The authors concluded that the addition of estramustine to docetaxel-based chemotherapy for men with prostate cancer was associated with almost equal overall survival and safety, but a higher prostate-specific antigen response rate compared with docetaxel-based therapy alone. Given concerns about the robustness of the review process and reliance on limited evidence, this conclusion might not be reliable.

To evaluate the efficacy and toxicity of adding estramustine to docetaxel-based chemotherapy in patients with castration-resistant prostate cancer.

PubMed and EMBASE were searched to April 2011. There were no language restrictions. Search terms were reported. Posters from annual meetings of the European Society of Medical Oncology and the American Society of Medical Oncology over the previous 10 years were reviewed.

Phase II and III randomised controlled trials (RCTs) that compared the efficacy and toxicity of docetaxel-based chemotherapy with or without estramustine were eligible for inclusion. Eligible patients had to have pathological diagnosis of prostate adenocarcinoma and progressive metastatic disease despite androgen deprivation.

Included trials were conducted in France, Italy, Belgium, and USA. Chemotherapy regimens varied. The primary outcome reported was overall survival from baseline to death from any cause. None of the trials reported on progression-free survival. Secondary outcomes reported were prostate-specific antigen response rate (decrease in the serum prostate-specific antigen level of 50% or more from baseline) and grade three or four toxicity. The mean age of included men ranged from 67.4 to 72 years.

The authors did not state how many reviewers were involved in the selection of studies.

Trial quality was assessed using the Jadad scale, which covered randomisation, blinding, and withdrawals/drop-outs. The maximum score awarded was 5 points.

The authors did not state how many reviewers were involved in quality assessment.

Data were extracted or calculated as hazard ratios (HRs) for overall survival and odds ratios (ORs) for prostate-specific antigen response rate and toxicity, with associated 95% confidence intervals (CIs). Data were extracted on an intention-to-treat basis.

Two reviewers independently extracted the data.

Effect sizes were pooled in a meta-analysis using a fixed-effect model where statistical heterogeneity was absent, and a random-effects model where heterogeneity existed. Heterogeneity was assessed Χ²and Ι².

Subgroup analysis was conducted according to characteristics including ethnicity and whether control groups were hospital-based or population-based.

Publication bias was assessed using the Begg and Egger tests.

Four RCTs (400 patients, sample size range 64 to 149) were included in the review. Three trials had a Jadad score of 3 points; one trial scored 2 points. Full results for quality were not reported, but the authors noted adequate randomisation and a lack of blinding across the trials.

There was no statistically significant difference in overall survival of patients between the chemotherapy groups with or without estramustine (three RCTs).

Prostate-specific antigen response rate was significantly improved in the chemotherapy group with added estramustine (OR 1.55, 95% CI 1.10 to 2.18; four RCTs; Ι²=25.9%).

Risks of grade three or four adverse events of neutropenia, anaemia, thrombocytopenia, diarrhoea, nausea, mucositis, and vomiting were comparable between the groups (four RCTs; not all RCTs reported all adverse events).

There was no significant heterogeneity in any of the analyses.

The results of the subgroup analysis were not presented.

There was no evidence of publication bias.

Compared with docetaxel-based chemotherapy alone, the addition of estramustine to this chemotherapy was associated with almost equivalent overall survival and safety, but a higher prostate-specific antigen response rate. Based on no gain for survival, the additional agent was not supported in the treatment of castration-resistant prostate cancer.

The review question was clear. Inclusion criteria were sufficiently replicable, although criteria for outcomes were broad. Two major databases were searched. The search strategy included attempts to minimise publication and language biases. The search might have benefited from further attempts to locate unpublished or ongoing trials. Publication bias was assessed. The process of data extraction was conducted with efforts to minimise error and bias, but it was unclear if this process was applied to the selection of studies and quality assessment.

A suitable quality assessment tool was applied; the results indicated some methodological limitations within the included trials. Trial details were presented. Statistical heterogeneity was assessed. The method of synthesis appeared broadly appropriate, but clinical heterogeneity between some of the trials suggested that fixed-effect pooling might not have been appropriate.

The review findings were based on a small number of trials with limited sample size. This, together with the lack of clarity on robustness of the review process and limited trial quality, means that this conclusion may not be reliable.

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

Research: The authors stated that high quality RCTs were needed to evaluate the effect of docetaxel-based therapy with estramustine on overall survival. Additionally, RCTs should investigate whether higher prostate-specific antigen response rate was associated with longer progression-free survival or overall survival. Results should be confirmed in Asia.

Not stated.

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.