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

Magnitude of risks and benefits of the addition of bevacizumab to chemotherapy for advanced breast cancer patients: meta-regression analysis of randomized trials

F Cuppone, E Bria, V Vaccaro, F Puglisi, A Fabi, I Sperduti, P Carlini, M Milella, C Nistico, M Russillo, P Papaldo, G Ferretti, M Aapro, D Giannarelli, and F Cognetti.

Review published: 2011.

CRD summary

This review concluded that the addition of bevacizumab to first-line chemotherapy improved progression-free survival and overall response rate but significant variation was observed; the risk of hypertension should be weighted with the overall benefit for each patient. These conclusions should be interpreted cautiously, given the unclear quality of included trials and significant variation found in the pooled outcomes.

Authors' objectives

To assess the efficacy and safety of adding bevacizumab to chemotherapy for the treatment of advanced breast cancer.

Searching

PubMed was searched for randomised clinical trials (RCTs) up to June 2010 with no language restrictions. Search terms were reported. Websites and meetings of the American Society of Clinical Oncology, European Society for Medical Oncology, Federation of European Cancer Societies and San Antonio Breast Cancer Symposium were also searched. Reference lists of relevant publications were screened.

Study selection

Phase III randomised controlled trials (RCTs) that compared the combination of chemotherapy plus bevacizumab versus chemotherapy alone, regardless of treatment lines, in patients with advanced or metastatic breast cancer were eligible for inclusion. The primary outcomes were progression free survival and overall survival. Secondary outcomes were overall response rate and grade 3 to 4 toxicities.

The included trials evaluated the addition of bevacizumab to capecitabine, paclitaxel, docetaxel or other chemotherapies. Most included trials evaluated the addition of bevacizumab as first-line treatment. Some trials evaluated the addition of bevacizumab as second-line treatment. The dosing regimen of bevacizumab in the included trials ranged from 7.5mg/kg to 15mg/kg. The percentage of patients with more than three sites of metastasis ranged from 27.8% to 54.5%. The percentage of patients who received prior taxanes ranged from 14.9% to 100%, those with hormonal receptor negative ranged from 17.1% to 36.7% and those who received prior anthracyclines ranged from 29.9% to 100% (where reported).

The authors did not state how many reviewers assessed studies for inclusion.

Assessment of study quality

The authors did not state that they assessed study quality.

Data extraction

Data were extracted on hazard ratios (HRs) for primary outcomes, with 95% confidence intervals (CIs). The number of events were extracted to calculate relative risks (RRs) for secondary outcomes, with 95% confidence intervals.

Four reviewers independently performed data extraction.

Methods of synthesis

The pooled hazard ratios or relative risks, with 95% confidence intervals (CIs), were calculated using the DerSimonian-Laird random-effects model. Statistical heterogeneity was assessed using the Q statistic. The numbers needed to treat (NNT) and numbers needed to harm (NNH) were calculated.

Separate analyses were conducted for first-line and second-line treatment. A meta-regression was performed to assess the impact of a number of factors (more than three sites of metastasis, prior anthracycline exposure) on the overall treatment effect.

Results of the review

Five trials were included in the review (n=3,841 patients). The sample size of included trials ranged from 462 to 736 patients.

Progression-free survival: Compared with chemotherapy alone, the addition of bevacizumab to chemotherapy was associated with a significant improvement in progression-free survival for the first-line treatment (HR 0.68, 95% CI 0.56 to 0.81; NNT=12; three RCTs). Significant heterogeneity was observed for this outcome (p=0.0001). There was no significant difference in progression-free survival between the two groups for the second line treatment.

Overall survival: No significant difference in overall survival was observed between the two groups for both first-line and second-line treatment.

Overall response rate: Compared with chemotherapy alone, the addition of bevacizumab to chemotherapy was associated with a significant improvement in the overall response rate for the first-line treatment (RR 1.46, 95% CI 1.21 to 1.77; NNT=8 to 9; three RCTs) and a marginally significant improvement in the overall response rate for the second-line treatment (RR 1.58, 95% CI 1.00 to 2.52; NNT=12; two RCTs). Significant heterogeneity was observed for both of the outcomes (first-line treatment p=0.008; second-line treatment p=0.09).

Toxicity: Compared with chemotherapy alone, the addition of bevacizumab to chemotherapy was significantly associated with an increased risk of hypertension (RR 5.15, 95% CI 1.60 to 16.6; NNH=22). Significant heterogeneity was observed for this outcome (p<0.0001). The other significant adverse events were proteinuria, neurotoxicity, febrile neutropenia and bleeding.

Meta-regression showed that more than three metastatic sites, prior anthracycline-exposure, no adjuvant chemotherapy and negative hormonal receptor status significantly affected progression-free survival of patients for first-line treatment.

Authors' conclusions

The addition of bevacizumab to first-line chemotherapy significantly improved progression-free survival and overall response rate, but significant heterogeneity was observed. The risk of hypertension should be weighted with the overall benefit on the individual patient basis.

CRD commentary

The inclusion criteria of the review were clear. Relevant sources were searched. Efforts were made to find both published and unpublished studies with no language restriction, which minimised the risk of publication and language biases. Steps were taken to minimise the reviewer bias and errors during the process of data extraction, but it was unclear whether study selection was performed in duplicate. No formal quality assessment of included trials was performed. Statistical heterogeneity was assessed. Appropriate methods were used to pool the results.

The authors' conclusions should be interpreted with caution given the lack of information on trial quality and significant heterogeneity found on the pooled outcomes.

Implications of the review for practice and research

Practice: The authors did not state any implications for practice.

Research: The authors stated that further studies were required to perform a deep analysis of the correlation between adverse events and deaths when adding bevacizumab to chemotherapy for the treatment of advanced breast cancer. These studies should also investigate the maximisation of the efficacy by restricting bevacizumab to the patients who will really benefit.

Funding

National Ministry of Health, Italy; Italian Association for Cancer Research (AIRC).

Bibliographic details

Cuppone F, Bria E, Vaccaro V, Puglisi F, Fabi A, Sperduti I, Carlini P, Milella M, Nistico C, Russillo M, Papaldo P, Ferretti G, Aapro M, Giannarelli D, Cognetti F. Magnitude of risks and benefits of the addition of bevacizumab to chemotherapy for advanced breast cancer patients: meta-regression analysis of randomized trials. Journal of Experimental and Clinical Cancer Research 2011; 30(1):54. [PMC free article: PMC3120715] [PubMed: 21569417]

PubMedID

21569417

Indexing Status

Subject indexing assigned by NLM

MeSH

Angiogenesis Inhibitors /adverse effects /therapeutic use; Antibodies, Monoclonal /adverse effects /therapeutic use; Antibodies, Monoclonal, Humanized; Antineoplastic Agents /adverse effects /therapeutic use; Breast Neoplasms /drug therapy /pathology; Female; Humans; Neoplasm Staging; Randomized Controlled Trials as Topic; Risk Assessment; Treatment Outcome

AccessionNumber

12011004270

Date bibliographic record published

12/10/2011

Date abstract record published

24/03/2012

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: 21569417

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