioration in Patients with Resectable Metastatic Colorectal Cancer Treated with FOLFOX4 versus Sequential Dose-Dense FOLFOX7 followed by FOLFIRI: The MIROX Randomized Phase III Trial.

    Directory of Open Access Journals (Sweden)

    Zeinab Hamidou

    Full Text Available We previously showed that a sequential chemotherapy with dose-dense oxaliplatin (FOLFOX7 and irinotecan (FOLFIRI; irinotecan plus 5-fluorouracil/leucovorin is not superior to FOLFOX4 in patients at advanced stage of colorectal cancer with liver metastases. Here we aimed to determine whether time to health-related quality of life (HRQoL score definitive deterioration (TUDD differs by study arm.HRQoL was evaluated using the European Organization for Research and Treatment of Cancer (EORTC QLQ-C30 at baseline and every 4 cycles until the end of the study or death. Functional scale, symptom scale, global health status, and financial difficulties were analyzed. The TUDD was defined as the time interval between randomization and the first decrease in HRQoL score ≥ 5-point with no further improvement in HRQoL score ≥ 5 points or any further HRQoL data. TUDD was estimated using the Kaplan-Meier method and the long-rank test. Cox regression analyses were used to identify HRQoL items influencing TUDD. Sensitivity analyses were done using a multiple imputation method and different definitions of TUDD.Of the 284 patients, 171 (60.2% completed HRQoL questionnaires. Cox multivariate analysis showed no statistically significant difference in TUDD for most of the QLQ-C30 scales between treatments. Patients with dyspnea and those without symptoms at baseline had a significantly longer TUDD when there was a delay >12 months between diagnosis of the primary tumor and metastases (HR 0.48 [0.26-0.89] and when there was diarrhea (HR 0.59 [0.36-0.96], respectively.This study shows that TUDD does not differ significantly according to type of treatment. The TUDD method produces meaningful longitudinal HRQoL results that may facilitate effective clinical decision making in patients with mCRC.ClinicalTrials.gov NCT00268398.

  4. HLA-G 3′UTR Polymorphisms Predict Drug-Induced G3-4 Toxicity Related to Folinic Acid/5-Fluorouracil/Oxaliplatin (FOLFOX4) Chemotherapy in Non-Metastatic Colorectal Cancer

    Science.gov (United States)

    Garziera, Marica; Virdone, Saverio; De Mattia, Elena; Scarabel, Lucia; Cecchin, Erika; Polesel, Jerry; D’Andrea, Mario; Pella, Nicoletta; Buonadonna, Angela; Favaretto, Adolfo; Toffoli, Giuseppe

    2017-01-01

    Polymorphisms in drug-metabolizing enzymes might not completely explain inter-individual differences in toxicity profiles of patients with colorectal cancer (CRC) that receive folinic acid/5-fluorouracil/oxaliplatin (FOLFOX4). Recent data indicate that the immune system could contribute to FOLFOX4 outcomes. In light of the immune inhibitory nature of human leukocyte antigen-G (HLA-G), a non-classical major histocompatibility complex (MHC) class I molecule, we aimed to identify novel genomic markers of grades 3 and 4 (G3-4) toxicity related to FOLFOX4 therapy in patients with CRC. We retrospectively analyzed data for 144 patients with stages II-III CRC to identify HLA-G 3′ untranslated region (3′UTR) polymorphisms and related haplotypes and evaluate their impact on the risk of developing G3-4 toxicities (i.e., neutropenia, hematological/non-hematological toxicity, neurotoxicity) with logistic regression. The rs1610696-G/G polymorphism was associated with increased risk of G3-4 neutropenia (OR = 3.76, p = 0.015) and neurotoxicity (OR = 8.78, p = 0.016); rs371194629-Ins/Ins was associated with increased risk of neurotoxicity (OR = 5.49, p = 0.027). HLA-G 3′UTR-2, which contains rs1610696-G/G and rs371194629-Ins/Ins polymorphisms, was associated with increased risk of G3-4 neutropenia (OR = 3.92, p = 0.017) and neurotoxicity (OR = 11.29, p = 0.009). A bootstrap analysis confirmed the predictive value of rs1610696 and rs371194629, but the UTR-2 haplotype was validated only for neurotoxicity. This exploratory study identified new HLA-G 3′UTR polymorphisms/haplotypes as potential predictive markers of G3-4 toxicities in CRC. PMID:28653974

  5. HLA-G 3′UTR Polymorphisms Predict Drug-Induced G3-4 Toxicity Related to Folinic Acid/5-Fluorouracil/Oxaliplatin (FOLFOX4 Chemotherapy in Non-Metastatic Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    Marica Garziera

    2017-06-01

    Full Text Available Polymorphisms in drug-metabolizing enzymes might not completely explain inter-individual differences in toxicity profiles of patients with colorectal cancer (CRC that receive folinic acid/5-fluorouracil/oxaliplatin (FOLFOX4. Recent data indicate that the immune system could contribute to FOLFOX4 outcomes. In light of the immune inhibitory nature of human leukocyte antigen-G (HLA-G, a non-classical major histocompatibility complex (MHC class I molecule, we aimed to identify novel genomic markers of grades 3 and 4 (G3-4 toxicity related to FOLFOX4 therapy in patients with CRC. We retrospectively analyzed data for 144 patients with stages II-III CRC to identify HLA-G 3′ untranslated region (3′UTR polymorphisms and related haplotypes and evaluate their impact on the risk of developing G3-4 toxicities (i.e., neutropenia, hematological/non-hematological toxicity, neurotoxicity with logistic regression. The rs1610696-G/G polymorphism was associated with increased risk of G3-4 neutropenia (OR = 3.76, p = 0.015 and neurotoxicity (OR = 8.78, p = 0.016; rs371194629-Ins/Ins was associated with increased risk of neurotoxicity (OR = 5.49, p = 0.027. HLA-G 3′UTR-2, which contains rs1610696-G/G and rs371194629-Ins/Ins polymorphisms, was associated with increased risk of G3-4 neutropenia (OR = 3.92, p = 0.017 and neurotoxicity (OR = 11.29, p = 0.009. A bootstrap analysis confirmed the predictive value of rs1610696 and rs371194629, but the UTR-2 haplotype was validated only for neurotoxicity. This exploratory study identified new HLA-G 3′UTR polymorphisms/haplotypes as potential predictive markers of G3-4 toxicities in CRC.

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

    Directory of Open Access Journals (Sweden)

    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.

  7. Proporção de linfonodos metastáticos como variável independente de prognóstico no câncer colorretal Metastatic lymph node ratio as an independent prognostic variable in colorectal cancer

    Directory of Open Access Journals (Sweden)

    Denise Gonçalves Priolli

    2008-12-01

    cinco anos (p=0,03. A análise multivariada demonstrou que o ILC é fator prognóstico independente (p=0,009. CONCLUSÃO: Os resultados do presente estudo permitem concluir que o ILC pode ser considerado uma variável independente preditora de sobrevida em doentes com câncer colorretal.In patients with colorectal cancer, the compromising of the lymph node is one of the most important prognostic factors. Aim: The aim of this study is to determine the prognostic independent value of relation between compromised and examined lymph nodes, (LNR in patients with colorectal cancer. METHOD: One hundred and thirteen 113 patients (62 women with colon ad upper rectum cancer were studied. Fifteen patients were staged to the stadium I of the TNM classification, 44 to II, 42 to III and 24 to the stadium IV. The lymph node ratio rate was determined by the relation between total number of compromised and examined lymph nodes. The patients were divided in three groups according to the proportion of compromised lymph nodes: LNR-0: when there was no lymph node involvement; LNR-1: when there was compromising of up to 20% of the examined lymph nodes and LNR-2: when there was compromising in 21% or more of the examined nodes. The relations between lymph node ratio, number of removed lymph nodes and number of compromising lymph nodes by cancer were determined. Patients younger than 18 years old who were submitted to neoadjuvant quimioradiation protocol were excluded as well as the ones who had less than 12 lymph nodes removed. The clinical and histopathological variables were analyzed through descriptive statistic. The correlation between the variables was valued by Spearman correlation test. The five years survival was determined by the tests of Kaplan-Meier, Log-rank and the multivariate analysis of the prognostic variables by the Cox model establishing level of significance of 5 % (p=0.05. RESULTS: There was significant difference in the five years overall survival in patients classified

  8. Registered Nurse (Associate Degree).

    Science.gov (United States)

    Ohio State Univ., Columbus. Center on Education and Training for Employment.

    This document, which is designed for use in developing a tech prep competency profile for the occupation of registered nurse (with an associate degree), lists technical competencies and competency builders for 19 units pertinent to the health technologies cluster in general and 5 units specific to the occupation of registered nurse. The following…

  9. The Danish Adoption Register

    DEFF Research Database (Denmark)

    Petersen, Liselotte; Sørensen, Thorkild I A

    2011-01-01

    The Danish Adoption Register was established in 1963-1964 to explore the genetic and environmental contribution to familial aggregation of schizophrenia.......The Danish Adoption Register was established in 1963-1964 to explore the genetic and environmental contribution to familial aggregation of schizophrenia....

  10. The Danish Pathology Register

    DEFF Research Database (Denmark)

    Bjerregaard, Beth; Larsen, Ole B

    2011-01-01

    The National Board of Health, Denmark in 1997 published guidelines for reporting of pathology data and the Danish Pathology Register (DPR) was established.......The National Board of Health, Denmark in 1997 published guidelines for reporting of pathology data and the Danish Pathology Register (DPR) was established....

  11. [Characteristics and Outcomes of Treatment in Patients with Stage IV Colorectal Cancer with Mismatch Repair Deficiency].

    Science.gov (United States)

    Ishibashi, Keiichiro; Chika, Noriyasu; Suzuki, Okihide; Ito, Tetsuya; Amano, Kunihiko; Kumamoto, Kensuke; Fukuchi, Minoru; Kumagai, Youichi; Mochiki, Erito; Ishida, Hideyuki

    2016-11-01

    Mismatch repair(MMR)protein deficiency in colorectal cancer is well correlated with high-level microsatellite instability (MSI-H). There are little data on mismatch repair deficiency(dMMR)colorectal cancers in Japan. In addition, we have no available data on the therapeutic efficacy of oxaliplatin(oxa)-based chemotherapy, one of the standard treatment regimens for metastatic colorectal cancer, for patients with dMMR colorectal cancer. The subjects were 254 patients with Stage IV colorectal cancer whose tumors were immunohistochemically stained for MMR proteins, MLH1, MSH2, MSH6, and PMS2. Patients who underwent R0 resection were excluded. Clinicopathologic factors and the efficacy of oxa-based chemotherapy were compared between patients with dMMR colorectal cancer and those with mismatch repair proficient(pMMR)colorectal cancer. There were 7(2.8%)patients with dMMR. Four patients demonstrated both MLH1 and PMS2 loss, while 3 patients demonstrated both MSH2 and MSH6 loss. Though the dMMR had a higher frequency in female patients(p=0.02) and a lower frequency in those with liver metastasis(pcolorectal cancers was lower than those(4-11%)reported in Western countries. Therefore, the clinical significance of universal screeningfor dMMR in all colorectal cancer samples may not be valid. Concerningsurvival benefit, oxa-based chemotherapy seems to be an effective alternative in clinical practice for metastatic colorectal cancer patients with dMMR.

  12. Vascular-endothelial-growth-factor (VEGF) targeting therapies for endocrine refractory or resistant metastatic breast cancer.

    Science.gov (United States)

    Wagner, Anna Dorothea; Thomssen, Christoph; Haerting, Johannes; Unverzagt, Susanne

    2012-07-11

    Vascular-endothelial-growth-factor (VEGF) is a key mediator of angiogenesis. VEGF-targeting therapies have shown significant benefits and been successfully integrated in routine clinical practice for other types of cancer, such as metastatic colorectal cancer. By contrast, individual trial results in metastatic breast cancer (MBC) are highly variable and their value is controversial. To evaluate the benefits (in progression-free survival (PFS) and overall survival (OS)) and harms (toxicity) of VEGF-targeting therapies in patients with hormone-refractory or hormone-receptor negative metastatic breast cancer. Searches of CENTRAL, MEDLINE, EMBASE, the Cochrane Breast Cancer Group's Specialised Register, registers of ongoing trials and proceedings of conferences were conducted in January and September 2011, starting in 2000. Reference lists were scanned and members of the Cochrane Breast Cancer Group, experts and manufacturers of relevant drug were contacted to obtain further information. No language restrictions were applied. Randomised controlled trials (RCTs) to evaluate treatment benefit and non-randomised studies in the routine oncology practice setting to evaluate treatment harms. We performed data collection and analysis according to the published protocol. Individual patient data was sought but not provided. Therefore, the meta-analysis had to be based on published data. Summary statistics for the primary endpoint (PFS) were hazard ratios (HRs). We identified seven RCTs, one register, and five ongoing trials from a total of 347 references. The published trials for VEGF-targeting drugs in MBC were limited to bevacizumab. Four trials, including a total of 2886 patients, were available for the comparison of first-line chemotherapy, with versus without bevacizumab. PFS (HR 0.67; 95% confidence interval (CI) 0.61 to 0.73) and response rate were significantly better for patients treated with bevacizumab, with moderate heterogeneity regarding the magnitude of the

  13. Colorectal cancer screening.

    Science.gov (United States)

    Burt, Randall W; Cannon, Jamie A; David, Donald S; Early, Dayna S; Ford, James M; Giardiello, Francis M; Halverson, Amy L; Hamilton, Stanley R; Hampel, Heather; Ismail, Mohammad K; Jasperson, Kory; Klapman, Jason B; Lazenby, Audrey J; Lynch, Patrick M; Mayer, Robert J; Ness, Reid M; Provenzale, Dawn; Rao, M Sambasiva; Shike, Moshe; Steinbach, Gideon; Terdiman, Jonathan P; Weinberg, David; Dwyer, Mary; Freedman-Cass, Deborah

    2013-12-01

    Mortality from colorectal cancer can be reduced by early diagnosis and by cancer prevention through polypectomy. These NCCN Guidelines for Colorectal Cancer Screening describe various colorectal screening modalities and recommended screening schedules for patients at average or increased risk of developing colorectal cancer. In addition, the guidelines provide recommendations for the management of patients with high-risk colorectal cancer syndromes, including Lynch syndrome. Screening approaches for Lynch syndrome are also described.

  14. Time to Definitive Health-Related Quality of Life Score Deterioration in Patients with Resectable Metastatic Colorectal Cancer Treated with FOLFOX4 versus Sequential Dose-Dense FOLFOX7 followed by FOLFIRI: The MIROX Randomized Phase III Trial

    Science.gov (United States)

    Hamidou, Zeinab; Chibaudel, Benoist; Hebbar, Mohamed; Hug de Larauze, Marine; André, Thierry; Louvet, Christophe; Brusquant, David; Garcia-Larnicol, Marie-Line; de Gramont, Aimery; Bonnetain, Franck

    2016-01-01

    Purpose We previously showed that a sequential chemotherapy with dose-dense oxaliplatin (FOLFOX7) and irinotecan (FOLFIRI; irinotecan plus 5-fluorouracil/leucovorin) is not superior to FOLFOX4 in patients at advanced stage of colorectal cancer with liver metastases. Here we aimed to determine whether time to health-related quality of life (HRQoL) score definitive deterioration (TUDD) differs by study arm. Methods HRQoL was evaluated using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 at baseline and every 4 cycles until the end of the study or death. Functional scale, symptom scale, global health status, and financial difficulties were analyzed. The TUDD was defined as the time interval between randomization and the first decrease in HRQoL score ≥ 5-point with no further improvement in HRQoL score ≥ 5 points or any further HRQoL data. TUDD was estimated using the Kaplan-Meier method and the long-rank test. Cox regression analyses were used to identify HRQoL items influencing TUDD. Sensitivity analyses were done using a multiple imputation method and different definitions of TUDD. Results Of the 284 patients, 171 (60.2%) completed HRQoL questionnaires. Cox multivariate analysis showed no statistically significant difference in TUDD for most of the QLQ-C30 scales between treatments. Patients with dyspnea and those without symptoms at baseline had a significantly longer TUDD when there was a delay >12 months between diagnosis of the primary tumor and metastases (HR 0.48 [0.26–0.89]) and when there was diarrhea (HR 0.59 [0.36–0.96]), respectively. Conclusion This study shows that TUDD does not differ significantly according to type of treatment. The TUDD method produces meaningful longitudinal HRQoL results that may facilitate effective clinical decision making in patients with mCRC. Trial Registration ClinicalTrials.gov NCT00268398 PMID:27310205

  15. Simultaneous resection of colorectal cancer and liver metastases in the right lobe using pure laparoscopic surgery.

    Science.gov (United States)

    Ando, Koji; Oki, Eiji; Ikeda, Tetsuo; Saeki, Hiroshi; Ida, Satoshi; Kimura, Yasue; Soejima, Yuuji; Morita, Masaru; Shirabe, Ken; Kusumoto, Tetuya; Maehara, Yoshihiko

    2014-08-01

    It is now common to resect colorectal cancer by laparoscopic surgery. Hepatectomy has become a standard treatment for patients with colorectal cancer with resectable liver metastases. The resection of liver tumors can now be done partly by laparoscopic surgery. However, metastatic tumors in the right lobe are often difficult to resect laparoscopically. Furthermore, simultaneous resection of the colorectum and liver may also be difficult. In this study, we evaluated a new method to resect both colorectal cancer and liver metastases in the right lobe by laparoscopic surgery. Two cases are presented that underwent total laparoscopic resection of a right lobe tumor, associated with laparoscopic colorectal resection. The metastatic tumor in the right lobe was first resected in the left hemi-prone position. Then, the colorectal cancer was resected in the lithotomy position. The method for resecting the right lobe liver tumor and colorectal cancer was safe and feasible. The mean duration of surgery was 443.5 min, and the mean blood loss was 158 mL. The postoperative course was uneventful. In selected patients, laparoscopic hepatectomy for right lobe synchronous metastatic tumors can be safely performed simultaneously with colorectal surgery.

  16. Metastatic Renal Cell Carcinoma to the Pancreas: A Review.

    Science.gov (United States)

    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.

  17. Lower Extremity Cutaneous Lesions as the Initial Presentation of Metastatic Adenocarcinoma of the Colon

    Directory of Open Access Journals (Sweden)

    Dhyan Rajan

    2012-01-01

    Full Text Available Cutaneous metastases from colorectal cancers are rare and are usually present on the abdominal wall or previous surgical incision sites. Remote cutaneous lesions have been reported, however, often occur in the setting of widespread metastatic disease including other visceral secondaries. We present a case of lower extremity cutaneous metastases as the first sign of metastatic disease in a patient with adenocarcinoma of the colon. This case illustrates that new skin lesions may be the initial presentation of metastatic disease in a patient with a history of cancer.

  18. Underpinning the repurposing of anthracyclines towards colorectal cancer

    DEFF Research Database (Denmark)

    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...

  19. [How I treat colorectal cancer. I. Prevention and adjuvant treatment].

    Science.gov (United States)

    Bours, V; Jerusalem, G; Fillet, G

    1998-04-01

    Colorectal adenocarcinoma is a major cause of cancer-related morbidity and mortality in Belgium and in other western countries. Prevention implies a modification of alimentation and maybe a chronic uptake of acetylsalicylic acid. Treatment of colorectal cancers is based on surgery and the prognosis is determined by the locoregional or metastatic tumor spread. Complete resection of any Astler Coller stage C colorectal malignant tumor has to be followed by a 5-fluorouracil-based adjuvant chemotherapy. In these protocols, 5-fluorouracil is administered together with folinic acid or levamisole. The administration of an adjuvant chemotherapy could also be considered for stage BII diseases. As rectal cancers are characterized by high local relapse rates, their treatment should associate radiotherapy, given either post-surgery or preferentially pre-surgery, with resection and chemotherapy. Appropriate treatment of colorectal cancers thus requires a concerted multidisciplinary approach.

  20. Get Tested for Colorectal Cancer

    Science.gov (United States)

    ... Print This Topic En español Get Tested for Colorectal Cancer Browse Sections The Basics Overview What to Expect ... section Overview 2 of 6 sections The Basics: Colorectal Cancer What is colorectal cancer? Colorectal cancer is a ...

  1. Nursing: Registered Nurses

    Science.gov (United States)

    ... a diploma from an approved nursing program. Registered nurses also must be licensed. Education In all nursing education programs, students take courses in anatomy, physiology, microbiology, chemistry, nutrition, psychology, and other social and ...

  2. IT Risk register

    OpenAIRE

    2011-01-01

    The theoretical part of the thesis analyzes several selected methodologies and best-practices related to information technology risks management, with focus on documents and guidance developed by ISACA. It builds a set of ideas and basic requirements for effective model of an IT risk register. Strong emphasis is placed on mapping CobiT 4.1 based Risk IT to COBIT 5. The practical part describes implementation of an exploratory web-based IT risk register in Python programming language utilizing...

  3. Correlation of N-myc downstream-regulated gene 1 overexpression with progressive growth of colorectal neoplasm

    Institute of Scientific and Technical Information of China (English)

    Zhen Wang; Fang Wang; Wei-Qi Wang; Qian Gao; Wan-Li Wei; Yun Yang; Guo-Ying Wang

    2004-01-01

    AIM: To study the function of N-myc downstream-regulated gene 1 (NDRG1) in colorectal carcinogenesis and its correlation with tumor lymph node metastasis.METHODS: NDRG1 was detected at its protein level by immunohistochemistry (IHC) and image analysis (IA), and NDRG1 mRNA was detected by in situ hybridization (ISH)in formalin-fixed and paraffin-embedded sections with a total of 190 specimens including 38 normal colorectal mucosae, 31 colorectal adenomas, 45 non-metastatic colorectal carcinomas (CRCs), 38 metastatic primary CRC and subsequently regional lymph nodes respectively. At the same time, the correlations of NDRG1 with sex, age of patients and histological types of colorectal carcinomas were observed.RESULTS: NDRG1 proteins were gradually increased in colorectal carcinogenesis (P<0.05 or P<0.01). There was a significant difference in the expression of NDRG1 between non-metastatic and metastatic CRCs (P<0.05), and the correlation was positive (P<0.01, rs=0.329). However, there was no obvious difference in the expression of NDRG1 between the primary sites of CRCs and that in the metastatic sites of corresponding regional lymph nodes, nor was there an apparent difference in sex, age, and histological types.The expression of NDRG1 mRNA was generally in concordance with that of NDRG1 protein.CONCLUSION: NDRG1 gene may play an important role in colorectal carcinogenesis. In addition, NDRG1 may be a putative tumor metastasis promoter gene and is regarded as one of the molecular biological markers that can forecast early metastasis of CRCs. NDRG1 gene in the metastatic sites of regional lymph nodes may preserve its expression characteristics in the primary sites of CRCs to some extent.The expression of NDRG1 is not affected by sex, age and histological types. The role of NDRG1 in tumor metastatic process can be demonstrated byin vivo and in vitro.

  4. Dissemination and clinical impact of minimal metastatic disease in gastrointestinal cancer

    NARCIS (Netherlands)

    Doekhie, Fania Shahanaaz

    2009-01-01

    In this thesis, we assess whether gastric and colorectal cancer (CRC) patients with minimal metastatic disease at the time of surgery who are at risk for disease recurrence, can be identified by detection of occult tumor cells (OTC) in lymph nodes or bone marrow or by analyzing the primary tumor for

  5. [Metastatic bronchial carcinoid tumors].

    Science.gov (United States)

    Bouledrak, K; Walter, T; Souquet, P J; Lombard-Bohas, C

    2016-02-01

    Bronchial carcinoids are uncommon pulmonary neoplasms and represent 1 to 2 % of all lung tumors. In early stage of disease, the mainstay and only curative treatment is surgery. Bronchial carcinoids are generally regarded as low-grade carcinomas and metastatic dissemination is unusual. The management of the metastatic stage is not currently standardized due to a lack of relevant studies. As bronchial carcinoids and in particular their metastatic forms are rare, we apply treatment strategies that have been evaluated in gastrointestinal and pancreatic neuroendocrine tumors. However, bronchial carcinoids have their own characteristic. A specific therapeutic feature of these metastatic tumors is that they require a dual approach: both anti-secretory for the carcinoid syndrome, and anti-tumoral.

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

    Directory of Open Access Journals (Sweden)

    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.

  7. Current treatment for colorectal liver metastases

    Institute of Scientific and Technical Information of China (English)

    Evangelos P Misiakos; Nikolaos P Karidis; Gregoryr Kouraklis

    2011-01-01

    Surgical resection offers the best opportunity for survival in patients with colorectal cancer metastatic to the liver, with five-year survival rates up to 58% in selected cases. However, only a minority are resectable at the time of diagnosis. Continuous research in this field aims at increasing the percentage of patients eligible for resection, refining the indications and contraindications for surgery , and improving overall survival. The use of surgical innovations, such as staged resection, portal vein embolization, and repeat resection has allowed higher resection rates in patients with bilobar disease. The use of neoadjuvant chemotherapy allows up to 38% of patients previously considered unresectable to be significantly downstaged and eligible for hepatic resection. Ablative techniques have gained wide acceptance as an adjunct to surgical resection and in the management of patients who are not surgical candidates. Curent management of colorectal liver metastases requires a multidisciplinary approach, which should be individu alized in each case.

  8. Choroidal and skin metastases from colorectal cancer.

    Science.gov (United States)

    Ha, Joo Young; Oh, Edward Hynseung; Jung, Moon Ki; Park, Song Ee; Kim, Ji Tak; Hwang, In Gyu

    2016-11-21

    Choroidal and skin metastasis of colon cancer is rare. In women, the frequency of cutaneous metastasis from colon cancer as the primary lesion in is 9% and skin metastasis occurs in 0.81% of all colorectal cancers. We report a patient with colonic adenocarcinoma who presented with visual disorder in her right eye and scalp pain as her initial symptoms. Contrast-enhance orbital magnetic resonance imaging with fat suppression revealed an infrabulbar mass, and skin biopsy of the posterior parietal scalp confirmed adenocarcinoma. These symptoms were diagnosed as being caused by choroidal and skin metastases of colonic adenocarcinoma. We started palliative chemotherapy with oral capecitabine (1000 mg/m(2), twice a day, on days 1-14) every 3 wk, which was effective at shrinking the brain masses and improving the visual disorder. This is the first report that capecitabine is effective at reducing a choroidal and cutaneous metastatic lesion from right-sided colorectal cancer.

  9. Immunotherapy and immunoescape in colorectal cancer

    Institute of Scientific and Technical Information of China (English)

    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 IFNy 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.

  10. Colorectal Cancer Prevention

    Science.gov (United States)

    ... alcoholic beverages per day increases the risk of colorectal cancer. Drinking alcohol is also linked to the risk of forming large colorectal adenomas (benign tumors). Cigarette smoking Cigarette smoking is ...

  11. Processor register error correction management

    Science.gov (United States)

    Bose, Pradip; Cher, Chen-Yong; Gupta, Meeta S.

    2016-12-27

    Processor register protection management is disclosed. In embodiments, a method of processor register protection management can include determining a sensitive logical register for executable code generated by a compiler, generating an error-correction table identifying the sensitive logical register, and storing the error-correction table in a memory accessible by a processor. The processor can be configured to generate a duplicate register of the sensitive logical register identified by the error-correction table.

  12. Pulmonary nodules and metastases in colorectal cancer

    DEFF Research Database (Denmark)

    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...... is minimal. Furthermore, the current staging practice is complicated by a high number of incidental findings on the thoracic CT, so-called indeterminate pulmonary nodules (IPN). IPN can potentially represent SPCM. The purpose of this thesis was to estimate the prevalence, characteristics and clinical...

  13. Cytogenetic findings in metastases from colorectal cancer

    DEFF Research Database (Denmark)

    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...... and lymph node metastases were analyzed. Cytogenetic similarities between the primary and secondary lesions were found in all 5 cases, indicating that many of the chromosomal aberrations presumably occurred before disease spreading took place. Compared with the primaries, the metastases appeared to exhibit...

  14. Register file soft error recovery

    Science.gov (United States)

    Fleischer, Bruce M.; Fox, Thomas W.; Wait, Charles D.; Muff, Adam J.; Watson, III, Alfred T.

    2013-10-15

    Register file soft error recovery including a system that includes a first register file and a second register file that mirrors the first register file. The system also includes an arithmetic pipeline for receiving data read from the first register file, and error detection circuitry to detect whether the data read from the first register file includes corrupted data. The system further includes error recovery circuitry to insert an error recovery instruction into the arithmetic pipeline in response to detecting the corrupted data. The inserted error recovery instruction replaces the corrupted data in the first register file with a copy of the data from the second register file.

  15. Treatment of metastatic brain lesion

    Directory of Open Access Journals (Sweden)

    A. M. Zaytsev

    2015-01-01

    Full Text Available Objective. Increasing survival in patients with secondary brain damage, and identifying the factors of favorable and adverse prognosis.Material and method. In P. A. Hertsen Moscow Oncology Research Institute from 2007 to 2013 there were treated 268 patients with brain metastases. The mean age was 55.8 years (from 24 to 81 years. Metastases of colorectal cancer identified in 7.8%, cases of lung cancer in 34%, melanoma 9.3 %, breast cancer in 26%, kidney cancer in 11%, with non-identified primary tumor in 4.5%, other tumors accounted for 6.7%. Solitary metastasis was diagnosed in 164 (61,19% patients, oligometastasis (2-3 - 72 (26,87% patients with polymetastasis (more than 3 – 32 (11,94% patients. In 106 (39,55% of patients with brain metastases it was the only manifestation of the generalization process. To control the radical removal of the tumor in 93 (34,7% patients we used the method of fluorescence navigation (FN with the drug Alasens. In 66 (24,6% patients intraoperatively was held a session of photodynamic therapy (PDT. In 212 (79,1% cases, the removal of metastasis performed totally, 55 (20,9% patients stated Subtotal removal.Results. The observation period for the patients ranged from 3 to 79 months. Survival median among the entire group of patients with metastatic brain lesion was 12 months. Overall survival was significantly dependent on RPA class, the volume of postoperative treatment, histological type of primary tumor, number of intracerebral metastases and the timing of the relapse-free period.Conclusions. Factors that affects the overall survival are the features of the histology of the primary lesion, multiplicity of metastatic lesions, RPA class and the synchronous nature of the metastasis. The median of overall survival of patients who did not receive after surgical treatment of a particular type of therapy was only 4 months. If to use the combined treatment (surgical treatment with the irradiation of the whole brain median

  16. The Danish Education Registers

    DEFF Research Database (Denmark)

    Jensen, Vibeke Myrup; Würtz Rasmussen, Astrid

    Collection of systematic information on education is a long established practice in Denmark. Since 1910, the Danish Ministry of Education’s annual reports collects information about individual-level test scores in e.g. compulsory schooling. Today, several registers from compulsory schooling to ad...... of missing information on immigrants, the level is still low in an international context....

  17. Register for Suicide Attempts

    DEFF Research Database (Denmark)

    Christiansen, Erik; Jensen, Børge Frank

    2004-01-01

    The Register for Suicide Attempts (RSA) is a product of the WHO research project "WHO/Euro Multicentre Study on Parasuicide", which, among other things, had the purpose of collecting data on suicide attempts from 13 European countries. Data is collected in order to calculate trends and identify...

  18. Hello! Are You Registered?

    Science.gov (United States)

    Institute for Political/Legal Education, Sewell, NJ.

    Organizational procedures and appropriate forms for high school students to conduct a community survey of non-registered voters are provided. Duties for student coordinator, field staff, and clerical staff are described and a flow chart depicts the relationship of personnel to one another and to the community. Students are instructed to notify…

  19. The Danish heart register

    DEFF Research Database (Denmark)

    Abildstrøm, Steen Z; Madsen, Mette

    2011-01-01

    Introduction: The Danish Heart Register (DHR) is a clinical database of invasive procedures within cardiology. Content: All providers of these procedures have been obliged to report to DHR since 2000. DHR is used to monitor the activity and quality of the procedures and serves as a data source...

  20. Register for Suicide Attempts

    DEFF Research Database (Denmark)

    Christiansen, Erik; Jensen, Børge Frank

    2004-01-01

    The Register for Suicide Attempts (RSA) is a product of the WHO research project "WHO/Euro Multicentre Study on Parasuicide", which, among other things, had the purpose of collecting data on suicide attempts from 13 European countries. Data is collected in order to calculate trends and identify...

  1. Hello! Are You Registered?

    Science.gov (United States)

    Institute for Political/Legal Education, Sewell, NJ.

    Organizational procedures and appropriate forms for high school students to conduct a community survey of non-registered voters are provided. Duties for student coordinator, field staff, and clerical staff are described and a flow chart depicts the relationship of personnel to one another and to the community. Students are instructed to notify…

  2. The process and outcomes of a nurse-led colorectal cancer follow-up clinic.

    Science.gov (United States)

    McFarlane, K; Dixon, L; Wakeman, C J; Robertson, G M; Eglinton, T W; Frizelle, F A

    2012-05-01

    Evidence suggests that follow-up after colorectal cancer improves survival. Colorectal cancer is so common that patient follow-up can overwhelm a service, affecting the ability to see new referrals and reassess patients seen previously who have new symptoms. In order to cope with this demand a nurse-led follow-up service was started in 2004. We aimed to review the results of a nurse-led colorectal cancer follow-up clinic. Between 1 December 2004 and 31 January 2011, patients who underwent resection for colorectal cancer were followed up by a nurse specialist according to a protocol determined by the colorectal surgeons in the unit. All patient details were recorded prospectively in a purpose designed database. Nine hundred and fifty patients were followed up over 7 years. Some 368 patients were discharged from the follow-up programme, 474 patients remain actively involved in the programme and 108 patients died. Of the patients discharged from the follow-up scheme 269 (73%) were discharged to their general practitioner free of disease after 5 years. Of the 108 who patients died, 98 were as a result of colorectal cancer. Twenty patients (2.1%) were identified with local (peri-anastomotic) disease recurrence and 93 patients (9.8%) were found to have developed distant metastatic disease. Of these, 65 patients (6.8%) were referred for palliative care and 28 (2.9%) had surgery for focal metastatic disease of whom 18 were still alive at the time of this analysis. This paper shows that a nurse-led clinic for colorectal cancer follow-up can achieve satisfactory results with detection rates of recurrent or metastatic disease comparable to consultant follow-up. A nurse-led clinic provides the benefits of follow-up without overwhelming the consultant colorectal surgical clinic practice. © 2011 The Authors. Colorectal Disease © 2011 The Association of Coloproctology of Great Britain and Ireland.

  3. CT findings of locoregional recurrence after curative resection of colorectal cancer

    Energy Technology Data Exchange (ETDEWEB)

    Shin, Sang Soo [Chonnam National University Hospital, Gwangju (Korea, Republic of); Jeong, Yong Yeon; Kang, Heoung Keun [Chonnam National University Hwasun Hospital, Hwasun (Korea, Republic of)

    2006-10-15

    Postoperative recurrence is a major cause of mortality and morbidity for the patients suffering with colorectal cancer. Therefore, patients with colorectal cancer are routinely followed up with CT to detect the presence of locoregional recurrence and distant metastases. A central goal of postoperative surveillance for colorectal cancer is to improve survival through the earlier identification of tumor recurrence. Locoregional recurrence refers to tumor occurring at or adjacent to the surgical site and at the regional lymph nodes. It has been reported that metastatic spread based on the site of the primary tumor shows a relatively predictable pattern. Given the prevalence of colorectal cancer and the role of CT for postoperative surveillance, radiologists should be familiar with the CT findings of locoregional recurrence after curative resection for colorectal cancer.

  4. PROX1 Promotes Metabolic Adaptation and Fuels Outgrowth of Wnthigh Metastatic Colon Cancer Cells

    Directory of Open Access Journals (Sweden)

    Simone Ragusa

    2014-09-01

    Full Text Available The Wnt pathway is abnormally activated in the majority of colorectal cancers, and significant knowledge has been gained in understanding its role in tumor initiation. However, the mechanisms of metastatic outgrowth in colorectal cancer remain a major challenge. We report that autophagy-dependent metabolic adaptation and survival of metastatic colorectal cancer cells is regulated by the target of oncogenic Wnt signaling, homeobox transcription factor PROX1, expressed by a subpopulation of colon cancer progenitor/stem cells. We identify direct PROX1 target genes and show that repression of a pro-apoptotic member of the BCL2 family, BCL2L15, is important for survival of PROX1+ cells under metabolic stress. PROX1 inactivation after the establishment of metastases prevented further growth of lesions. Furthermore, autophagy inhibition efficiently targeted metastatic PROX1+ cells, suggesting a potential therapeutic approach. These data identify PROX1 as a key regulator of the transcriptional network contributing to metastases outgrowth in colorectal cancer.

  5. 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.

  6. Colorectal Cancer: A Personal Journey

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