Trabectedin with concomitant radiotherapy in resectable retroperitoneal L-sarcoma: A multicenter, prospective, phase I/II trial—A collaborative study by the Spanish (GEIS), Italian (ISG), and French (FSG) groups.
Abstract
11507 Background: Liposarcoma (LPS) and leiomyosarcoma (LMS) account for most retroperitoneal sarcomas. Despite complete resection, local recurrence remains high, particularly in dedifferentiated LPS (DDLPS). While preoperative radiotherapy (RT) may improve local control, optimal multimodal strategies are undefined. Trabectedin (T) is active in L-sarcomas, with emerging clinical evidence supporting its radiosensitizing properties and its efficacy in combination with RT. A preoperative short course of T with concurrent low-dose RT was investigated in a multicenter, phase I/II trial in patients (pts) with centrally confirmed resectable retroperitoneal L-sarcoma (grade 2-3 DDLPS with >30% dedifferentiated component or grade 2-3 LMS). Methods: Pts received 3 cycles of T in combination with RT (45 Gy in 25 x 1.8 Gy). Phase I followed a 3+3 dose-escalation design with T dose levels 1.5 (0), 1.3 (-1), and 1.1mg/m 2 (-2). Dose-limiting toxicity was any grade ≥3 adverse events (excluding neutropenia <5 days, elevated transaminases without treatment delay, and nausea/vomiting due to inadequate prophylaxis). Phase I primary endpoint was safety and the determination of the recommended Phase II dose (RP2D). Phase II primary endpoint was centrally assessed Choi response. Secondary endpoints included relapse-free survival (RFS; from surgery), progression-free survival (PFS; from first T cycle), overall survival (OS), RECIST and pathological response, and treatment-related toxicity according to CTCAE v5.0. Results: From February 2019 to January 2025, 56 pts, 6 in phase I and 50 in phase II, (M/F: 31/25) with a median age of 61 years (range: 19-75) and a median tumor size of 17 cm (range: 12-30) were enrolled. 51 pts had grade 2-3 DDLPS, and 5 pts had grade 2-3 LMS. A T dose of 1.5 mg/m 2 was the RP2D. Per-protocol therapy was completed in 47 pts (84%); discontinuations were due to local progression (N=1), toxicity (N=6), or refusal (N=2). The most common grade 3/4 toxicities were neutropenia (21.4%), leukopenia (8.9%), fatigue (8.9%), and increased ALT, febrile neutropenia, and thrombocytopenia (7.1% each). 51 pts (91%) underwent surgery, with 96% achieving complete resection. According to the central review, Choi (N=45) showed 12 PR (26.7%) and 33 SD (73.3%). RECIST 1.1 (N=53): PR 1 (2%), SD 51 (96%), PD 1 (2%). At a median follow-up of 40 months (95% CI, 36-43), from the start of T (N=53), 3-year PFS was 70% (95 CI, 56-83) and 3-year OS was 85% (95 CI, 75-95). Conclusions: Preoperative concurrent T and RT was feasible and safe for resectable retroperitoneal L-sarcomas, yielding density responses in over 25% of pts and promising survival outcomes. A phase III trial is warranted to compare this regimen against RT alone. Clinical trial information: NCT02275286 .
Article Details
Journal Info
Journal of Clinical Oncology
Lippincott Williams & Wilkins
Authors (20)
Rosa Maria Alvarez Alvarez
Hospital General Universitario Gregorio Marañón, Madrid, Spain
Nadia Hindi
Irene Carrasco-Garcia
Hospital Universitario Virgen del Rocio, Seville, Spain
Roberta Sanfilippo
European Institute of Oncology, Milan, Italy
Ana Sebio
Hospital de la Santa Creu i Sant Pau, Medical Oncology, Barcelona, Spain
Andres Redondo
From the National Surgical Adjuvant Breast and Bowel Project (NSABP) Foundation (C.E.G., E.P.M., N.W., P.R., I.L.W., A.M.B.) and University of Pittsburgh School of Medicine–UPMC Hillman Cancer Center (C.E.G., N.W., P.R., A.M.B.) — both in Pittsburgh; AGO-B and Helios Klinikum Berlin–Buch, Berlin (M.U.), the National Center for Tumor Diseases, Heidelberg University Hospital, and German Cancer Research Center, Heidelberg (A.S.), Evangelische Kliniken Gelsenkirchen, Gelsenkirchen (H.H.F.), Arbeitsgemeinschaft Gynäkologische Onkologie–Breast and Sana Klinikum Offenbach, Offenbach (C.J.), the Department of Gynecology and Obstetrics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen–EMN, Friedrich–Alexander University Erlangen–Nuremberg, Erlangen (P.A.F.), German Breast Group, Neu-Isenburg (P.W., S.L.), and the Center for Hematology and Oncology Bethanien, Goethe University, Frankfurt (S.L.) — all in Germany; National Taiwan University Hospital and National Taiwan University College of Medicine,...
Ana Alvarez
HGUGM, Madrid, Spain
Carlo Morosi
Department of Radiology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
Cleofé Romagosa
Vicente Artigas
Department of Surgery. Autonomous University of Barcelona, Barcelon, Spain
Cristobal Muñoz Casares
Hospital Virgen del Rocío, Sevilla, Spain
José Manuel Asencio
Department of Surgery, Hospital General Universitario Gregorio Marañón, Madrid, Spain
Laura Guzmán-Gómez
Fundación Jiménez Díaz, Madrid, Spain
José González-Lopez
Hospital de la Santa Creu i Sant Pau, Surgery Department, Barcelona, Spain
Belen Belinchon
Hospital Universitario La Paz, Madrid, Spain
Claudia Sangalli
Department of Radiation Oncology, Istituto Nazionale Dei Tumori, Milan, Italy
Antonio Gutiérrez
Josefina Cruz Jurado
Hospital Universitario de Canarias, Tenerife, Spain
Javier Martin Broto
Hospital Universitario Fundacion Jimenez Diaz, Madrid, Spain
Alessandro Gronchi
Fahima Dossa, MD, PhD, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA; Chandrajit P. Raut, MD, Department of Surgery, Mass General Brigham, Harvard Medical School, Boston, MA; Andrew J. Wagner, MD, PhD, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Robin L. Jones, MD, Sarcoma Unit, The Royal Marsden NHS Foundation Trust and Institute of Cancer Research, London, United Kingdom; Rebecca A. Gladdy, MD, PhD, Department of Surgical Oncology, Mount Sinai Hospital and Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada; Abha A. Gupta, MD, Division of Medical Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada; Kenneth Cardona, MD, Division of Surgical Oncology, Department of Surgery, Winship Cancer Institute, Emory University, Atlanta, GA; David E. Gyorki, MD, Division of Cancer Surgery, Peter MacCallum Cancer Centre, and Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Au...