Phase 3 data do not support adding ifosfamide to adjuvant treatment with methotrexate, doxorubicin, and cisplatin (MAP) in patients with high-grade osteosarcoma, according to a presentation at ESMO Congress 2022. 

Patients with a poor initial response to MAP did not benefit from the addition of ifosfamide in this trial, according to study presenter Hiroaki Hiraga, MD, PhD, of the National Hospital Organization/Hokkaido Cancer Center in Sapporo, Japan. 

The phase 3 JCOG0905 trial enrolled patients 50 years of age or younger with operable, high-grade osteosarcoma. Prior to randomization, patients completed 2 cycles of MAP, underwent complete resection of their primary tumor, and received 1 postoperative cycle of doxorubicin and cisplatin. 

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Patients with a poor response to MAP — defined as greater than 10% viable tumor cells at surgery — were randomly assigned to receive additional treatment with MAP alone (n=51) or ifosfamide plus MAP (n=52). Ifosfamide was given at 15 g/m2 for 6 courses.

At baseline, the median age in both arms was 15 years. Most patients were male, and the most common tumor site was the lower limbs (49 patients in each arm).

Overall, 44 patients completed treatment with MAP alone, and 32 completed treatment with ifosfamide plus MAP. Reasons for discontinuation in the ifosfamide arm were adverse events (n=9), patient refusal (n=7), and disease progression (n=7). Reasons for discontinuation in the MAP-alone arm were patient refusal (n=5) and disease progression (n=2).

The study’s primary endpoint was disease-free survival (DFS). At the second interim analysis, the safety monitoring committee recommended terminating the study because the hazard ratio (HR) was above the prespecified threshold of 1.0.

The 3-year DFS rate was 64.3% in both arms (HR, 1.05; 95% CI, 0.55-1.98). The 3-year overall survival rate was 86.5% in the MAP-alone arm and 78.8% in the ifosfamide-MAP arm (HR, 1.48; 95% CI, 0.68-3.22). 

Dr Hiraga said these results do not support adding ifosfamide to MAP for poor-response patients, even if the total dose of ifosfamide is 90 mg/m2.


Hiraga H, Machida R, Kawai A, et al. A phase III study comparing methotrexate (M), adriamycin (A) and cisplatin (P) with MAP + ifosfamide (MAP + IF) for the treatment of osteosarcoma: JCOG0905. Presented at ESMO 2022; September 9-13, 2022. Abstract 1482O.