Alessandro Gronchi1, Emanuela Palmerini2, Vittorio Quagliuolo3, Javier Martin Broto4,5, Antonio Lopez Pousa6, Giovanni Grignani7, Antonella Brunello8, Jean-Yves Blay9,10, Oscar Tendero11, Robert Diaz Beveridge12, Virginia Ferraresi13, Iwona Lugowska14, Domenico Franco Merlo15, Valeria Fontana16, Emanuela Marchesi17, Luca Braglia15, Davide Maria Donati18, Elena Palassini19, Giuseppe Bianchi18, Andrea Marrari20, Carlo Morosi21, Silvia Stacchiotti19, Silvia Bagué22, Jean Michel Coindre23, Angelo Paolo Dei Tos24,25, Piero Picci26, Paolo Bruzzi16, Paolo Giovanni Casali19,27. 1. Department of Surgery, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Nazionale dei Tumori, Milan, Italy. 2. Chemotherapy Unit, IRCCS, Istituto Ortopedico Rizzoli, Bologna, Italy. 3. Department of Surgery, Istituto Clinico Humanitas, Rozzano, Italy. 4. Medical Oncology Department, University Hospital Virgen del Rocio, Sevilla, Spain. 5. Institute of Biomedicine of Sevilla, University of Sevilla, Sevilla, Spain. 6. Department of Cancer Medicine, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. 7. Department of Cancer Medicine, Fondazione del Piemonte per l'Oncologia, IRCCS, Candiolo, Turin, Italy. 8. Department of Oncology, Medical Oncology 1 Unit, Istituto Oncologico Veneto, IRCCS, Padova, Italy. 9. Department of Cancer Medicine, Centre Léon Bérard Cancer Center, Lyon, France. 10. Université Claude Beranrd Lyon I, Lyon, France. 11. Department of Surgery, Hospital Universitari Son Espases, Palma de Mallorca, Spain. 12. Department of Cancer Medicine, Hospital Universitari i Politècnic La Fe, Valencia, Spain. 13. Department of Cancer Medicine, Istituto Regina Elena, Rome, Italy. 14. Department of Soft Tissue/Bone Sarcoma and Melanoma, Centrum Onkologii, Instytutim, Marii Sklodowskiej-Curie, Warszawa, Poland. 15. Research and Statistics Infrastructure, Azienda Unità Sanitaria Locale, IRCCS, Reggio Emilia, Italy. 16. Clinical Trial Center and Department of Epidemiology, IRCCS Azienda Ospedaliera Universitaria San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy. 17. Clinical Trial Center, Italian Sarcoma Group, Bologna, Italy. 18. Department of Orthopedic Oncology, Istituto Ortopedico Rizzoli, Bologna, Italy. 19. Department of Cancer Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 20. Department of Cancer Medicine, Istituto Clinico Humanitas, Rozzano, Italy. 21. Department of Radiology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 22. Department of Pathology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. 23. Department of Pathology, Institut Bergonié, Bordeaux, France. 24. Department of Pathology, Treviso General Hospital Treviso, Padova, Italy. 25. University of Padua, Padova, Italy. 26. Laboratory of Oncologic Research, Istituto Ortopedico Rizzoli, Bologna, Italy. 27. Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
Abstract
PURPOSE: To determine whether the administration of histology-tailored neoadjuvant chemotherapy (HT) was superior to the administration of standard anthracycline plus ifosfamide neoadjuvant chemotherapy (A+I) in high-risk soft tissue sarcoma (STS) of an extremity or the trunk wall. PATIENTS AND METHODS: This was a randomized, open-label, phase III trial. Patients had localized high-risk STS (grade 3; size, ≥ 5 cm) of an extremity or trunk wall, belonging to one of the following five histologic subtypes: high-grade myxoid liposarcoma (HG-MLPS); leiomyosarcoma (LMS), synovial sarcoma (SS), malignant peripheral nerve sheath tumor (MPNST), and undifferentiated pleomorphic sarcoma (UPS). Patients were randomly assigned in a 1:1 ratio to receive three cycles of A+I or HT. The HT regimens were as follows: trabectedin in HG-MLPS; gemcitabine plus dacarbazine in LMS; high-dose prolonged-infusion ifosfamide in SS; etoposide plus ifosfamide in MPNST; and gemcitabine plus docetaxel in UPS. Primary and secondary end points were disease-free survival (DFS) and overall survival (OS), estimated using the Kaplan-Meier method and compared using Cox models adjusted for treatment and stratification factors. The study is registered at ClinicalTrials.gov (identifier NCT01710176). RESULTS: Between May 2011 and May 2016, 287 patients (UPS: n = 97 [33.8%]; HG-MLPS: n = 65 [22.6%]; SS: n = 70 [24.4%]; MPNST: n = 27 [9.4%]; and LMS: n = 28 [9.8%]) were randomly assigned to either A+I or HT. At the final analysis, with a median follow-up of 52 months, the projected DFS and OS probabilities were 0.55 and 0.47 (log-rank P = .323) and 0.76 and 0.66 (log-rank P = .018) at 60 months in the A+I arm and HT arm, respectively. No treatment-related deaths were observed. CONCLUSION: In a population of patients with localized high-risk STS, HT was not associated with a better DFS or OS, suggesting that A+I should remain the regimen to choose whenever neoadjuvant chemotherapy is used in patients with high-risk STS.
RCT Entities:
PURPOSE: To determine whether the administration of histology-tailored neoadjuvant chemotherapy (HT) was superior to the administration of standard anthracycline plus ifosfamide neoadjuvant chemotherapy (A+I) in high-risk soft tissue sarcoma (STS) of an extremity or the trunk wall. PATIENTS AND METHODS: This was a randomized, open-label, phase III trial. Patients had localized high-risk STS (grade 3; size, ≥ 5 cm) of an extremity or trunk wall, belonging to one of the following five histologic subtypes: high-grade myxoid liposarcoma (HG-MLPS); leiomyosarcoma (LMS), synovial sarcoma (SS), malignant peripheral nerve sheath tumor (MPNST), and undifferentiated pleomorphic sarcoma (UPS). Patients were randomly assigned in a 1:1 ratio to receive three cycles of A+I or HT. The HT regimens were as follows: trabectedin in HG-MLPS; gemcitabine plus dacarbazine in LMS; high-dose prolonged-infusion ifosfamide in SS; etoposide plus ifosfamide in MPNST; and gemcitabine plus docetaxel in UPS. Primary and secondary end points were disease-free survival (DFS) and overall survival (OS), estimated using the Kaplan-Meier method and compared using Cox models adjusted for treatment and stratification factors. The study is registered at ClinicalTrials.gov (identifier NCT01710176). RESULTS: Between May 2011 and May 2016, 287 patients (UPS: n = 97 [33.8%]; HG-MLPS: n = 65 [22.6%]; SS: n = 70 [24.4%]; MPNST: n = 27 [9.4%]; and LMS: n = 28 [9.8%]) were randomly assigned to either A+I or HT. At the final analysis, with a median follow-up of 52 months, the projected DFS and OS probabilities were 0.55 and 0.47 (log-rank P = .323) and 0.76 and 0.66 (log-rank P = .018) at 60 months in the A+I arm and HT arm, respectively. No treatment-related deaths were observed. CONCLUSION: In a population of patients with localized high-risk STS, HT was not associated with a better DFS or OS, suggesting that A+I should remain the regimen to choose whenever neoadjuvant chemotherapy is used in patients with high-risk STS.
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