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Use of bevacizumab in metastatic colorectal cancer: report from the Mexican opinion and analysis forum on colorectal cancer treatment with bevacizumab (September 2009).

Zinser-Sierra JW, Rodríguez-Ramírez S, Villalobos-Valencia R, Ramírez-Márquez M - Drugs R D (2011)

Bottom Line: In patients who have progressed on a bevacizumab-containing regimen, continuation of bevacizumab is significantly associated with an improved survival based on observational cohort studies.In a study of 219 patients, the addition of bevacizumab to FOLFOX was associated with a significant increase in major or complete pathologic response compared with FOLFOX alone.This approach achieves similar efficacy outcomes with reduced toxicity, and investigation of the role of bevacizumab as maintenance therapy is ongoing.

View Article: PubMed Central - PubMed

Affiliation: Instituto Nacional de Cancerologa (INCan), Mexico City, Mexico. juanwzinser@infosel.net.mx

ABSTRACT
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 guide therapy. Prognostic markers indicate patient survival independent of therapy and include disease stage, mutational status, and carcinoembryonic antigen. More recently, predictive markers of treatment outcomes have been identified. The most studied are mutations of the KRAS and BRAF genes, which are associated with resistance to epidermal growth factor receptor-targeted therapy. Tumor blood vessels have a number of structural and functional abnormalities that result in increased tumor vascularity and growth driven by angiogenesis. The anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab, which binds to and neutralizes VEGF-A, has become a central part of the treatment of metastatic colorectal cancer. The addition of bevacizumab to fluorouracil (5-FU)/leucovorin, irinotecan plus bolus 5-FU/leucovorin, or irinotecan plus infusional 5-FU/leucovorin significantly improves the overall survival of patients with previously untreated metastatic colorectal cancer. In addition, a significant increase in overall survival is seen when bevacizumab is added to oxaliplatin plus infusional 5-FU/leucovorin (FOLFOX) in patients with metastatic colorectal cancer who progressed on a non-bevacizumab-containing regimen. Although the majority of studies were performed prior to the identification of KRAS and BRAF as predictive biomarkers, subsequent analysis has shown the benefits of bevacizumab occur independently of the mutational status of these genes. In patients who have progressed on a bevacizumab-containing regimen, continuation of bevacizumab is significantly associated with an improved survival based on observational cohort studies. Surgical resection is recommended in patients with metastatic colorectal cancer where complete removal of tumors can be achieved. Perioperative chemotherapy using FOLFOX for 3 months before and 3 months after surgery is associated with a 9% improvement in 3-year survival. The use of chemotherapy in patients initially deemed unresectable has produced resection rates approaching 40%, and the addition of bevacizumab to chemotherapy in this setting is feasible, safe, and effective. In a study of 219 patients, the addition of bevacizumab to FOLFOX was associated with a significant increase in major or complete pathologic response compared with FOLFOX alone. Improvements in patient survival have changed the treatment paradigm for metastatic colorectal cancer. Newer approaches view treatment not as distinct lines of therapy but as a continuum that includes personalized treatment plans offering maintenance therapy and even drug holidays between aggressive treatment periods. This approach achieves similar efficacy outcomes with reduced toxicity, and investigation of the role of bevacizumab as maintenance therapy is ongoing.

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Trial names
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Tab1: Trial names

Mentions: The RAS and RAF families of proteins act as transducers and integrators of signals from a number of surface growth factors with downstream effects on subsequent transducers, such as PI3K and MAPK. Mutations of KRAS occur in approximately 40% of colorectal cancer specimens,[16] and although these mutations do not appear to be a prognostic factor in colorectal cancer, they do confer resistance to epidermal growth factor receptor (EGFR)-targeted therapy. For example, in the CRYSTAL trial (see table I for full trial names), in which patients with metastatic EGFR-expressing colorectal cancer received irinotecan plus infusional 5-FU/leucovorin (FOLFIRI) with or without cetuximab, the benefit of the anti-EGFR monoclonal antibody was confined to patients without KRAS mutations.[17] Based on these and other findings, the European Medicines Agency approved the EGFR inhibitor panitumumab for use in patients with wild-type KRAS only.[18] BRAF mutations occur less frequently, but are also associated with reduced response to EGFR inhibitors. The BRAF-V600E mutation, in particular, impairs the therapeutic effects of cetuximab and panitumumab.[19] Consensus guidelines recommend that the presence of KRAS mutations be determined in all patients diagnosed with stage IV colorectal cancer.[14]


Use of bevacizumab in metastatic colorectal cancer: report from the Mexican opinion and analysis forum on colorectal cancer treatment with bevacizumab (September 2009).

Zinser-Sierra JW, Rodríguez-Ramírez S, Villalobos-Valencia R, Ramírez-Márquez M - Drugs R D (2011)

Trial names
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585989&req=5

Tab1: Trial names
Mentions: The RAS and RAF families of proteins act as transducers and integrators of signals from a number of surface growth factors with downstream effects on subsequent transducers, such as PI3K and MAPK. Mutations of KRAS occur in approximately 40% of colorectal cancer specimens,[16] and although these mutations do not appear to be a prognostic factor in colorectal cancer, they do confer resistance to epidermal growth factor receptor (EGFR)-targeted therapy. For example, in the CRYSTAL trial (see table I for full trial names), in which patients with metastatic EGFR-expressing colorectal cancer received irinotecan plus infusional 5-FU/leucovorin (FOLFIRI) with or without cetuximab, the benefit of the anti-EGFR monoclonal antibody was confined to patients without KRAS mutations.[17] Based on these and other findings, the European Medicines Agency approved the EGFR inhibitor panitumumab for use in patients with wild-type KRAS only.[18] BRAF mutations occur less frequently, but are also associated with reduced response to EGFR inhibitors. The BRAF-V600E mutation, in particular, impairs the therapeutic effects of cetuximab and panitumumab.[19] Consensus guidelines recommend that the presence of KRAS mutations be determined in all patients diagnosed with stage IV colorectal cancer.[14]

Bottom Line: In patients who have progressed on a bevacizumab-containing regimen, continuation of bevacizumab is significantly associated with an improved survival based on observational cohort studies.In a study of 219 patients, the addition of bevacizumab to FOLFOX was associated with a significant increase in major or complete pathologic response compared with FOLFOX alone.This approach achieves similar efficacy outcomes with reduced toxicity, and investigation of the role of bevacizumab as maintenance therapy is ongoing.

View Article: PubMed Central - PubMed

Affiliation: Instituto Nacional de Cancerologa (INCan), Mexico City, Mexico. juanwzinser@infosel.net.mx

ABSTRACT
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 guide therapy. Prognostic markers indicate patient survival independent of therapy and include disease stage, mutational status, and carcinoembryonic antigen. More recently, predictive markers of treatment outcomes have been identified. The most studied are mutations of the KRAS and BRAF genes, which are associated with resistance to epidermal growth factor receptor-targeted therapy. Tumor blood vessels have a number of structural and functional abnormalities that result in increased tumor vascularity and growth driven by angiogenesis. The anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab, which binds to and neutralizes VEGF-A, has become a central part of the treatment of metastatic colorectal cancer. The addition of bevacizumab to fluorouracil (5-FU)/leucovorin, irinotecan plus bolus 5-FU/leucovorin, or irinotecan plus infusional 5-FU/leucovorin significantly improves the overall survival of patients with previously untreated metastatic colorectal cancer. In addition, a significant increase in overall survival is seen when bevacizumab is added to oxaliplatin plus infusional 5-FU/leucovorin (FOLFOX) in patients with metastatic colorectal cancer who progressed on a non-bevacizumab-containing regimen. Although the majority of studies were performed prior to the identification of KRAS and BRAF as predictive biomarkers, subsequent analysis has shown the benefits of bevacizumab occur independently of the mutational status of these genes. In patients who have progressed on a bevacizumab-containing regimen, continuation of bevacizumab is significantly associated with an improved survival based on observational cohort studies. Surgical resection is recommended in patients with metastatic colorectal cancer where complete removal of tumors can be achieved. Perioperative chemotherapy using FOLFOX for 3 months before and 3 months after surgery is associated with a 9% improvement in 3-year survival. The use of chemotherapy in patients initially deemed unresectable has produced resection rates approaching 40%, and the addition of bevacizumab to chemotherapy in this setting is feasible, safe, and effective. In a study of 219 patients, the addition of bevacizumab to FOLFOX was associated with a significant increase in major or complete pathologic response compared with FOLFOX alone. Improvements in patient survival have changed the treatment paradigm for metastatic colorectal cancer. Newer approaches view treatment not as distinct lines of therapy but as a continuum that includes personalized treatment plans offering maintenance therapy and even drug holidays between aggressive treatment periods. This approach achieves similar efficacy outcomes with reduced toxicity, and investigation of the role of bevacizumab as maintenance therapy is ongoing.

Show MeSH
Related in: MedlinePlus