EORTC 62012

Background

EORTC 62012 — Phase III open-label randomised controlled trial. N=455 patients with locally advanced, unresectable or metastatic soft-tissue sarcoma, previously untreated with palliative chemotherapy, WHO PS ≤2. Enrolled at 38 centres in Europe and Australia 2002–2009. Hypothesis: intensifying first-line treatment by adding ifosfamide to doxorubicin would improve overall survival compared with doxorubicin alone in advanced STS. Registration ISRCTN62350865.

Interventions and follow up

Arm A: Doxorubicin 75 mg/m² q3w × up to 6 cycles
Arm B: Doxorubicin 75 mg/m² + ifosfamide 10 g/m² q3w × up to 6 cycles (with G-CSF support)
Primary endpoint: Overall survival (intention-to-treat)
mFollow up: Median 56 month

Results

mOS: 14.3 months (AI) vs 12.8 months (dox alone); HR 0.83 (95% CI 0.67–1.03), P=.076 — not significant
mPFS: 7.4 vs 4.6 months; HR 0.74 (95% CI 0.60–0.90), P=.0021 — significant
ORR: 26.5% (AI) vs 13.6% (dox alone) — significant

Adverse events

Main adverse events: Grade ≥3 febrile neutropenia: 46% (AI) vs 14% (dox alone). Grade ≥3 anaemia: 21% vs 14%. Grade ≥3 fatigue: 13% vs 7%. Discontinuations due to AEs: 32% (AI) vs 17% (dox alone). Eight treatment-related deaths in each arm. No significant difference in QOL.

Conclusions

Intensified doxorubicin + ifosfamide significantly improved ORR and PFS compared with doxorubicin alone but did not improve overall survival (P=.076). This landmark trial established that higher response rates with combination chemotherapy do not translate to OS benefit in advanced STS, and doxorubicin monotherapy remains the appropriate standard first-line option for most patients.

Key Limitations

The primary endpoint (OS) was not met at the prespecified P<.05 threshold. PFS improvement and 1.5-month OS trend are potentially clinically meaningful but inconclusive. The intensified arm had substantially more toxicity and treatment discontinuations. Heterogeneous STS histotypes were included — histotype-specific effects may be masked. The trial predates current understanding of histotype-directed therapy (e.g., trabectedin for LMS, gemcitabine-docetaxel for LMS/UPS).

Clinical Context

EORTC 62012 confirmed doxorubicin monotherapy (75 mg/m²) as the standard first-line option for advanced STS. The AI combination may be considered in highly selected patients requiring rapid tumour shrinkage (e.g., visceral compression, rapid progression) where response rate matters more than survival. ESMO guidelines designate both regimens as options. The LMS04 trial (doxorubicin + trabectedin for LMS, NEJM 2024) and histotype-specific approaches are now preferred in selected patients. Pembrolizumab-RT combinations are being investigated for specific subtypes.
Arm A (doxorubicin alone, n=227): Doxorubicin 75 mg/m² IV q3w × 6 cycles
Arm B (intensified AI, n=228): Doxorubicin 60 mg/m² IV + ifosfamide 6 g/m² IV over 72 hours (with G-CSF support) q3w × 6 cycles

References