Background
EORTC 62931 — Phase III multicentre randomised controlled trial. N=351 patients with macroscopically resected Trojani grade II–III soft-tissue sarcoma (any site), age 16–70 years, no metastases, enrolled 1995–2003 at EORTC institutions. Randomised within 4 weeks of definitive surgery. Hypothesis: intensive adjuvant chemotherapy with doxorubicin and ifosfamide would improve survival after resection of high-risk STS.
Interventions and follow up
Arm A: Adjuvant doxorubicin 75 mg/m² + ifosfamide 5 g/m² × 5 cycles q3w (with or without prior radiotherapy)
Arm B: Observation (no adjuvant chemotherapy)
Primary endpoint: Overall survival (intention-to-treat)
mFollow up: Median 7.3 year
Arm B: Observation (no adjuvant chemotherapy)
Primary endpoint: Overall survival (intention-to-treat)
mFollow up: Median 7.3 year
Results
OS: HR 0.94 (95% CI 0.68–1.31), P=.72 — not significant
RFS: HR 0.91 (95% CI 0.67–1.22), P=.51 — not significant
5-year OS: 66.5% (chemotherapy) vs 67.8% (control)
RFS: HR 0.91 (95% CI 0.67–1.22), P=.51 — not significant
5-year OS: 66.5% (chemotherapy) vs 67.8% (control)
Adverse events
Main adverse events: Chemotherapy well tolerated; 80% of 163 patients who started completed all 5 cycles. Grade 3–4 fever or infection: 10% (16 patients). No treatment-related deaths. Lenograstim G-CSF support was used.
Conclusions
Adjuvant chemotherapy with doxorubicin and ifosfamide showed no benefit in relapse-free survival or overall survival after resection of high-risk soft-tissue sarcoma. This is the largest randomised trial of adjuvant chemotherapy in STS and establishes that routine adjuvant chemotherapy cannot be recommended for all resected high-risk STS.
Key Limitations
Heterogeneous population including all anatomical sites and multiple histological subtypes — histotype-specific effects may be diluted. Grade II tumours may have lower benefit potential. No stratification by tumour size or grade. A meta-analysis of individual patient data (SMAC) suggested a modest DFS benefit from doxorubicin-based chemotherapy in resected STS, but this trial found no such effect. Five cycles of full-dose dox+ifos may still offer benefit in specific high-risk histotypes (e.g., synovial sarcoma, myxoid liposarcoma) not discernible in an unselected population.
Clinical Context
EORTC 62931 remains the definitive negative RCT for adjuvant chemotherapy in STS. Adjuvant chemotherapy is not standard of care for resected STS per ESMO and NCCN guidelines, though it may be discussed for very high-risk cases (large, grade 3, deep, extremity). The perioperative pembrolizumab approach (SU2C-SARC032) and neoadjuvant histotype-tailored strategies represent newer investigational directions. Selected patients may benefit from neoadjuvant chemotherapy before resection (as in ISG-STS 1001 framework), but adjuvant use remains non-standard.
Arm A (adjuvant chemotherapy, n=175): Doxorubicin 75 mg/m² IV + ifosfamide 5 g/m² IV + lenograstim × 5 cycles q3w starting within 4 weeks of surgery
Arm B (control, n=176): Observation (surgery alone). Both groups received radiotherapy if resection was marginal or tumour was recurrent.
Arm A (adjuvant chemotherapy, n=175): Doxorubicin 75 mg/m² IV + ifosfamide 5 g/m² IV + lenograstim × 5 cycles q3w starting within 4 weeks of surgery
Arm B (control, n=176): Observation (surgery alone). Both groups received radiotherapy if resection was marginal or tumour was recurrent.