A META-ANALYSIS (MA) OF RANDOMIZED TRIALS (RCT’s) OF DOXORUBICIN (DOX) ALONE VS DOXORUBICIN COMBINATION CHEMOTHERAPY (DOX-COMB) IN ADVANCED/METASTATIC ADULT SOFT TISSUE SARCOMA (ASTS)

Bramwell V, Anderson D. London Regional Cancer Centre, London, Ontario N6A 4L6 and Cancer Care Ontario Practice Guidelines Initiative, Health Sciences Centre, Hamilton, Ontario, Canada.

PURPOSE: In advanced/metastatic ASTS a wide range (9-70%) of response rates (RR) have been reported across multiple studies of single agent DOX. A similar range of activity has been documented for multiple different DOX-COMB. This MA of RCT’s addresses the questions:

  1. Is there any advantage, in terms of RR or survival (S), in using DOX-COMB compared with single agent DOX for palliative treatment of patients (pt) with locally advanced or metastatic ASTS?
  2. Are DOX-COMB associated with increased toxic effects in this setting?

METHODS: Systematic search of MEDLINE, CANCERLIT, EMBASE, Cochrane Library, PDQ clinical trials data base and relevant conference proceedings, to Dec 1998, was performed to identify RCT’s of DOX vs DOX-COMB in advanced/metastatic ASTS, reporting outcomes of RR, S and toxicities. Data for RR and S were pooled using the software program Metaanalyst 0.988 (Dr. J Lau, Boston, MA).

RESULTS: 8 RCT’s meeting the inclusion criteria were included in the analysis. There were 9 DOX arms (1,086 pt) in 8 RCT, with DOX doses 60-80 mg/m2 IV bolus q 3 wk. These were compared with 10 DOX-COMB (1,195 pt) which include DOX with vindesine or streptozotocin or cyclophosphamide; DOX with ifosfamide in 2 trials; DOX with dacarbazine (DTIC) in 2 trials; DOX with mitomycin/ cisplatin; DOX with vincristine/cyclophosphamide ± DTIC in 2 trials. For RR, combining data across all 8 trials, there was a statistically non-significant trend favouring DOX-COMB (Odds Ratio 0.78; 95% CI 0.60-1.05; p=0.10). Data on S could only be extracted for 6 trials and results were not statistically significant (Odds Ratio 0.84; 95% CI 0.67-1.06, p=0.13). Both analyses used the random effects model. Variable reporting of toxicities made comparisons difficult. However, nausea, vomiting and myelosuppression were consistently more severe with DOX-COMB. Cardiotoxicity depended more on total DOX dose than type of regimen. None of the studies provided data on quality of life.

CONCLUSIONS: For patients with advanced/metastatic ASTS, who are candidates for palliative chemotherapy, single agent DOX is a reasonable first-line chemotherapy option. Some DOX-COMB given in conventional doses, produce only marginal increases in RR at the expense of increased toxicities and with no improvement in S. Future RCT’s should compare active new regimens (include high dose therapies) identified in single arm studies, with single agent DOX, and include quality of life as an endpoint.

 

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