CRD summary

This generally well-conducted review concluded that the benefits of treatment with bevacizumab outweighed the side-effects that may occur, enough to justify its use by patients with advanced colorectal cancer. However, the mixed quality of the evidence, possible underpowered trials, and unclear extent of variation between trials potentially limit the reliability of the pooled results.

Authors' objectives

To assess the overall risk of bevacizumab-related side-effects in patients affected by advanced colorectal cancer, and to compare this with the overall benefit.

Searching

PubMed, CANCERLIT, EMBASE, and the Cochrane Library were searched to March 2010 for articles in English. Search terms were reported. Five relevant conference sites were searched up to March 2010.

Study selection

Randomised controlled trials (RCTs) that compared bevacizumab plus chemotherapy versus chemotherapy alone in patients with histologically confirmed metastatic colon cancer were eligible for inclusion. Trials had to report on safety (primary outcome), overall survival and progression-free survival (secondary outcomes). Outcome definitions were reported in the paper.

The included trials studied bevacizumab (5mg/kg to 10mg/kg dose) in combination with leucovorin, fluorouracil, irinotecan, oxaliplatin, mitomycin, and/or capecitabine. The comparators were various chemotherapy regimens alone. Trials were published from 2003 up to 2010.

The authors did not state how many reviewers performed the study selection.

Assessment of study quality

Trial quality was assessed using the Cochrane handbook, but using criteria specifically designed for the review. The tool appraised seven quality factors including randomisation/sequence generation, allocation concealment, and baseline characteristics.

Two reviewers independently performed the quality assessment; disagreements were resolved by a third reviewer.

Data extraction

Data were extracted on adverse events and discontinuation rates, and used to calculate relative risk (RRs) and 95% confidence intervals (CIs). Data on overall survival and progression free survival were also extracted and used to calculate hazard ratios (HRs) and 95% confidence intervals.

Two reviewers independently performed the data extraction; disagreements were resolved by discussion.

Methods of synthesis

A random-effect meta-analysis was used to calculate pooled relative risks and hazard ratios, together with 95% confidence intervals, using the inverse variance method. Statistical heterogeneity was assessed using the Cochran Q-test and I². The number needed to harm (NNH) and the number needed to treat (NNT) were estimated.

Results of the review

Six RCTs (3,385 patients) were included in the review. Trial sample size ranged from 103 to 1,400 patients. The quality of the included trials was mixed: three trials reported randomisation sequence, two reported allocation concealment, and five reported similar baseline characteristics.

Safety: Compared with chemotherapy, treatment with bevacizumab plus chemotherapy was associated with a statistically significantly higher risk of any grade bleeding (RR 2.07, 95% CI 1.19 to 3.62; NNH=32), any grade hypertension (RR 2.98, 95% CI 2.32 to 3.84; NNH=12), any grade proteinuria (RR 1.88, 95% CI 1.19 to 2.97; NNH=15), and any grade gastrointestinal perforations (RR 5.04, 95% CI 1.72 to 14.79; NNH=124). For grade 3/4 adverse events, bevacizumab was associated with a statistically significant increase in grade 3/4 hypertension (RR 4.27, 95% CI 2.80 to 6.51; NNH=19) and arterial thrombotic events (RR 1.57, 95% CI 1.07 to 2.32; NNH=73).

Efficacy: Compared with chemotherapy, treatment with bevacizumab plus chemotherapy was associated with a statistically significantly greater overall survival (HR 0.80, 95% CI 0.71 to 0.91; I²=39%; NNT=12) and progression free survival (HR 0.62, 95% CI 0.52 to 0.74; I²=73%; NNT=6).

Authors' conclusions

The benefits of treatment with bevacizumab outweighed the toxicity that may occur, enough to justify its use in advanced colorectal cancer.

CRD commentary

Inclusion criteria for the review were clearly defined. Several relevant data sources were searched. There may have been the potential for language bias, as only English language articles were included. Although unpublished data were sought and included in the review, publication bias was not formally assessed. Attempts were made to reduce reviewer error and bias throughout the data extraction and quality assessment, but it was unclear if same methods were used for study selection.

Quality assessment was undertaken using a specially designed checklist; it indicated the variable quality of the included trials (which the authors acknowledged). Trials were combined using appropriate statistical methods. Statistical heterogeneity results were not presented for all analyses, which made it difficult to estimate the suitability of trials for pooling. Some of the adverse events had a low incidence of occurrence; it was not clear if the trials were powered to detect statistical differences.

The review was generally well conducted, but the mixed quality of the evidence, possible underpowered trials, and unclear extent of heterogeneity potentially limits the reliability of the pooled results.

Implications of the review for practice and research

Practice: The authors stated that clinicians should be highly vigilant to detect any signs of perforation as early as possible.

Research: The authors stated that further research was needed to develop specific tests to identify those patients who have a greater chance of developing bevacizumab related toxicities and to further reduce the incidence of serious adverse events.

Funding

Not stated.

Bibliographic details

Galfrascoli E, Piva S, Cinquini M, Rossi A, La Verde N, Bramati A, Moretti A, Manazza A, Damia G, Torri V, Muserra G, Farina G, Garassino MC, . Risk/benefit profile of bevacizumab in metastatic colon cancer: a systematic review and meta-analysis. Digestive and Liver Disease 2011; 43(4): 286-294. [PubMed: 21146479]

Original Paper URL

http://www.dldjournalonline.com/article/S1590-8658(10)00346-4/abstract

Indexing Status

Subject indexing assigned by NLM

MeSH

Angiogenesis Inhibitors /adverse effects /therapeutic use; Antibodies, Monoclonal /adverse effects /therapeutic use; Antibodies, Monoclonal, Humanized; Colorectal Neoplasms /drug therapy /mortality /pathology; Disease-Free Survival; Humans; Neoplasm Metastasis; Risk Assessment; Survival Rate

AccessionNumber

12011002214

Database entry date

30/11/2011

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.