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Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet]. York (UK): Centre for Reviews and Dissemination (UK); 1995-.

Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet].

Bevacizumab in the treatment of ovarian cancer: a meta-analysis from four phase III randomized controlled trials

Q Ye and HL Chen.

Review published: 2013.

CRD summary

This review concluded that the addition of bevacizumab to chemotherapy meaningfully improved the objective response rate and progression-free survival, for patients with ovarian cancer, but did not improve overall survival, and increased adverse events. Despite a key limitation to their analyses, the authors' conclusions seem reasonable; the magnitude of the effect is unclear. Eight ongoing trials were identified.

Authors' objectives

To summarise the efficacy and safety of bevacizumab for the treatment of ovarian cancer.

Searching

PubMed and Web of Science were searched for articles included to September 2012. Search terms were reported. Annual meeting records, and posters from two relevant oncology societies, for the previous 10 years, were searched.

Study selection

Randomised controlled trials (RCTs) of adult women, with histologically proven ovarian cancer, were eligible for inclusion if they compared conventional chemotherapy plus bevacizumab versus conventional chemotherapy alone or with placebo. The outcome measures of interest were the objective response rate, according to Response Evaluation Criteria In Solid Tumours (RECIST); progression-free survival; and overall survival. Adverse events were considered.

Three of the four included trials were published in full; the fourth was presented at a meeting. Two trials did not report overall survival data, and a further eight ongoing trials were identified. Most of the trials were multicentre, recruiting in up to 11 countries, across Europe, USA, New Zealand, and other countries. The average age of participants was between 57 and 62 years. Conventional chemotherapy included carboplatin, gemcitabine, and paclitaxel, in various combinations. Two trials were placebo controlled. Two trials recruited patients with recurrent cancer, and the other two included patients receiving first-line treatment.

It was unclear how many reviewers selected the studies.

Assessment of study quality

The Cochrane Risk of Bias tool was used to assess methodological quality. Trial aspects were judged to be adequate, unclear, or have potential for bias.

Decisions were made independently by two reviewers and disagreements were resolved by discussion.

Data extraction

Progression-free survival was defined as the time from randomisation to disease progression or death from any cause. Overall survival was defined as the time from randomisation to death from any cause. Outcomes were extracted as medians, odds ratios, or hazard ratios, with 95% confidence intervals. All adverse event incidences were extracted.

Outcomes were extracted independently by two reviewers and disagreements were resolved by discussion.

Methods of synthesis

Statistical heterogeneity was assessed using Χ² and Ι², with an Ι² of more than 50% representing significant variation between trials. If heterogeneity was not present a fixed-effect model was used, otherwise data were pooled using a DerSimonian and Laird random-effects model. Summary hazard ratios for the time to event data, and odds ratios for dichotomous data were calculated.

Publication bias was assessed using Begg's and Egger's tests. Subgroup analyses were performed, based on patient inclusion criteria (patients on first-line treatment or those with recurrent ovarian cancer).

Results of the review

Four RCTs (4,246 participants) were included, sample sizes ranged from 361 to 1,873 participants. Two trials were rated at a low risk of bias for all criteria, apart from allocation concealment. A third trial was rated as being at risk of bias in its blinding. The fourth trial was only available as a conference paper, and was rated unclear for all quality criteria.

Objective response rate: Over the four trials, the pooled odds ratio indicated that combining bevacizumab with conventional chemotherapy significantly increased the objective response rate, compared with chemotherapy alone (OR 2.17, 95% CI 1.51 to 3.10; Ι²=84%). Significant heterogeneity was present. In the subgroup analysis, the addition of bevacizumab was significantly beneficial for both first-line therapy (OR 1.90, 95% CI 1.17 to 3.06; Ι²=90%) and patients with recurrent ovarian cancer (OR 2.77, 95% CI 2.00 to 3.83; Ι²=0).

Progression-free survival: In the four trials, the addition of bevacizumab significantly improved progression-free survival, compared with chemotherapy alone (HR 0.69, 95% CI 0.52 to 0.87; Ι²=92%); significant heterogeneity was present. The subgroup analysis found a significant increase in progression-free survival, with bevacizumab, for both first-line therapy patients (HR 0.83, 95% CI 0.71 to 0.95; Ι²=71%) and patients with recurrent ovarian cancer (HR 0.48, 95% CI 0.41 to 0.56; Ι²=0).

Overall survival: Three trials, with 3,885 participants, reported overall survival. There was no significant difference between participants receiving conventional chemotherapy and those who also received bevacizumab, regardless of patient treatment status.

Adverse events: Across all four trials, compared with controls, patients receiving bevacizumab had a 2.7 times greater risk of a grade two or higher gastrointestinal event (95% CI 1.58 to 4.76; Ι²=0); a 4.6 times greater risk of grade two or higher hypertension (95% CI 3.74 to 5.74; Ι²=84%); a 4.9 times greater risk of grade three or higher proteinuria (95% CI 2.62 to 9.07; Ι²=58%); and a 2.0 times greater risk of arterial thrombosis (95% CI 1.21 to 3.29; Ι²=30%). There was no difference in the risk of venous thromboembolism.

There was no indication of publication bias from the Begg and Egger tests.

Authors' conclusions

The addition of bevacizumab to chemotherapy meaningfully improved the objective response rate and progression-free survival, for patients with ovarian cancer, but it did not improve overall survival and it increased the occurrence of adverse events (gastrointestinal events, hypertension, proteinuria, and arterial thromboembolism).

CRD commentary

This review addressed a clear question with detailed inclusion criteria. The searches included databases and other sources of unpublished data, but they were limited in scope. Publication bias was assessed, but these tests are unreliable for so few trials (four). No language restrictions were mentioned, and processes to prevent reviewer error and bias were reported for some stages.

The trials were assessed for quality, but this information was not used to inform the analyses. The trial details were partly reported and indicated considerable clinical variation between trials. The choice of a random-effects model to pool the trials may have been appropriate, but some statistical heterogeneity remained unexplained. For one large three-armed trial, the control arm results were counted twice in many of the analyses.

Despite a key limitation to their analyses, the authors' conclusions seem reasonable; the magnitude of the effect is unclear. The authors identified eight additional ongoing trials that would significantly add to the evidence, particularly if analysed according to best practice.

Implications of the review for practice and research

The authors made no recommendations for practice and research, but they noted that eight trials were being conducted.

Funding

Not stated.

Bibliographic details

Ye Q, Chen HL. Bevacizumab in the treatment of ovarian cancer: a meta-analysis from four phase III randomized controlled trials. Archives of Gynecology and Obstetrics 2013; 288(3): 655-666. [PubMed: 23543268]

Indexing Status

Subject indexing assigned by CRD

MeSH

Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Ovarian Neoplasms; Humans

AccessionNumber

12013019421

Database entry date

19/06/2013

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.

CRD has determined that this article meets the DARE scientific quality criteria for a systematic review.

Copyright © 2014 University of York.

PMID: 23543268

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