PMID- 20434400 OWN - NLM STAT- MEDLINE DCOM- 20100630 LR - 20220410 IS - 1474-5488 (Electronic) IS - 1470-2045 (Print) IS - 1470-2045 (Linking) VI - 11 IP - 6 DP - 2010 Jun TI - Neo-adjuvant chemotherapy alone or with regional hyperthermia for localised high-risk soft-tissue sarcoma: a randomised phase 3 multicentre study. PG - 561-70 LID - 10.1016/S1470-2045(10)70071-1 [doi] AB - 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 (> or = 5 cm, Federation 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) 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 first randomised phase 3 trial to show that regional hyperthermia increases the benefit of chemotherapy. Adding regional hyperthermia to chemotherapy is a new effective 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). CI - Copyright 2010 Elsevier Ltd. All rights reserved. FAU - Issels, Rolf D AU - Issels RD AD - Klinikum der Universitat Munchen-Campus Grosshadern, Munchen, Germany. Rolf.Issels@med.uni-muenchen.de FAU - Lindner, Lars H AU - Lindner LH FAU - Verweij, Jaap AU - Verweij J FAU - Wust, Peter AU - Wust P FAU - Reichardt, Peter AU - Reichardt P FAU - Schem, Baard-Christian AU - Schem BC FAU - Abdel-Rahman, Sultan AU - Abdel-Rahman S FAU - Daugaard, Soeren AU - Daugaard S FAU - Salat, Christoph AU - Salat C FAU - Wendtner, Clemens-Martin AU - Wendtner CM FAU - Vujaskovic, Zeljko AU - Vujaskovic Z FAU - Wessalowski, Rudiger AU - Wessalowski R FAU - Jauch, Karl-Walter AU - Jauch KW FAU - Durr, Hans Roland AU - Durr HR FAU - Ploner, Ferdinand AU - Ploner F FAU - Baur-Melnyk, Andrea AU - Baur-Melnyk A FAU - Mansmann, Ulrich AU - Mansmann U FAU - Hiddemann, Wolfgang AU - Hiddemann W FAU - Blay, Jean-Yves AU - Blay JY FAU - Hohenberger, Peter AU - Hohenberger P CN - European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group (EORTC-STBSG) CN - European Society for Hyperthermic Oncology (ESHO) LA - eng SI - ClinicalTrials.gov/NCT00003052 GR - P01 CA042745/CA/NCI NIH HHS/United States GR - P01 CA042745-23/CA/NCI NIH HHS/United States GR - P01 CA42745/CA/NCI NIH HHS/United States PT - Clinical Trial, Phase III PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20100429 PL - England TA - Lancet Oncol JT - The Lancet. Oncology JID - 100957246 RN - 6PLQ3CP4P3 (Etoposide) RN - 80168379AG (Doxorubicin) RN - UM20QQM95Y (Ifosfamide) RN - AVI protocol SB - IM CIN - Lancet Oncol. 2010 Jun;11(6):505. PMID: 20522373 CIN - Lancet Oncol. 2017 Nov;18(11):e629. PMID: 29208383 CIN - Lancet Oncol. 2017 Nov;18(11):e630. PMID: 29208384 MH - Adolescent MH - Adult MH - Aged MH - Antineoplastic Combined Chemotherapy Protocols/administration & dosage/*therapeutic use MH - Combined Modality Therapy MH - Disease-Free Survival MH - Doxorubicin/administration & dosage MH - Etoposide/administration & dosage MH - Female MH - Humans MH - *Hyperthermia, Induced MH - Ifosfamide/administration & dosage MH - Male MH - Middle Aged MH - *Neoadjuvant Therapy MH - Neoplasm Recurrence, Local MH - Retroperitoneal Neoplasms MH - Sarcoma/drug therapy/mortality/*therapy MH - Survival Rate MH - Young Adult PMC - PMC3517819 MID - NIHMS322633 COIS- Conflicts of interest RDI, LHL and SA-R have received consulting fees from Medtherm. All other authors declared no conflicts of interest. EDAT- 2010/05/04 06:00 MHDA- 2010/07/01 06:00 PMCR- 2012/12/09 CRDT- 2010/05/04 06:00 PHST- 2010/05/04 06:00 [entrez] PHST- 2010/05/04 06:00 [pubmed] PHST- 2010/07/01 06:00 [medline] PHST- 2012/12/09 00:00 [pmc-release] AID - S1470-2045(10)70071-1 [pii] AID - 10.1016/S1470-2045(10)70071-1 [doi] PST - ppublish SO - Lancet Oncol. 2010 Jun;11(6):561-70. doi: 10.1016/S1470-2045(10)70071-1. Epub 2010 Apr 29.