Adjuvant chemotherapy for localised resectable soft tissue sarcoma in adults
Individually, randomised trials have not shown conclusively whether adjuvant chemotherapy benefits adult patients with localised resectable soft‐tissue sarcoma.
Adjuvant chemotherapy aims to lessen the recurrence of cancer after surgery with or without radiotherapy. The objective of this review was to assess the effects of adjuvant chemotherapy in adults with resectable soft tissue sarcoma after such local treatment.
We searched the Cochrane Controlled Trials Register, UKCCCR Register of Cancer Trials, Physicians Data Query, EMBASE, MEDLINE and CancerLit.
Randomised trials of adjuvant chemotherapy after local treatment in adults with localised resectable soft tissue sarcoma were included. Only trials in which accrual was completed by December 1992 were included.
Data collection and analysis
Individual patient data were obtained. Accuracy of data and quality of randomisation and follow‐up of trials was assessed.
Fourteen trials of doxorubicin‐based adjuvant chemotherapy involving 1568 patients were included. Median follow‐up was 9.4 years. For local recurrence‐free interval the hazard ratio (HR) with chemotherapy was 0.73 (95% Confidence Interval (CI) 0.56 to 0.94). For distant recurrence‐free interval it was 0.70 (95% CI 0.57 to 0.85). For overall recurrence‐free survival it was 0.75 (95% CI 0.64 to 0.87). These correspond to significant absolute benefits of 6 to 10% at 10 years. For overall survival (OS) the HR of 0.89 (95% CI 0.76 to 1.03) was not significant but potentially represents an absolute benefit of 4% (95% CI 1 to 9) at 10 years. There was no consistent evidence of a difference in effect according to age, sex, stage, site, grade, histology, extent of resection, tumour size or exposure to radiotherapy. However, the strongest evidence of a beneficial effect on survival was shown in patients with sarcoma of the extremities.
Doxorubicin‐based adjuvant chemotherapy appears to significantly improve time to local and distant recurrence and overall recurrence‐free survival in adults with localised resectable soft tissue sarcoma. There is some evidence of a trend towards improved overall survival.
Plain language summary
Doxorubicin after initial treatment for sarcoma reduces risk of recurrence
Usually at diagnosis sarcoma shows no sign of having spread outside the original site and treatment is surgery (with/without radiotherapy). In about half the patients the cancer recurs. There is evidence that doxorubicin‐based chemotherapy after initial treatment reduces recurrence, either at the original site or elsewhere in the body. Chemotherapy also seems to increase the length of time patients live, but this is less certain.Greater benefit was seen in men and those whose tumour originated in a limb, but these results may have occurred by chance.
Implications for practice
Although this meta‐analysis can provide only average estimates of the effect of adjuvant chemotherapy for localised resectable soft tissue sarcoma, it is probably the best evidence on which to base treatment policy. Overall, the analyses suggest that immediate doxorubicin‐based chemotherapy can lengthen the time alive without recurrence, and there is a trend toward improved survival. However, the analyses cannot provide any guidance with respect to particular drug regimens and doses. Although the trials included in the meta‐analysis did not collect data on patient‐reported quality‐of‐life measures, doxorubicin toxicity was reported. Common acute effects were leucopenia, alopecia, nausea and vomiting, sometimes leading to lack of compliance or reduction in doxorubicin dose. Serious cardiac complications associated with doxorubicin were observed in some trials, but cardiotoxic death was relatively uncommon. Furthermore, such deaths will have been accounted for in our analyses, which included deaths by all causes.
There was little evidence that certain types of patients benefited more or less from adjuvant chemotherapy. However, soft‐tissue sarcomas are a heterogeneous group, affecting a broad patient population and their underlying prognoses will assist both clinicians and patients in assessing whether the net benefit of treatment is clinically worthwhile, particularly in the light of doxorubicin toxicity.
Implications for research
Further follow‐up, particularly of the later trials and inclusion of current randomised trials of adjuvant chemotherapy, will add to the evidence in future updates of this meta‐analysis.
The rarity and complexity of soft tissue sarcomas has meant that accrual of sufficient numbers of patients into trials has been, and continues to be, difficult. Our results may convince some researchers that future trials should contain a doxorubicin‐based chemotherapy control arm. Others may consider that an overall survival advantage of doxorubicin‐based chemotherapy is still in question (except perhaps for extremity sarcomas). In either case, future randomised trials must be larger than those undertaken previously, if they are to reliably detect treatment effects of moderate size ‐ generally the best that can be expected from new treatments. For example, to detect differences of around 10% in overall survival or recurrence‐free survival would require around 900 patients. This is clearly not possible without large‐scale collaboration between research groups and preferential entry of patients into sarcoma trials.