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Meta-Analysis
. 2009 Jul 8;2009(3):CD005392.
doi: 10.1002/14651858.CD005392.pub3.

Anti-angiogenic therapies for metastatic colorectal cancer

Anna Dorothea A D W Wagner  1 , Dirk Arnold, Axel A G Grothey, Johannes Haerting, Susanne Unverzagt
Affiliations
Meta-Analysis

Anti-angiogenic therapies for metastatic colorectal cancer

Anna Dorothea A D W Wagner et al. Cochrane Database Syst Rev. .

Abstract

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.

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

PubMed Disclaimer

Conflict of interest statement

None

Figures

1
1
Flowchart of the search process
2
2
Funnel plot of comparison: 1 First‐line CTX with versus without Bevacizumab, outcome: 1.1 Progression Free Survival.
3
3
Funnel plot of comparison: 1 First‐line CTX with versus without Bevacizumab, outcome: 1.2 Overall Survival.
4
4
Forest plot of comparison: 1 First‐line CTX with versus without Bevacizumab, outcome: 1.1 Progression Free Survival.
5
5
Forest plot of comparison: 1 First‐line CTX with versus without Bevacizumab, outcome: 1.2 Overall Survival.
6
6
Forest plot of comparison: 2 Second‐line CTX with versus without Bevacizumab, outcome: 2.1 Progression Free Survival.
7
7
Forest plot of comparison: 2 Second‐line CTX with versus without Bevacizumab, outcome: 2.2 Overall Survival.
8
8
Forest plot of comparison: 3 First‐line CTX with versus without Vatalanib (PTK 787/ZK 222584), outcome: 3.1 Progression Free Survival.
9
9
Forest plot of comparison: 3 First‐line CTX with versus without Vatalanib (PTK 787/ZK 222584), outcome: 3.2 Overall Survival.
1.1
1.1. Analysis
Comparison 1 First‐line CTX with versus without Bevacizumab, Outcome 1 Progression Free Survival.
1.2
1.2. Analysis
Comparison 1 First‐line CTX with versus without Bevacizumab, Outcome 2 Overall Survival.
1.3
1.3. Analysis
Comparison 1 First‐line CTX with versus without Bevacizumab, Outcome 3 Tumour Response.
1.4
1.4. Analysis
Comparison 1 First‐line CTX with versus without Bevacizumab, Outcome 4 Toxicity ‐ 60‐day mortality.
1.5
1.5. Analysis
Comparison 1 First‐line CTX with versus without Bevacizumab, Outcome 5 Toxicity ‐ treatment related deaths.
1.6
1.6. Analysis
Comparison 1 First‐line CTX with versus without Bevacizumab, Outcome 6 Toxicity ‐ treatment discontinuation.
1.7
1.7. Analysis
Comparison 1 First‐line CTX with versus without Bevacizumab, Outcome 7 Toxicity ‐ any adverse event (grade 3 or 4).
1.8
1.8. Analysis
Comparison 1 First‐line CTX with versus without Bevacizumab, Outcome 8 Toxicity ‐ hypertension (grade 3 or 4).
1.9
1.9. Analysis
Comparison 1 First‐line CTX with versus without Bevacizumab, Outcome 9 Toxicity ‐ thrombembolic events (grade 3 or 4).
1.10
1.10. Analysis
Comparison 1 First‐line CTX with versus without Bevacizumab, Outcome 10 Toxicity ‐ arterial thrombembolic event (grade 3 or 4).
1.11
1.11. Analysis
Comparison 1 First‐line CTX with versus without Bevacizumab, Outcome 11 Toxicity ‐ proteinuria (grade 3 or 4).
1.12
1.12. Analysis
Comparison 1 First‐line CTX with versus without Bevacizumab, Outcome 12 Toxicity ‐ bleeding (grade 3 or 4).
1.13
1.13. Analysis
Comparison 1 First‐line CTX with versus without Bevacizumab, Outcome 13 Toxicity ‐ gastrointestinal perforation.
2.1
2.1. Analysis
Comparison 2 Second‐line CTX with versus without Bevacizumab, Outcome 1 Progression Free Survival.
2.2
2.2. Analysis
Comparison 2 Second‐line CTX with versus without Bevacizumab, Outcome 2 Overall Survival.
2.3
2.3. Analysis
Comparison 2 Second‐line CTX with versus without Bevacizumab, Outcome 3 Tumour Response.
2.4
2.4. Analysis
Comparison 2 Second‐line CTX with versus without Bevacizumab, Outcome 4 Toxicity ‐60‐ day mortality.
2.5
2.5. Analysis
Comparison 2 Second‐line CTX with versus without Bevacizumab, Outcome 5 Toxicity ‐ treatment related deaths.
2.6
2.6. Analysis
Comparison 2 Second‐line CTX with versus without Bevacizumab, Outcome 6 Toxicity ‐ treatment discontinuation.
2.7
2.7. Analysis
Comparison 2 Second‐line CTX with versus without Bevacizumab, Outcome 7 Toxicity ‐ any adverse event (grade 3 or 4).
2.8
2.8. Analysis
Comparison 2 Second‐line CTX with versus without Bevacizumab, Outcome 8 Toxicity ‐ hypertension (grade 3 or 4).
2.9
2.9. Analysis
Comparison 2 Second‐line CTX with versus without Bevacizumab, Outcome 9 Toxicity ‐ thromboembolic event (grade 3 or 4).
2.10
2.10. Analysis
Comparison 2 Second‐line CTX with versus without Bevacizumab, Outcome 10 Toxicity ‐ arterial thromboembolic event (grade 3 or 4).
2.11
2.11. Analysis
Comparison 2 Second‐line CTX with versus without Bevacizumab, Outcome 11 Toxicity ‐ proteinuria (gade 3 or 4).
2.12
2.12. Analysis
Comparison 2 Second‐line CTX with versus without Bevacizumab, Outcome 12 Toxicity ‐ bleeding (grade 3 or 4).
2.13
2.13. Analysis
Comparison 2 Second‐line CTX with versus without Bevacizumab, Outcome 13 Toxicity ‐ gastrointestinal perforation.
3.1
3.1. Analysis
Comparison 3 First‐line CTX with versus without Vatalanib (PTK 787/ZK 222584), Outcome 1 Progression Free Survival.
3.2
3.2. Analysis
Comparison 3 First‐line CTX with versus without Vatalanib (PTK 787/ZK 222584), Outcome 2 Overall Survival.
3.3
3.3. Analysis
Comparison 3 First‐line CTX with versus without Vatalanib (PTK 787/ZK 222584), Outcome 3 Tumour Response.
3.4
3.4. Analysis
Comparison 3 First‐line CTX with versus without Vatalanib (PTK 787/ZK 222584), Outcome 4 Toxicity ‐ 28‐day mortality.
3.5
3.5. Analysis
Comparison 3 First‐line CTX with versus without Vatalanib (PTK 787/ZK 222584), Outcome 5 Toxicity ‐ hypertension (grade 3 or 4).
3.6
3.6. Analysis
Comparison 3 First‐line CTX with versus without Vatalanib (PTK 787/ZK 222584), Outcome 6 Toxicity ‐ thromboembolic events (DVT) (grade 3 or 4).
3.7
3.7. Analysis
Comparison 3 First‐line CTX with versus without Vatalanib (PTK 787/ZK 222584), Outcome 7 Toxicity ‐ thromboembolic events (pulmonary embolism) (grade 3 or 4).
3.8
3.8. Analysis
Comparison 3 First‐line CTX with versus without Vatalanib (PTK 787/ZK 222584), Outcome 8 Toxicity ‐ arterial thromboembolic events (grade 3 or 4).
3.9
3.9. Analysis
Comparison 3 First‐line CTX with versus without Vatalanib (PTK 787/ZK 222584), Outcome 9 Toxicity ‐ bleeding (grade 3 or 4).
3.10
3.10. Analysis
Comparison 3 First‐line CTX with versus without Vatalanib (PTK 787/ZK 222584), Outcome 10 Toxicity ‐ gastrointestional perforation.
4.1
4.1. Analysis
Comparison 4 First‐line 5‐FU/LV with versus without Bevacizumab, Outcome 1 Progression Free Survival.
4.2
4.2. Analysis
Comparison 4 First‐line 5‐FU/LV with versus without Bevacizumab, Outcome 2 Overall Survival.
5.1
5.1. Analysis
Comparison 5 First‐line IFL with versus without Bevacizumab, Outcome 1 Progression Free Survival.
5.2
5.2. Analysis
Comparison 5 First‐line IFL with versus without Bevacizumab, Outcome 2 Overall Survival.
6.1
6.1. Analysis
Comparison 6 First‐line Oxaliplatin with versus without Bevacizumab, Outcome 1 Progression Free Survival.
6.2
6.2. Analysis
Comparison 6 First‐line Oxaliplatin with versus without Bevacizumab, Outcome 2 Overall Survival.
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    1. Study of FOLFIRI chemotherapy with or without Sunitinib In Metastatic Colorectal Cancer. Ongoing study June 2007.
NCT00484939 {published data only}
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