Adult Soft Tissue Sarcoma Treatment (PDQ®): Treatment - Health Professional Information [NCI] - Treatment Option Overview
In yet another underpowered trial, 137 patients with high-risk soft tissue sarcomas (93% with extremity or truncal primary tumors) who met the eligibility criteria were randomly assigned to undergo surgical resection (with or without radiation) or to receive three preoperative 21-day cycles of doxorubicin plus ifosfamide. This multicenter European Organization for Research and Treatment of Cancer trial (EORTC-62874) was closed because of slow accrual and results that were not promising enough to continue. With a median follow-up of 7.3 years, the 5-year DFS in the surgery alone and chemotherapy plus surgery arms was 52% and 56%, respectively (P = .35); and OS was 64% and 65%, respectively (P = .22).
These last four trials have been combined with the 14 first-generation trials in a trial-level meta-analysis. Of the 18 randomized trials of patients with resectable soft tissue sarcomas, five trials used a combination of doxorubicin (50–90 mg/m2 per cycle) plus ifosfamide (1500–5000 mg/m2 per cycle). The remaining 13 trials used doxorubicin (50–70 mg/m2 per cycle) alone or with other drugs. The absolute risk reduction in local recurrence rates associated with any chemotherapy added to local therapy was 4 percentage points (95% CI, 0%–7%), and it was 5 percentage points (95% CI, 1%–12%) when ifosfamide was combined with doxorubicin. The absolute reduction in overall mortality was 6 percentage points with any chemotherapy (95% CI, 2%–11%; [i.e., a reduction from 46%–40%]), 11 percentage points for doxorubicin plus ifosfamide (95% CI, 3%–19%; [i.e., a reduction from 41%–30%]), and 5 percentage points for doxorubicin without ifosfamide.[Level of evidence: 1iiA]
An additional multicenter randomized trial (EORTC-62931 [NCT00002641]), the largest trial reported to date using adjuvant doxorubicin (75 mg/m2) plus ifosfamide (5000 mg/m2), was subsequently published in abstract form and was not included in the above meta-analysis. The results differed from those reported in the meta-analysis. After local therapy, 351 patients were randomly assigned to five 21-day cycles of adjuvant therapy versus observation. The trial was stopped for futility because the 5-year RFS was 52% in both arms. OS was 64% in the chemotherapy arm versus 69% in the observation arm. In a subsequent abstract, the EORTC investigators reported a combined analysis of this trial and their previous trial (EORTC-62771)  of adjuvant cyclophosphamide plus doxorubicin plus DTIC (CYVADIC), representing the two largest trials of adjuvant therapy for adult soft tissue sarcoma in the literature. The combined analysis showed no improvement in either RFS or OS associated with adjuvant chemotherapy.[Level of evidence: 1iiA]
In summary, the impact of adjuvant chemotherapy on survival is not clear but is likely to be small in absolute magnitude. Therefore, in discussions with a patient, any potential benefits should be considered in the context of the short- and long-term toxicities of the chemotherapy.