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

Summary 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 compare...

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Published in:The lancet oncology 2010-06, Vol.11 (6), p.561-570
Main Authors: Issels, Rolf D, Dr, Prof, Lindner, Lars H, MD, Verweij, Jaap, Prof, Wust, Peter, Prof, Reichardt, Peter, MD, Schem, Baard-Christian, MD, Abdel-Rahman, Sultan, MS, Daugaard, Soeren, MD, Salat, Christoph, MD, Wendtner, Clemens-Martin, Prof, Vujaskovic, Zeljko, MD, Wessalowski, Rüdiger, MD, Jauch, Karl-Walter, Prof, Dürr, Hans Roland, Prof, Ploner, Ferdinand, MD, Baur-Melnyk, Andrea, MD, Mansmann, Ulrich, Prof, Hiddemann, Wolfgang, Prof, Blay, Jean-Yves, Prof, Hohenberger, Peter, Prof
Format: Article
Language:English
Subjects:
Adolescent
Adult
Aged
Antineoplastic Combined Chemotherapy Protocols - administration & dosage
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Combined Modality Therapy
Disease-Free Survival
Doxorubicin - administration & dosage
Etoposide - administration & dosage
Female
Hematology, Oncology and Palliative Medicine
Humans
Hyperthermia, Induced
Ifosfamide - administration & dosage
Male
Middle Aged
Neoadjuvant Therapy
Neoplasm Recurrence, Local
Retroperitoneal Neoplasms
Sarcoma - drug therapy
Sarcoma - mortality
Sarcoma - therapy
Survival Rate
Young Adult
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Summary:Summary 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 parallel-group randomised controlled trial to assess the safety and efficacy 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. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov , 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 difference 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 pre-specified 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)
ISSN:1470-2045
1474-5488
DOI:10.1016/S1470-2045(10)70071-1