Does Intensified Postoperative Chemotherapy for High-Grade Osteosarcoma Benefit Poor Responders to Preoperative Therapy?


Key Points

  • In patients with newly diagnosed high-grade osteosarcoma, adding ifosfamide/etoposide to cisplatin, doxorubicin, and methotrexate postoperatively did not improve event-free survival vs cisplatin, doxorubicin, and methotrexate in poor responders to preoperative chemotherapy.
  • The addition of ifosfamide/etoposide to the regimen was associated with increased toxicity.

In a phase III trial (EURAMOS-1) reported in The Lancet Oncology, Marina et al found no improvement in event-free survival by adding postoperative ifosfamide/etoposide to cisplatin, doxorubicin, and methotrexate in patients with newly diagnosed high-grade osteosarcoma who responded poorly to preoperative chemotherapy.

Study Details

In the open-label trial, 2,260 patients from 325 sites in 17 countries were enrolled between April 2005 and June 2011. All patients received preoperative cisplatin, doxorubicin, and methotrexate (MAP) for 10 weeks. Of them, 618 poor responders to preoperative chemotherapy, defined as (≥ 10% viable tumor) were randomized to receive postoperative MAP plus ifosfamide/etoposide (MAPIE; n = 308) or MAP at preoperative doses (n = 310).

MAP consisted of cisplatin at 120 mg/m2 over 2 or 3 days and doxorubicin at 37.5 mg/m2/d on days 1 and 2 during weeks 1 and 6 followed 3 weeks later by high-dose methotrexate at 12 g/m2 over 4 hours. MAPIE consisted of MAP plus high-dose ifosfamide (14 g/m2) at 2.8 g/m2/d with equidose mesna uroprotection followed by etoposide at 100 mg/m2/d over 1 hour on days 1 to 5. The primary endpoint was event-free survival in the intent-to-treat population.

Event-Free Survival

Median follow-up was 62.1 months. A total of 307 event-free survival events occurred, including 154 in the MAPIE group and 153 in the MAP group. The hazard ratio (HR) for event-free survival for MAPIE vs MAP was 0.98 (P = .86), but hazards were nonproportional over time (P = .0003). Mean time to first event also did not differ between the groups (44.1 vs 43.3, P = .69). Estimated 3-year event-free survival was 53% vs 55%.

A total of 193 deaths occurred, including 92 in the MAPIE group and 101 in the MAP group. Overall survival data are immature. The estimated hazard ratio was 0.97 (P = .86). Estimated 3-year overall survival was 77% vs 72%.

Adverse Events

The most common grade 3 or 4 adverse events were neutropenia (90% of the MAPIE group vs 89% of the MAP group), thrombocytopenia (83% vs 78%), and febrile neutropenia without documented infection (73% vs 50%). Grade 4 nonhematologic toxicity was more common with MAPIE (24% vs 12%).

The investigators concluded: “EURAMOS-1 results do not support the addition of ifosfamide and etoposide to postoperative chemotherapy in patients with poorly responding osteosarcoma because its administration was associated with increased toxicity without improving event-free survival. The results define standard of care for this population. New strategies are required to improve outcomes in this setting.”

The study was funded by the UK Medical Research Council, the National Cancer Institute, the European Science Foundation, St. Anna Kinderkrebsforschung, Fonds National de la Recherche Scientifique, and many others.

Matthew R. Sydes, MSc, of the Medical Research Council Clinical Trials Unit, University College London, is the corresponding author of The Lancet Oncology article.

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