1482O - A phase III study comparing methotrexate (M), adriamycin (A) and cisplatin (P) with MAP + ifosfamide (MAP + IF) for the treatment of osteosarcoma: JCOG0905

Background

Our previous phase II studies on high-grade osteosarcoma, NECO93J and 95J, suggested that application of Ifosfamide (IF) (16 g/m² × 6 courses) to patients with a poor response (PrRsp) to preoperative chemotherapy using Methotrexate, Adriamycin, and Cisplatin (MAP) improves their prognosis. The JCOG0905 randomized controlled trial investigated the efficacy and safety of adding IF in patients with PrRsp (> 10% viable tumor cells at surgery).

Methods

Patients ≤ 50 years old with operable, high-grade osteosarcoma (Stage IIA, IIB, III, UICC TNM 6th edition) of the extremities, limb girdles, and thoracic wall were eligible for registration at diagnosis. Eligibility for randomization included: completion of 2 MAP cycles preoperatively, followed by complete resection of the primary tumor and 1 postoperative cycle of Adriamycin and Cisplatin with no disease progression; and known histological response. PrRsp patients were randomized (1:1) to continuation of MAP or MAP + IF (15 g/m² × 6 courses). The primary endpoint was disease-free survival (DFS), and the secondary endpoints included overall survival (OS) and safety. The planned sample size was 100 with a one-sided alpha of 0.1 and power of 0.7, assuming 3-year DFS of MAP and MAP + IF of 50% and 65%, respectively.

Results

Of the 287 patients registered from Feb. 2010 to Aug. 2020, 51 and 52 patients were randomly assigned to MAP and MAP + IF, respectively. At the second interim-analysis on March 2022, the 3-year DFS was 64.3% (95% confidence interval (CI) 49.4-75.8) in MAP and 64.3% (49.3-75.8) in MAP + IF (hazard ratio (HR) 1.05, 95% CI 0.57-1.91). The 3-year OS was 86.5% (72.4-93.7) in MAP and 78.8% (64.1-88.0) in MAP + IF (HR 1.48, 0.68-3.22). There were no treatment-related deaths in both arms. Nine patients in MAP + IF terminated protocol treatment due to adverse events, whereas none in MAP terminated treatment. Based on the results of this analysis, the Data and Safety Monitoring Committee of JCOG recommended terminating the study since the point estimate of HR was above the pre-specified HR of 1.0.

Conclusions

Evidence from JCOG0905 does not support adding IF in PrRsp patients, even at a total dose of 90 g/m², which is higher than the dose of 60 g/m² in EURAMOS-1.

Clinical trial identification

Editorial acknowledgement

Monisha R, MD, Forte Science Communications.

Legal entity responsible for the study

National Cancer Center.

Funding

the National Cancer Center Research and Development Fund (2020-J-3) and the Japan Agency for Medical Research and Development (AMED) under grant number JP20ck0106614.

Disclosure

All authors have declared no conflicts of interest.