Effect of Neoadjuvant Chemotherapy Plus Regional Hyperthermia on Long-term Outcomes Among Patients With Localized High-Risk Soft Tissue Sarcoma: The EORTC 62961-ESHO 95 Randomized Clinical Trial

Abstract

Importance: Patients with soft tissue sarcoma are at risk for local recurrence and distant metastases despite optimal local treatment. Preoperative anthracycline plus ifosfamide chemotherapy improves outcome in common histological subtypes.

Objective: To analyze whether the previously reported improvement in local progression-free survival by adding regional hyperthermia to neoadjuvant chemotherapy translates into improved survival.

Design, setting, and participants: Open-label, phase 3 randomized clinical trial to evaluate the efficacy and toxic effects of neoadjuvant chemotherapy plus regional hyperthermia. Adult patients (age ≥18 years) with localized soft tissue sarcoma (tumor ≥5 cm, French Federation Nationale des Centers de Lutte Contre le Cancer [FNCLCC] grade 2 or 3, deep) were accrued across 9 centers (6, Germany; 1, Norway; 1, Austria; 1, United States) from July 1997 to November 2006. Follow-up ended December 2014.

Interventions: After stratification for tumor presentation and site, patients were randomly assigned to either neoadjuvant chemotherapy consisting of doxorubicin, ifosfamide, and etoposide alone, or combined with regional hyperthermia.

Main outcomes and measures: The primary end point was local progression-free survival. Secondary end points included treatment safety and survival, with survival defined from date of randomization to death due to disease or treatment. Patients lost to follow-up were censored at the date of their last follow-up.

Results: A total of 341 patients were randomized, and 329 (median [range] age, 51 [18-70] years; 147 women, 182 men) were eligible for the intention-to-treat analysis. By December 2014, 220 patients (67%; 95% CI, 62%-72%) had experienced disease relapse, and 188 (57%; 95% CI, 52%-62%) had died. Median follow-up was 11.3 years. Compared with neoadjuvant chemotherapy alone, adding regional hyperthermia improved local progression-free survival (hazard ratio [HR], 0.65; 95% CI, 0.49-0.86; P = .002). Patients randomized to chemotherapy plus hyperthermia had prolonged survival rates compared with those randomized to neoadjuvant chemotherapy alone (HR, 0.73; 95% CI, 0.54-0.98; P = .04) with 5-year survival of 62.7% (95% CI, 55.2%-70.1%) vs 51.3% (95% CI, 43.7%-59.0%), respectively, and 10-year survival of 52.6% (95% CI, 44.7%-60.6%) vs 42.7% (95% CI, 35.0%-50.4%).

Conclusions and relevance: Among patients with localized high-risk soft tissue sarcoma the addition of regional hyperthermia to neoadjuvant chemotherapy resulted in increased survival, as well as local progression-free survival. For patients who are candidates for neoadjuvant treatment, adding regional hyperthermia may be warranted.

Trial registration: clinicaltrials.gov Identifier: NCT00003052.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Issels has received travel support and honoraria from Pyrexar, PharmaMar, Medtherm and Bayer. Dr Lindner has received research and travel support from Dr Sennewald Medizintechnik; travel support from PharmaMar; and honoraria from Novartis, Lilly, Eisai, EL Medconsult. Mr Abdel-Rahman has received travel support and honoraria from Pyrexar and Medtherm. No other conflicts are reported.

Figures

Figure 1.. CONSORT Flow Diagram

Number of patients who were randomly assigned to a treatment group, and outcomes. NACT indicates neoadjuvant chemotherapy consisting of doxorubicin, ifosfamide, and etoposide; RHT, regional hyperthermia; STS, soft tissue sarcomas.

Figure 2.. Kaplan-Meier Survival Curves

A, Median local progression free survival was 5.6 years (95% CI, 2.9-8.7) in the NACT plus RHT group compared with 2.4 years (95% CI, 1.7-4.2) in the NACT-alone group. B, Median disease-free survival was 2.8 years (95% CI, 2.0-4.9) in the NACT plus RHT group compared with 1.5 years (95% CI, 1.1-2.1) in the NACT-alone group. C, Median survival was 15.4 years (95% CI, 6.6 to >17.0 [the upper confidence limit cannot be estimated and represents the lower bound for the value to be expected]) in the NACT plus RHT group compared with 6.2 years (95% CI, 3.2-10.3) in the NACT-alone group. D, Extremity tumor–survival rates at 5 and 10 years were 75.2% and 68.3% in the NACT plus RHT group compared with 60.8% and 59.2% in the NACT-alone group. The absolute difference at 5 years was 14.4% (95% CI, 0%-29.5%) and was 9.1% (95% CI, 0%-24.7%) at 10 years. Nonextremity tumor–survival rates at 5 years and 10 years were 53.5% and 41.3% in the NACT plus RHT group compared with 44.0% and 29.9% in the NACT-alone group. The absolute difference at 5 years was 9.5% (95% CI, 0%-23.8%) and was 11.4% (95% CI, 0%-25.1%) at 10 years. NACT indicates neoadjuvant chemotherapy consisting of doxorubicin, ifosfamide, and etoposide; RHT, regional hyperthermia.

Figure 3.. Forest Plot Survival for 329 Patients

Analyses were univariate and not stratified according to subgroup.