Is There a Role for Mifamurtide in Nonmetastatic High-Grade Osteosarcoma? Results From the Italian Sarcoma Group (ISG/OS-2) and Spanish Sarcoma Group (GEIS-33) Trials
Abstract
PURPOSE Outcome of patients with localized osteosarcoma is challenging. The role of mifamurtide is still a matter of debate. Two prospective trials were carried out in Italy (ISG/OS-2) and Spain (GEIS-33) with mifamurtide in ABCB1/P-glycoprotein (Pgp)–positive patients. PATIENTS AND METHODS Patients age ≤40 years with localized extremity high-grade osteosarcoma were eligible. Analysis of Pgp expression from diagnostic biopsy was centralized. Patients received two cycles of preoperative methotrexate, doxorubicin, and cisplatinum (MAP) before surgery. Postoperatively, in case of Pgp overexpression (Pgp-positive), mifamurtide was added, combined with doxorubicin (one cycle) and four consecutive cycles of high-dose ifosfamide (HDIFO) for patients with poor histologic response, or with MAP in case of good response. Patients who were Pgp-negative received MAP postoperatively. We present the merged analysis of ISG/OS-2 and GEIS-33 trial, an observational study with same inclusion criteria and treatment of ISG/OS-2. The primary endpoint was 5-year event-free survival (EFS) according to the use of mifamurtide. Secondary endpoint was overall survival (OS). RESULTS From March 2013 to April 2018, 398 patients were analyzed. The median age was 14 years (range, 4-40), male/female: 238/160 (1.48/1.0); 211 of 398 (53%) tumors were Pgp-positive, and 204 of 398 (51.3%) patients received mifamurtide. With a median follow-up of 70 months (IQR, 49-90 months), the 5-year EFS and OS were 65.2% (95% CI, 60.1 to 69.8) and 74.8% (95% CI, 69.8 to 79.0), respectively, with superior EFS for patients undergoing mifamurtide and chemotherapy as compared with EFS of patients undergoing chemotherapy alone (5-year EFS 71.4% v 58.3%; P = .0139) not confirmed at multivariable analysis ( P = .0593). CONCLUSION In this merged analysis with a risk-adapted strategy for nonmetastatic osteosarcoma, the group with unfavorable prognoses, identified by Pgp expression, performed well when mifamurtide, combined with HDIFO in case of poor response, was administered after surgery.
Article Details
Journal Info
Journal of Clinical Oncology
Lippincott Williams & Wilkins
Authors (31)
Emanuela Palmerini
Osteoncologia, Sarcomi dell'Osso e dei Tessuti Molli, e Terapie Innovative - IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
Cristina Meazza
Istituto Nazionale Tumori, Milan, Italy
Angela Tamburini
Department of Paediatric Haematology-Oncology, Meyer Children's Hospital IRCCS, Florence, Italy
Catalina Márquez-Vega
Pediatric Oncology Unit, Hospital Infantil Universitario Virgen del Rocío, Sevilla, Spain
Gianni Bisogno
Franca Fagioli
1Regina Margherita Children's Hospital, University of Turin, Department of Pediatric Hematology/Oncology, Turin, Italy
Virginia Ferraresi
Sarcomas and Rare Tumors Departmental Unit - IRCCS Regina Elena National Cancer Institute, Roma, Italy
Giuseppe Maria Milano
Division of Pediatric Hematology and Oncology, Gene and Cellular Therapy, IRCCS Ospedale Pediatrico Bambino Gesù, Roma, Italy
Luca Coccoli
Alba Rubio-San-Simon
Oscar Gallego
Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
María Esther Llinares Riestra
Pediatric Oncology Unit, Hospital Infantil Universitario Clinico Virgen de la Arrixca, Murcia, Spain
Carla Manzitti
Jaume Mora
Mᵃ Ángeles Vaz-Salgado
Hospital Universitario Ramón y Cajal, Irycis, Madrid, Spain
Roberto Luksch
Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
Cristina Mata
Michela Pierini
Istituto Ortopedico Rizzoli IRCCS, Bologna, Italy
Elisa Carretta
Department of Programming and Monitoring, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
Marilena Cesari
Anna Paioli
Osteoncology, Bone and Soft Tissue Sarcomas, and Innovative Therapies Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
Andrea Marrari
Osteoncology, Bone and Soft Tissue Sarcomas, and Innovative Therapies Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
Katia Scotlandi
Massimo Serra
Emanuela Palmerini, MD, PhD, Osteoncology, Bone and Soft Tissue Sarcomas, and Innovative Therapies Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL; Massimo Serra, PhD, and Toni Ibrahim, MD, PhD, Osteoncology, Bone and Soft Tissue Sarcomas, and Innovative Therapies Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy; and Javier Martín Broto, MD, PhD, Research Health Institute of Fundacion Jimenez Diaz (IIS/FJD; UAM), Madrid, Spain, Department of Medical Oncology, Fundacion Jimenez Diaz University Hospital, Madrid, Spain, University Hospital General de Villalba, Madrid, Spain
Sebastian Dorin Asaftei
S.C. Oncoematologia Pediatrica—Regina Margherita Children's Hospital, A.O.U. Città della Salute e della Scienza di Torino, Torino, Italy
Marco Gambarotti
Piero Picci
Stefano Ferrari
Claudia Valverde
Toni Ibrahim
Javier Martin Broto
Hospital Universitario Fundacion Jimenez Diaz, Madrid, Spain