The addition of bevacizumab to chemotherapy of metastatic colorectal cancer prolongs both progression-free survival as well as overall survival in first- and second line therapy.

Angiogenesis refers to the development of new blood vessels from the pre-existing vascular bed. Tumours are dependent on the formation of new blood vessels for their growth. Agents which inhibit the formation of new blood vessels are commonly referred to as "anti-angiogenic therapies". They are a new class of molecular designed drugs, among which one (bevacizumab) is already routinely used in clinical practice. Data from 5 randomized trials, which included a total of 3101 patients and evaluated the effect of bevacizumab, are currently available. Furthermore, data from one study, which included a total of 1168 patients and evaluated the effect of valatinib is published. The addition of bevacizumab to chemotherapy prolongs both progression-free survival from about 7.1 to 9.7 months when used as primary treatment and overall survival from about 17.7 to 20.5 months after prior use of chemotherapy (so called "second-line therapy") for metastatic colorectal cancer. However, the magnitude of the effect on progression-free survival is variable and probably depends on the type of chemotherapy to which it is associated. Vatalanib has no significant effect on progression-free and overall survival. Adverse effects of bevacizumab include increased frequencies of high blood pressure, arterial thromboembolic events and bowel perforations.

Authors' conclusions: 

The addition of bevacizumab to chemotherapy of metastatic colorectal cancer prolongs both PFS and OS in first-and second-line therapy.

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Background: 

Angiogenesis inhibitors have been developed to block tumour angiogenesis and target vascular endothelial cells. While some of them have already been approved by the health authorities and are successfully integrated into patient care, many others are still under development, and the clinical value of this approach has to be established.

Objectives: 

To assess the efficacy and toxicity of targeted anti-angiogenic therapies, in addition to chemotherapy, in patients with metastatic colorectal cancer. Primary endpoints are both progression-free and overall survival. Response rates, toxicity and secondary resectability were secondary endpoints. Comparisons were first-line chemotherapy in combination with angiogenesis inhibitor, to the same chemotherapy without angiogenesis inhibitor; and second-line chemotherapy, to the same chemotherapy without angiogenesis inhibitor.

Search strategy: 

We searched the Cochrane Central Register of Controlled Trials, MEDLINE, as well as proceedings from ECCO, ESMO and ASCO until November 2008. In addition, reference lists from trials were scanned, experts in the field and drug manufacturers were contacted to obtain further information.

Selection criteria: 

Randomized controlled trials on targeted anti-angiogenic drugs in metastatic colorectal cancer (MCRC).

Data collection and analysis: 

Data collection and analysis was performed, according to a previously published protocol. Because individual patient data was not provided, aggregate data had to be used for the analysis. Summary statistics for the primary endpoints were hazard ratios (HR's) and their 95% confidence intervals.

Main results: 

At present, eligible first line trials for this meta-analysis were available for bevacizumab (5 trials including 3101 patients) and vatalanib (1 trial which included 1168 patients). The overall HR´s for PFS (0.61, 95% CI 0.45 - 0.83) and OS (0.81, 95% 0.73 - 0.90) for the comparison of first-line chemotherapy, with or without bevacizumab, confirms significant benefits in favour of the patients treated with bevacizumab. However, the effect on PFS shows significant heterogeneity. For second-line chemotherapy, with or without bevacizumab, a benefit in both PFS (HR 0.61, 95% CI 0.51 - 0.73) and OS (HR 0.75, 95% CI 0.63-0.89) was demonstrated in a single, randomized trial. While differences in treatment-related deaths and 60-day mortality were not significant, higher incidences in grade III/IV hypertension, arterial thrombembolic events and gastrointestinal perforations were observed in the patients treated with bevacizumab. For valatanib, currently available data showed a non-significant benefit in PFS and OS.

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