Anti-angiogenic therapies for metastatic colorectal cancer.
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.


OBJECTIVE
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.


METHODS
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.


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


METHODS
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.


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.


CONCLUSIONS
The addition of bevacizumab to chemotherapy of metastatic colorectal cancer prolongs both PFS and OS in first-and second-line therapy.
Wagner
Anna Dorothea A D W
AD
Fondation du Centre Pluridisciplinaire d'Oncologie, Centre Hospitalier Universitaire Vaudois, Rue du Bugnon 46, Lausanne, Switzerland, 1011.
Arnold
Dirk
D
Grothey
Axel A G
AA
Haerting
Johannes
J
Unverzagt
Susanne
S
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D015179:Colorectal Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology; D003131:Combined Modality Therapy / Q000379:methods; D018572:Disease-Free Survival; D006801:Humans; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000401:mortality; D010793:Phthalazines / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D010793:Phthalazines; D011725:Pyridines; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; C404768:vatalanib