Methotrexate, Doxorubicin, and Cisplatin Versus Methotrexate, Doxorubicin, and Cisplatin + Ifosfamide in Poor Responders to Preoperative Chemotherapy for Newly Diagnosed High-Grade Osteosarcoma (JCOG0905): A Multicenter, Open-Label, Randomized Trial

Abstract

Purpose: Our previous NECO phase II studies on high-grade osteosarcoma suggested that administering ifosfamide (IF; 16 g/m² [4g/m² once on day 1, then 2g/m² once on days 2-7] × six) to patients showing a poor response (PrRsp) to preoperative chemotherapy with methotrexate, doxorubicin, and cisplatin (MAP) improves their prognoses. In this Japan Clinical Oncology Group (JCOG) study, JCOG0905, we aimed to investigate the efficacy and safety of IF in patients with PrRsp.

Methods: JCOG0905 is a multicenter, open-label, multi-institutional, randomized trial. Eligible patients (50 years and younger) had resectable, high-grade osteosarcoma (stage II or III, Union for International Cancer Control TNM) of the extremities, limb girdles, and thoracic wall. After two MAP cycles and tumor resection, patients with PrRsp were randomly assigned to either the MAP or MAP plus 15 g/m² (3g/m² once daily on days 1-5) × six IF (MAP + IF [MAPIF]) group. The primary end point was disease-free survival (DFS); secondary end points were overall survival (OS) and safety. The planned sample size was 100 patients with a one-sided α of .1 and a power of 0.7, assuming a 3-year DFS of 50% and 65% for MAP and MAPIF, respectively. This trial is registered with the Japan Registry of Clinical Trials (jRCT; jRCTs031180126).

Results: Of the 287 patients registered between February 2010 and August 2020, 51 and 52 patients with PrRsp were assigned to the MAP and MAPIF groups, respectively. As of March 2022, DFS did not differ between groups (hazard ratio [HR], 1.05 [95% CI, 0.55 to 1.98]) and OS was numerically inferior in the MAPIF group (HR, 1.48 [95% CI, 0.68 to 3.22]). Nine and zero patients in the MAPIF and MAP groups discontinued treatment because of adverse events, respectively.

Conclusion: Evidence from JCOG0905 does not support the addition of IF for patients with PrRsp.

FIG 1.

CONSORT diagram. MAP, methotrexate, doxorubicin, and cisplatin; MAPIF, MAP + ifosfamide.

FIG 2.

Survival analysis of the MAP and MAPIF arms. Kaplan-Meier curves showing (A) DFS and (B) OS for the MAP and MAPIF arms. (C) Kaplan-Meier curve showing DFS and OS in the good responders. DFS, disease-free survival; HR, hazard ratio; MAP, methotrexate, doxorubicin, and cisplatin; MAPIF, MAP + ifosfamide; OS, overall survival.

FIG A1.

(A) Scheme of JCOG0905. (B) Scheme of each treatment segment. Registered patients received two cycles of preoperative MAP therapy: AP was administered at weeks 1 and 6, and high-dose M at weeks 4, 5, 9, and 10. Two additional M treatments were permitted if fabricating and delivering an expandable prosthesis for skeletally immature children were time-consuming. Wide excision of the tumor was performed within 5 weeks of starting the last course of preoperative chemotherapy. All patients received one cycle of AP between 1 and 5 weeks after surgery. After the second registration, the subsequent treatment was to be started within 1 week. Good and poor responders randomly assigned to the MAP arm were administered M at weeks 1, 2, 6, 7, 12, and 13; A at weeks 3 and 14; and AP at week 8. Poor responders randomly assigned to the MAPIF arm were administered IF at weeks 1, 4, 13, 16, 21, and 24; M at weeks 7, 8, 19, and 20; and AP at week 9. A, doxorubicin; AP, doxorubicin and cisplatin; IF, ifosfamide; JCOG, Japan Clinical Oncology Group; M, methotrexate; MAP, methotrexate, doxorubicin, and cisplatin; MAPIF, MAP + ifosfamide; T, T factor.

FIG A2.

Subgroup analysis for DFS of the MAP and MAPIF arms. Kaplan-Meier curves showing DFS of patients with a histologic effect of (A) grade 1 and (B) grade 2 for the MAP and MAPIF arms. DFS, disease-free survival; MAP, methotrexate, doxorubicin, and cisplatin; MAPIF, MAP + ifosfamide.