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

Metastatic renal cell cancer treatments: an indirect comparison meta-analysis

EJ Mills, B Rachlis, C O'Regan, L Thabane, and D Perri.

Review published: 2009.

CRD summary

The review investigated the optimal treatment for metastatic renal cell carcinoma. The authors found that sunitinib, bevacizumab and temsirolimus all offer improved progression-free survival compared to interferon-α or placebo. This was a well-conducted review and the conclusions based on the direct comparisons are likely to be reliable, but those from the indirect comparisons should be treated with suitable caution.

Authors' objectives

To determine the optimal treatment for metastatic renal cell carcinoma.

Searching

The following databases were searched from inception to April 2008: AMED, CINAHL, Cochrane Library, EMBASE and MEDLINE. In addition, the clinicaltrials.gov website and the UK National Research Register were also searched. The American Society of Clinical Oncology (ASCO) website was scanned for studies published as conference abstracts. Authors of abstracts were contacted for further information. Handsearches of the bibliographies of key papers were also performed.

Study selection

Randomised controlled trial RCTs evaluating the therapeutic efficacy of bevacizumab, sorafenib, sunitinib or temsirolimus, as either sole treatment or adjunct treatment in patients with metastatic renal cell carcinoma, were eligible for inclusion. The primary outcome was progression-free survival.

In the included trials, the median age, where stated, ranged from 53 to 61 years, and approximately 30% were women. Participants in the included trials were a mix of those with poor or favourable prognosis, with or without having been treated with previous therapy. Interferon-α and placebo were used as comparators. Where stated, dosage regimes in the included trials were: bevacizumab 3 or 10 mg/kg; sorafenib 400 mg twice daily; sunitinib 50 mg orally daily for fours weeks then two weeks off; temsirolimus 25mg weekly infusion; interferon 9 MIU three times a week. Median treatment duration ranged from eight weeks to 11 months.

It appears that two reviewers independently screened studies for inclusion.

Assessment of study quality

Validity was assessed based on the following aspects of study design: methods of sequence generation, allocation concealment, complete description of who was blinded, use of intention-to-treat analysis and whether the trial was stopped prior to the planned study end.

Two reviewers independently performed the validity assessment, and discrepancies were resolved by discussion with a third reviewer.

Data extraction

To estimate the primary outcome (progression-free survival), and secondary outcomes (overall survival, median duration of treatment, duration of treatment response, overall response rate and adverse events), the authors either extracted the hazard ratios (HR) and 95% confidence intervals (CIs) from the paper, contacted the primary study authors, or estimated the HR based on the results presented in the paper.

Two reviewers independently performed the data abstraction, and discrepancies were resolved by discussion with a third reviewer.

Methods of synthesis

Trials of the same drug were pooled for each drug using DerSimonian and Laird random-effects models. Indirect comparisons of the interventions versus similar comparators across similar patient groups were made using the methods of Bucher et al (1997).

Results of the review

Seven trials (five full papers and two abstracts, n=3,957 participants) were included in the review. Only one trial reported sequence generation process and adequately described allocation concealment. Three trials reported descriptions of blinding. Five trials utilised an intent-to-treat design. Five trials adequately described safety monitoring and four trials employed stopping rules.

Direct analysis of interventions: The pooling of two trials showed that bevacizumab plus interferon-α was superior to interferon-α alone (hazard ratio 0.68, 95% confidence interval (CI): 0.60 to, 0.76; p=0.001, n=1,381 participants). A single trial found sunitinib superior to interferon-α (hazard ratio 0.51, 95% CI: 0.43 to 0.61; n=750 participants). Another trial found temsirolimus superior to interferon-α (hazard ratio 0.69, 95% CI: 0.57 to 0.85; n=629 participants). No difference between sorafenib and interferon-α was found in a single trial. Compared to placebo, sorafenib (hazard ratio 0.51, 95% CI: 0.43 to 0.60; n=649 participants) and bevacizumab (hazard ratio 0.63, 95% CI: 0.48 to 0.81; n=108 participants) were beneficial.

Indirect analysis of interventions: Sunitinib was superior to sorafenib (hazard ratio 0.58, 95% CI: 0.38 to 0.86; p<0.001), and superior to bevacizumab plus interferon-α (hazard ratio 0.75, 95% CI: 0.60 to 0.93; p=0.001). There was no difference in efficacy of sorafenib compared to bevacizumab alone or bevacizumab plus interferon-α.

Authors' conclusions

Sunitinib, bevacizumab and temsirolimus all offer improved progression-free survival compared to interferon-α or placebo.

CRD commentary

The review addressed a clear question. Inclusion criteria were clearly stated. The search strategy included a range of databases, and attempts were made to locate unpublished data and studies published only in abstract form. Search terms were not listed in the paper, but it was stated that an information specialist was involved in developing the search. Two authors performed the study selection, data extraction and validity assessment, thus reducing the chance of bias. Validity was assessed and reported for each study. The methods of synthesis involved indirect comparisons of the interventions. The authors acknowledge the limitation of this, but stated that no head-to-head studies of the intervention drugs had been carried out. This was a well-conducted review and the conclusions based on the direct comparisons are likely to be reliable, but those from indirect comparisons should be treated with suitable caution.

Implications of the review for practice and research

Research: The authors stated that future randomised controlled trials should examine combination therapies of sunitinib, bevacizumab and temsirolimus.

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

Funding

Pfizer Ltd.

Bibliographic details

Mills E J, Rachlis B, O'Regan C, Thabane L, Perri D. Metastatic renal cell cancer treatments: an indirect comparison meta-analysis. BMC Cancer 2009; 9:34. [PMC free article: PMC2637892] [PubMed: 19173737]

Indexing Status

Subject indexing assigned by NLM

MeSH

Angiogenesis Inhibitors /therapeutic use; Antibodies, Monoclonal /therapeutic use; Antibodies, Monoclonal, Humanized; Antineoplastic Agents /therapeutic use; Benzenesulfonates /therapeutic use; Carcinoma, Renal Cell /drug therapy /secondary; Disease-Free Survival; Humans; Indoles /therapeutic use; Interferon-alpha /therapeutic use; Kidney Neoplasms /drug therapy /secondary; Niacinamide /analogs & derivatives; Phenylurea Compounds; Pyridines /therapeutic use; Pyrroles /therapeutic use; Randomized Controlled Trials as Topic; Sirolimus /analogs & derivatives /therapeutic use

AccessionNumber

12009103037

Database entry date

05/08/2009

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: 19173737