RTOG 9514

Background

RTOG 9514 — Phase II multi-institutional Intergroup trial. N=64 patients (66 enrolled, 64 analysed) with high-grade (grade 2–3) soft-tissue sarcoma ≥8 cm of the extremities or body wall. Enrolled at RTOG/ECOG institutions. Based on a positive single-institution pilot study at Massachusetts General Hospital by DeLaney et al, evaluating a combined modality neoadjuvant regimen of chemotherapy interdigitated with preoperative radiotherapy. This was the first cooperative-group validation of this approach in STS.

Interventions and follow up

Regimen: Three cycles of MAID (mesna + doxorubicin + ifosfamide + dacarbazine) interdigitated with preoperative RT (44 Gy in 11 fx split-course) → surgery → 3 additional cycles of postoperative MAID
Primary endpoint: 3-year disease-free and overall survival (efficacy); safety
mFollow up: Not specified; analysis at median follow-up allowing 3-year estimate

Results

3-year DFS: 56.6%
3-year OS: 75.1%
3-year distant DFS: 64.5%
Local-regional failure rate: 17.6% (amputation as failure) or 10.1% (amputation excluded)
R0 resection: 58 of 61 operated patients

Adverse events

Main adverse events: Fatal grade 5 toxicity: 5% (3 patients — 2 myelodysplasias, 1 infection). Grade 4 toxicity: 83% of patients; grade 4 haematologic: 78%; grade 4 non-haematologic: 19%. 79% completed preoperative chemotherapy; 59% completed all planned chemotherapy. 5 amputations among 61 who underwent surgery.

Conclusions

The neoadjuvant MAID + interdigitated RT regimen was deliverable in a multi-institutional setting with efficacy consistent with prior single-institution experience. However, the regimen is highly toxic with 5% fatal toxicities and 83% grade 4 events, and represents an intensive approach used before an era of improved supportive care. Results suggest potential benefit in high-risk STS in terms of local control and survival compared to historical controls.

Key Limitations

Single-arm phase II study — no concurrent randomised control. 5% fatal toxicity rate is unacceptably high for a non-curative neoadjuvant setting by contemporary standards. The MAID regimen (dacarbazine + doxorubicin + ifosfamide) is rarely used in current practice. Comparison to historical controls is subject to selection bias. The regimen was replaced by less toxic chemotherapy approaches with or without preoperative RT in subsequent trials. DFS of 56.6% in this high-risk population (≥8 cm, grade 2–3) is modest.

Clinical Context

RTOG 9514 established the feasibility of concurrent chemoradiotherapy for large, high-risk extremity STS but highlighted the substantial toxicity of the MAID backbone. The NCI/MGH approach has evolved to use modern preoperative RT (50 Gy conventional fractionation) with or without chemotherapy in selected patients. Current standard for extremity STS ≥5 cm, high-grade, deep is resection with preoperative or postoperative RT; chemotherapy addition is optional and individualised. The SU2C-SARC032 trial has since demonstrated benefit from perioperative pembrolizumab in selected histotypes.
Treatment (all patients, single arm): 3 cycles neoadjuvant MAID chemotherapy (mesna, doxorubicin 20 mg/m² D1–4, ifosfamide 2.5 g/m² D1–4, dacarbazine 300 mg/m² D1–4) with interdigitated preoperative RT (44 Gy in split courses), then surgery, then 3 cycles postoperative MAID

References