Limits...
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.

Show MeSH

Related in: MedlinePlus

Suggested treatment continuums for metastatic colorectal cancer using (a) intensive or (b) less intensive therapy.[54] 5-FU = fluorouracil; FOLFIRI = irinotecan plus infusional fluorouracil/leucovorin; FOLFOX = oxaliplatin plus infusional fluorouracil/leucovorin; LV = leucovorin. * indicates that cetuximab may be administered alone for patients intolerant to irinotecan. Reproduced from Goldberg et al.,[54] copyright 2007, with permission of AlphaMed Press, Inc.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3585989&req=5

Fig3: Suggested treatment continuums for metastatic colorectal cancer using (a) intensive or (b) less intensive therapy.[54] 5-FU = fluorouracil; FOLFIRI = irinotecan plus infusional fluorouracil/leucovorin; FOLFOX = oxaliplatin plus infusional fluorouracil/leucovorin; LV = leucovorin. * indicates that cetuximab may be administered alone for patients intolerant to irinotecan. Reproduced from Goldberg et al.,[54] copyright 2007, with permission of AlphaMed Press, Inc.

Mentions: The improvements in survival seen with the increased number of chemotherapeutic agents and the expanded ways in which these agents are used have brought about a changing paradigm for the treatment of colorectal cancer (figure 3). In the past, metastatic colorectal cancer was treated with first-line therapy until progression, at which point treatment was switched to a regimen active in the second-line setting. This pattern was continued until patients had received all five active classes of drug, after which they were enrolled in clinical trials. The new approach to treatment views the choice of first and subsequent lines of treatment as a continuum rather than isolated choices. A patient’s treatment may be changed prior to disease progression. Alternately, treatment may consist of aggressive treatment periods followed by breaks or maintenance therapy following treatment response. This approach to treatment may minimize the toxicity seen with individual agents.[54] For example, oxaliplatin is associated with both acute and delayed sensory neuropathy, and a large proportion of patients receiving cumulative doses of oxaliplatin develop grade 3 cumulative neurotoxicity that may take several months to resolve.[54] A balance between efficacy and toxicity was illustrated in the OPTIMOX 1 and 2 trials. In the OPTIMOX 1 trial, patients were randomized to FOLFOX4 every 2 weeks until disease progression or high-dose FOLFOX7 for six cycles followed by 5-FU/leucovorin for 12 cycles, after which they restarted FOLFOX7.[55] Disease duration and overall survival was similar in each group, but patients receiving FOLFOX7 had a greatly reduced incidence of peripheral neuropathy, particularly during the later stages of treatment. To refine these data, the OPTIMOX 2 study randomized patients to six cycles of modified FOLFOX7 followed by 5-FU/leucovorin maintenance until progression, or six cycles of modified FOLFOX7 followed by cessation of therapy until tumor progression; in both groups, modified FOLFOX7 was reintroduced at disease progression.[56] The duration of disease control and progression-free survival was significantly higher in patients receiving maintenance therapy, but the overall survival was similar in both groups. Therefore, although the authors of OPTIMOX 2 concluded that chemotherapy discontinuation could be safely considered in selected patients, these results suggest maintenance therapy in metastatic colorectal cancer is important, although its role is not yet clearly defined. As a final note on the future treatment of colorectal cancer, the cytostatic mechanism of action and relatively low toxicity make bevacizumab a suitable agent for use as maintenance therapy in colorectal cancer, as it is in non-small-cell lung cancer. An ongoing, randomized, phase III study investigating this use is currently ongoing and results are eagerly awaited to further help guide the use of bevacizumab in these patients.


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)

Suggested treatment continuums for metastatic colorectal cancer using (a) intensive or (b) less intensive therapy.[54] 5-FU = fluorouracil; FOLFIRI = irinotecan plus infusional fluorouracil/leucovorin; FOLFOX = oxaliplatin plus infusional fluorouracil/leucovorin; LV = leucovorin. * indicates that cetuximab may be administered alone for patients intolerant to irinotecan. Reproduced from Goldberg et al.,[54] copyright 2007, with permission of AlphaMed Press, Inc.
© Copyright Policy
Related In: Results  -  Collection

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

Fig3: Suggested treatment continuums for metastatic colorectal cancer using (a) intensive or (b) less intensive therapy.[54] 5-FU = fluorouracil; FOLFIRI = irinotecan plus infusional fluorouracil/leucovorin; FOLFOX = oxaliplatin plus infusional fluorouracil/leucovorin; LV = leucovorin. * indicates that cetuximab may be administered alone for patients intolerant to irinotecan. Reproduced from Goldberg et al.,[54] copyright 2007, with permission of AlphaMed Press, Inc.
Mentions: The improvements in survival seen with the increased number of chemotherapeutic agents and the expanded ways in which these agents are used have brought about a changing paradigm for the treatment of colorectal cancer (figure 3). In the past, metastatic colorectal cancer was treated with first-line therapy until progression, at which point treatment was switched to a regimen active in the second-line setting. This pattern was continued until patients had received all five active classes of drug, after which they were enrolled in clinical trials. The new approach to treatment views the choice of first and subsequent lines of treatment as a continuum rather than isolated choices. A patient’s treatment may be changed prior to disease progression. Alternately, treatment may consist of aggressive treatment periods followed by breaks or maintenance therapy following treatment response. This approach to treatment may minimize the toxicity seen with individual agents.[54] For example, oxaliplatin is associated with both acute and delayed sensory neuropathy, and a large proportion of patients receiving cumulative doses of oxaliplatin develop grade 3 cumulative neurotoxicity that may take several months to resolve.[54] A balance between efficacy and toxicity was illustrated in the OPTIMOX 1 and 2 trials. In the OPTIMOX 1 trial, patients were randomized to FOLFOX4 every 2 weeks until disease progression or high-dose FOLFOX7 for six cycles followed by 5-FU/leucovorin for 12 cycles, after which they restarted FOLFOX7.[55] Disease duration and overall survival was similar in each group, but patients receiving FOLFOX7 had a greatly reduced incidence of peripheral neuropathy, particularly during the later stages of treatment. To refine these data, the OPTIMOX 2 study randomized patients to six cycles of modified FOLFOX7 followed by 5-FU/leucovorin maintenance until progression, or six cycles of modified FOLFOX7 followed by cessation of therapy until tumor progression; in both groups, modified FOLFOX7 was reintroduced at disease progression.[56] The duration of disease control and progression-free survival was significantly higher in patients receiving maintenance therapy, but the overall survival was similar in both groups. Therefore, although the authors of OPTIMOX 2 concluded that chemotherapy discontinuation could be safely considered in selected patients, these results suggest maintenance therapy in metastatic colorectal cancer is important, although its role is not yet clearly defined. As a final note on the future treatment of colorectal cancer, the cytostatic mechanism of action and relatively low toxicity make bevacizumab a suitable agent for use as maintenance therapy in colorectal cancer, as it is in non-small-cell lung cancer. An ongoing, randomized, phase III study investigating this use is currently ongoing and results are eagerly awaited to further help guide the use of bevacizumab in these patients.

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