Sylvie Bonvalot1, Alessandro Gronchi2, Cécile Le Péchoux3, Carol J Swallow4, Dirk Strauss5, Pierre Meeus6, Frits van Coevorden7, Stephan Stoldt8, Eberhard Stoeckle9, Piotr Rutkowski10, Marco Rastrelli11, Chandrajit P Raut12, Daphne Hompes13, Antonino De Paoli14, Claudia Sangalli15, Charles Honoré16, Peter Chung17, Aisha Miah18, Jean Yves Blay19, Marco Fiore2, Jean-Jacques Stelmes20, Angelo P Dei Tos21, Elizabeth H Baldini22, Saskia Litière23, Sandrine Marreaud24, Hans Gelderblom25, Rick L Haas26. 1. Department of Surgical Oncology, Institut Curie, Université Paris Sciences et Lettres, Paris, France. Electronic address: sylvie.bonvalot@curie.fr. 2. Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 3. Department of Radiation Oncology, Gustave Roussy Cancer Campus, Villejuif, France. 4. Department of Surgical Oncology, Princess Margaret Cancer Centre, Toronto, ON, Canada. 5. Department of Surgical Oncology, Royal Marsden Hospital, London, UK. 6. Department of Surgical Oncology, Centre Léon Bérard, Lyon, France. 7. Department of Surgical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands. 8. Department of Surgical Oncology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway. 9. Department of Surgical Oncology, Institut Bergonié, Bordeaux, France. 10. Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland. 11. Department of Surgery, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy. 12. Department of Surgery, Brigham and Women's Hospital, Boston, MA, USA; Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. 13. Department of Surgical Oncology, University Hospitals Gasthuisberg, Leuven, Belgium. 14. Centro di Riferimento Oncologico CRO-IRCCS, Aviano, Italy. 15. Department of Radiation Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 16. Department of Surgical Oncology, Gustave Roussy Cancer Campus, Villejuif, France. 17. Department of Radiation Oncology, Princess Margaret Cancer Centre, Toronto, ON, Canada. 18. Department of Radiation Oncology, Royal Marsden Hospital, London, UK. 19. Department of Medical Oncology, Centre Léon Bérard, Lyon, France. 20. Quality Assurance in Radiotherapy, European Organisation for Research and Treatment of Cancer, Brussels, Belgium. 21. Department of Medicine, University of Padua School of Medicine, Padua, Italy. 22. Department of Radiation Oncology, Brigham and Women's Hospital, Boston, MA, USA; Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. 23. Department of Statistics, European Organisation for Research and Treatment of Cancer, Brussels, Belgium. 24. Headquarters, European Organisation for Research and Treatment of Cancer, Brussels, Belgium. 25. Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands. 26. Department of Radiation Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Abstract
BACKGROUND: Unlike for extremity sarcomas, the efficacy of radiotherapy for retroperitoneal sarcoma is not established. The aim of this study was to evaluate the impact of preoperative radiotherapy plus surgery versus surgery alone on abdominal recurrence-free survival. METHODS: EORTC-62092 is an open-label, randomised, phase 3 study done in 31 research institutions, hospitals, and cancer centres in 13 countries in Europe and North America. Adults (aged ≥18 years) with histologically documented, localised, primary retroperitoneal sarcoma that was operable and suitable for radiotherapy, who had not been previously treated and had a WHO performance status and American Society of Anesthesiologists score of 2 or lower, were centrally randomly assigned (1:1), using an interactive web response system and a minimisation algorithm, to receive either surgery alone or preoperative radiotherapy followed by surgery. Randomisation was stratified by hospital and performance status. Radiotherapy was delivered as 50·4 Gy (in 28 daily fractions of 1·8 Gy) in either 3D conformal radiotherapy or intensity modulated radiotherapy, and the objective of surgery was a macroscopically complete resection of the tumour mass with en-bloc organ resection as necessary. The primary endpoint was abdominal recurrence-free survival, as assessed by the investigator, and was analysed in the intention-to-treat population. Safety was analysed in all patients who started their allocated treatment. This trial is registered with ClinicalTrials.gov, NCT01344018. FINDINGS:Between Jan 18, 2012 and April 10, 2017, 266 patients were enrolled, of whom 133 were randomly assigned to each group. The median follow-up was 43·1 months (IQR 28·8-59·2). 128 (96%) patients from the surgery alone group had surgery, and 119 (89%) patients in the radiotherapy and surgery group had both radiotherapy and surgery. Median abdominal recurrence-free survival was 4·5 years (95% CI 3·9 to not estimable) in the radiotherapy plus surgery group and 5·0 years (3·4 to not estimable) in the surgery only group (hazard ratio 1·01, 95% CI 0·71-1·44; log rank p=0·95). The most common grade 3-4 adverse events were lymphopenia (98 [77%] of 127 patients in the radiotherapy plus surgery group vs one [1%] of 128 patients in the surgery alone group), anaemia (15 [12%] vs ten [8%]), and hypoalbuminaemia (15 [12%] vs five [4%]). Serious adverse events were reported in 30 (24%) of 127 patients in the radiotherapy plus surgery group, and in 13 (10%) of 128 patients in the surgery alone group. One (1%) of 127 patients in the radiotherapy plus surgery group died due to treatment-related serious adverse events (gastropleural fistula), and no patients in the surgery alone group died due to treatment-related serious adverse events. INTERPRETATION:Preoperative radiotherapy should not be considered as standard of care treatment for retroperitoneal sarcoma. FUNDING: European Organisation for Research and Treatment of Cancer, and European Clinical Trials in Rare Sarcomas.
RCT Entities:
BACKGROUND: Unlike for extremity sarcomas, the efficacy of radiotherapy for retroperitoneal sarcoma is not established. The aim of this study was to evaluate the impact of preoperative radiotherapy plus surgery versus surgery alone on abdominal recurrence-free survival. METHODS: EORTC-62092 is an open-label, randomised, phase 3 study done in 31 research institutions, hospitals, and cancer centres in 13 countries in Europe and North America. Adults (aged ≥18 years) with histologically documented, localised, primary retroperitoneal sarcoma that was operable and suitable for radiotherapy, who had not been previously treated and had a WHO performance status and American Society of Anesthesiologists score of 2 or lower, were centrally randomly assigned (1:1), using an interactive web response system and a minimisation algorithm, to receive either surgery alone or preoperative radiotherapy followed by surgery. Randomisation was stratified by hospital and performance status. Radiotherapy was delivered as 50·4 Gy (in 28 daily fractions of 1·8 Gy) in either 3D conformal radiotherapy or intensity modulated radiotherapy, and the objective of surgery was a macroscopically complete resection of the tumour mass with en-bloc organ resection as necessary. The primary endpoint was abdominal recurrence-free survival, as assessed by the investigator, and was analysed in the intention-to-treat population. Safety was analysed in all patients who started their allocated treatment. This trial is registered with ClinicalTrials.gov, NCT01344018. FINDINGS: Between Jan 18, 2012 and April 10, 2017, 266 patients were enrolled, of whom 133 were randomly assigned to each group. The median follow-up was 43·1 months (IQR 28·8-59·2). 128 (96%) patients from the surgery alone group had surgery, and 119 (89%) patients in the radiotherapy and surgery group had both radiotherapy and surgery. Median abdominal recurrence-free survival was 4·5 years (95% CI 3·9 to not estimable) in the radiotherapy plus surgery group and 5·0 years (3·4 to not estimable) in the surgery only group (hazard ratio 1·01, 95% CI 0·71-1·44; log rank p=0·95). The most common grade 3-4 adverse events were lymphopenia (98 [77%] of 127 patients in the radiotherapy plus surgery group vs one [1%] of 128 patients in the surgery alone group), anaemia (15 [12%] vs ten [8%]), and hypoalbuminaemia (15 [12%] vs five [4%]). Serious adverse events were reported in 30 (24%) of 127 patients in the radiotherapy plus surgery group, and in 13 (10%) of 128 patients in the surgery alone group. One (1%) of 127 patients in the radiotherapy plus surgery group died due to treatment-related serious adverse events (gastropleural fistula), and no patients in the surgery alone group died due to treatment-related serious adverse events. INTERPRETATION: Preoperative radiotherapy should not be considered as standard of care treatment for retroperitoneal sarcoma. FUNDING: European Organisation for Research and Treatment of Cancer, and European Clinical Trials in Rare Sarcomas.
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