An Italian Sarcoma Group randomized trial versus no chemotherapy was indicative of an OS benefit with 5 cycles of adjuvant full-dose epirubicin + ifosfamide in localized high-risk STS (JCO 2001;19:1238). A subsequent randomized trial showed no difference between 3 vs 5 cycles of the same neo-adjuvant regimen (JCO 2012;30:850).
This multicenter European randomized trial compared epirubicin 120 mg/sqm + ifosfamide 9 g/sqm versus an histology-driven regimen: gemcitabine + docetaxel in undifferentiated pleomorphic sarcoma (UPS); trabectedin in high-grade myxoid liposarcoma; high-dose prolonged-infusion ifosfamide in synovial sarcoma (SS); etoposide + ifosfamide in malignant peripheral nerve sheath tumors (MPNST); gemcitabine + dacarbazine in leiomyosarcoma (LMS). Patients had localized high-risk STS (grade = 3; size >5 cm; deep site) of extremities or trunk wall. Primary end-point was RFS. With an expected accrual of 350 randomized patients, the trial was powered to show a 1/3 reduction in the hazard risk of relapse in favor of histology-driven therapy (with 80% power at the 5% [1-sided] significance level). Yearly futility analyses were conducted.
From May 2011 to May 2016, 287 patients were randomized (97 = UPS; 65 = myxoid liposarcoma; 70 = SS; 27 = MPNST; 28 = LMS). At the third futility analysis, with a median follow-up of 12.3 months, the RFS probability at 46 months was 0.62 and 0.38 (log rank p = 0.004; figure 1) and OS probability at 46 months was 0.89 and 0.64 (log rank p = 0.033; figure 2), in the standard and in the histology-driven arm, respectively. In agreement with the Independent Reviewing Committee, the study was closed in advance. The analysis is being updated and subgroup analyses will be reported.
This trial provides randomized evidence that a neo-adjuvant chemotherapy with 3 full-dose courses of an anthracycline plus ifosfamide full-dose regimen can be associated with an absolute benefit averaging 20% for both RFS and OS over a different chemotherapy regimen, in a population of STS patients selected by a risk of relapse averaging 60-70%.
Clinical trial identification
NCT01710176; EUDRACT 2010 – 023484 – 17
Legal entity responsible for the study
Italian Sarcoma Group
Eurosarc FP7 278472
All authors have declared no conflicts of interest.