ISG-STS 1001

Background

ISG-STS 1001 — Phase III open-label randomised controlled trial. N=287 patients with localised, high-risk (high-grade, ≥5 cm, deeply located) soft-tissue sarcoma of the extremities or trunk wall, belonging to one of five histological subtypes: high-grade myxoid liposarcoma, leiomyosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumour (MPNST), or undifferentiated pleomorphic sarcoma (UPS). Enrolled at 32 hospitals in Italy, Spain, France, and Poland (2011–2016). Registration NCT01710176.

Interventions and follow up

Arm A: Histotype-tailored neoadjuvant chemotherapy (regimens specific to each subtype) × 3 cycles
Arm B: Standard epirubicin 120 mg/m² + ifosfamide 9 g/m² × 3 cycles (with or without preop RT)
Primary endpoint: Disease-free survival (intention-to-treat)
mFollow up: 12.3 months (IQR 2.75–28.20) at third futility analysi

Results

Projected 46-mo DFS (standard): 62% (95% CI 48–77%)
Projected 46-mo DFS (histotype-tailored): 38% (95% CI 22–55%)
HR: 2.00 (95% CI 1.22–3.26), P=.006 — favoring standard chemotherapy

Adverse events

Main adverse events: Grade ≥3 neutropenia: 86% standard vs 26% histotype-tailored. Grade ≥3 anaemia: 19% vs not reported. No treatment-related deaths in either arm. Both regimens were feasible; the standard arm was more myelotoxic.

Conclusions

Histotype-tailored neoadjuvant chemotherapy did not improve DFS compared with standard epirubicin + ifosfamide and was associated with inferior DFS outcomes, leading to early trial closure after third futility analysis. Paradoxically, the robust DFS in the standard arm supports that neoadjuvant epirubicin + ifosfamide may itself be beneficial in this selected high-risk population — a conclusion often cited as a key finding of this trial.

Key Limitations

Trial stopped early for futility after third interim analysis (n=287 of planned size) — underpowered for definitive conclusions. The histotype-tailored regimens used were based on limited retrospective evidence; the specific agents chosen may not have been optimal. Median follow-up was only ~12 months — late recurrences may not have been captured. The unexpectedly good performance of standard chemotherapy complicates interpretation. No control (surgery-only) arm; beneficial effect of neoadjuvant chemotherapy itself cannot be established from this design.

Clinical Context

ISG-STS 1001 does not support histotype-tailored neoadjuvant chemotherapy over standard epirubicin + ifosfamide in high-risk extremity/trunk STS. However, the strong DFS in the standard arm has reinvigorated interest in neoadjuvant use of epirubicin + ifosfamide in carefully selected patients. Histotype-specific systemic therapy remains important in the metastatic setting (e.g., trabectedin for LMS, gemcitabine + docetaxel for LMS/UPS). The ISG group subsequently launched ISG-STS 1001-2 building on these findings. ESMO and NCCN do not currently recommend histotype-tailored neoadjuvant regimens as standard of care.
Arm A (standard chemotherapy, n=145): Epirubicin 60 mg/m²/day days 1–2 + ifosfamide 3 g/m²/day days 1–3, q21d × 3 cycles (neoadjuvant), then surgery
Arm B (histotype-tailored chemotherapy, n=142): Trabectedin (myxoid LPS), gemcitabine + dacarbazine (LMS), high-dose ifosfamide (synovial), etoposide + ifosfamide (MPNST), or gemcitabine + docetaxel (UPS) × 3 cycles (neoadjuvant), then surgery

References