To compare adjuvant chemotherapy with no adjuvant chemotherapy for localised soft-tissue sarcoma (STS).

MEDLINE and Cancerlit were searched, and the reference lists of identified trials, review articles and books were examined. Trials had to have taken place between January 1970 and December 1992.

Study designs of evaluations included in the review

Randomised controlled trials (RCTs) were included.

Specific interventions included in the review

Adjuvant chemotherapy using doxorubicin (200 to 550 mg/m2), either as a single agent or in combination with cyclophosphamide plus one or more of vincristine, methotrexate, dactinomycin and dacarbazine.

Participants included in the review

Adult patients with localised, resectable STS. The extremities were the main tumour sites accounting for more than half of all randomised patients. Other tumour sites included head and neck, breast, trunk, retroperitoneum and uterus.

Outcomes assessed in the review

The outcomes were 2- and 5-year survival and disease-free survival

How were decisions on the relevance of primary studies made?

The authors do not state how the papers were selected for the review, or how many of the authors performed the selection.

The authors do not report a method for assessing validity. However, only trials using a method of randomisation that precluded prior knowledge of treatment assignment, were included. [A: Judgements of study validity were made by three independent researchers.]

The authors do not state how the data were extracted for the review, or how many of the authors performed the data extraction. However, 2- and 5-year survival rates were taken from the most recent publication for each trial. If the survival rates were not quoted, they were estimated from the published curves and the numbers at risk reduced, where appropriate, to allow for immature follow-up. [A: Data extraction was carried out by three independent researchers.]

How were the studies combined?

A qualitative review and meta-analysis of included trials were undertaken. For each trial the odds ratio (OR) was calculated from the number of patients at risk and the observed number of deaths on each arm. The 95 and 99% confidence intervals (CIs)were also calculated. An overall OR was calculated along with 95% CIs. The disease-free survival rates were not combined to produce an overall OR because this is a less reliable end point than overall survival.

How were differences between studies investigated?

A chi-squared test of heterogeneity was undertaken.

Fifteen RCTs (n=1,546) were included.

Two-year survival (13 RCTs, n=1,049): the overall OR is 0.73(95% CI: 0.53, 0.99, p=0.044) in favour of chemotherapy. However, the trials were found to be heterogeneous (p=0.022).

Five-year survival (11 RCTs, n=892): the overall OR is 0.59 (95% CI: 0.45, 0.78, p=0.0002) in favour of chemotherapy. This suggests a 41% (95% CI: 22, 55) reduction in the risk of death at 5 years, corresponding to a 12% (95% CI: 6, 17) improvement in absolute survival at 5 years. No statistical heterogeneity was found across the trials (p=0.394).

The qualitative review of included trials was inconclusive.

The meta-analysis suggests an improvement in survival at 2 and 5 years in favour of chemotherapy. However, the assumptions and approximations required to conduct this quantitative summary require that the results are interpreted with caution. The only reliable means of assessing the current evidence on whether adjuvant chemotherapy has a role in the treatment of patients with STS, is to reanalyse individual patient data from each trial. Such an analysis is currently being undertaken by an international collaborative group.

A clear and well-discussed review that may have been enhanced by a more detailed search strategy and validity assessment.[A: Figure 1 has a minor error in the number of events/number entered column for the control group of the ECOG study, and should read 5/10 (not 2/13)]. The authors have initiated an international collaborative meta-analysis, analysing individual patient data, to overcome the problems associated with the current review.

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.