Neo-adjuvant chemotherapy alone or with regional hyperthermia for localised high-risk soft-tissue sarcoma: a randomised phase 3 multicentre study

Background The optimum treatment for high-risk soft-tissue sarcoma (STS) in adults is unclear. Regional hyperthermia
concentrates the action of chemotherapy within the heated tumour region. Phase 2 studies have shown that chemotherapy
with regional hyperthermia improves local control compared with chemotherapy alone. We designed a parallelgroup
randomised controlled trial to assess the safety and effi cacy of regional hyperthermia with chemotherapy.
Methods Patients were recruited to the trial between July 21, 1997, and November 30, 2006, at nine centres in Europe and
North America. Patients with localised high-risk STS (“5 cm, Fédération Nationale des Centres de Lutte Contre le Cancer
[FNCLCC] grade 2 or 3, deep to the fascia) were randomly assigned to receive either neo-adjuvant chemotherapy
consisting of etoposide, ifosfamide, and doxorubicin (EIA) alone, or combined with regional hyperthermia (EIA plus
regional hyperthermia) in addition to local therapy. Local progression-free survival (LPFS) was the primary endpoint.
Effi cacy analyses were done by intention to treat. This trial is registered with, number NCT 00003052.
Findings 341 patients were enrolled, with 169 randomly assigned to EIA plus regional hyperthermia and 172 to EIA alone.
All patients were included in the analysis of the primary endpoint, and 332 patients who received at least one cycle of
chemotherapy were included in the safety analysis. After a median follow-up of 34 months (IQR 20–67), 132 patients had
local progression (56 EIA plus regional hyperthermia vs 76 EIA). Patients were more likely to experience local progression
or death in the EIA-alone group compared with the EIA plus regional hyperthermia group (relative hazard [RH] 0·58,
95% CI 0·41–0·83; p=0·003), with an absolute diff erence in LPFS at 2 years of 15% (95% CI 6–26; 76% EIA plus regional
hyperthermia vs 61% EIA). For disease-free survival the relative hazard was 0·70 (95% CI 0·54–0·92, p=0·011) for EIA
plus regional hyperthermia compared with EIA alone. The treatment response rate in the group that received regional
hyperthermia was 28·8%, compared with 12·7% in the group who received chemotherapy alone (p=0·002). In a prespecifi
ed per-protocol analysis of patients who completed EIA plus regional hyperthermia induction therapy compared
with those who completed EIA alone, overall survival was better in the combined therapy group (HR 0·66, 95% CI
0·45–0·98, p=0·038). Leucopenia (grade 3 or 4) was more frequent in the EIA plus regional hyperthermia group
compared with the EIA-alone group (128 of 165 vs 106 of 167, p=0·005). Hyperthermia-related adverse events were pain,
bolus pressure, and skin burn, which were mild to moderate in 66 (40·5%), 43 (26·4%), and 29 patients (17·8%), and
severe in seven (4·3%), eight (4·9%), and one patient (0·6%), respectively. Two deaths were attributable to treatment in
the combined treatment group, and one death was attributable to treatment in the EIA-alone group.
Interpretation To our knowledge, this is the fi rst randomised phase 3 trial to show that regional hyperthermia
increases the benefi t of chemotherapy. Adding regional hyperthermia to chemotherapy is a new eff ective treatment
strategy for patients with high-risk STS, including STS with an abdominal or retroperitoneal location.
Funding Deutsche Krebshilfe, Helmholtz Association (HGF), European Organisation of Research and Treatment of
Cancer (EORTC), European Society for Hyperthermic Oncology (ESHO), and US National Institute of Health (NIH).