Adjuvant chemotherapy (CT) with doxorubicin and ifosfamide in resected soft tissue sarcoma (STS): Interim analysis of a randomised phase III trial

Abstract

10008 Background: The impact of adjuvant CT on survival for resected STS remains uncertain. In a 1997 meta-analysis, doxorubicin-based CT significantly improved local and overall relapse free survival (RFS), but not overall survival. Many of the CT regimens used would now be considered suboptimal. We therefore undertook a multicentre randomised trial of intensive CT in patients with excised high grade STS. Methods: Patients with macroscopically resected, Trojani grade II-III STS at any site, no metastases, performance status (PS) <2 and age = 70 were eligible within 4 weeks of surgery. Patients were randomised to observation or CT with 5 cycles of doxorubicin 75 mg/m2, ifosfamide 5 g/m2q 21 days and lenograstim. Patients in both arms received radiotherapy (RT) if the resection was marginal or the tumor recurrent. Stratifications were for institution, disease site, tumor size, planned RT and isolated limb perfusion therapy. Results: Between 1995 and 2003, 351 patients were recruited. 9.5% were ineligible and 4.8% did not receive the allocated treatment. Patient characteristics were evenly distributed between the two arms: 47% > 50 years; 54% male; 33% PS 1. The commonest pathological subtypes were leiomyo- 15%, lipo- 13%, MFH 11%, synovial sarcoma 11%. 60% were grade III. 66% were extremity tumors. Of 175 patients allocated CT, 163 started and 127 completed 5 cycles. 38% had dose reductions or delays, mostly for hematologic toxicity or infection. 88% of patients received RT. An interim analysis for futility has been performed, because survival in the observation arm was better than expected: estimated 5-yr RFS was 52% in both arms and OS 69% (observation arm) and 64% (CT arm). The hypotheses that adjuvant CT improves RFS and OS (with hazard ratios = 0.621) can both be rejected. Conclusions: This is the largest study of adjuvant CT with ifosfamide and doxorubicin ever undertaken in STS. It fails to show a survival advantage for adjuvant CT. Improved survival over previous studies might be due to better surgery and increased use of adjuvant RT. Further analysis of this study will allow more detailed assessment of the role of adjuvant CT in resected STS and will contribute to an updated meta-analysis. [Table: see text]