Addition of Interferon Alfa-2b to MAP Does Not Meet Event-Free Survival Objective in Osteosarcoma With Good Response to Preoperative MAP


Key Points

  • 24% of patients did not start interferon and 39% of those who started treatment stopped early.
  • The addition of interferon to MAP was associated with a nonsignificant event-free survival benefit. 

In the phase III EURAMOS-1 trial reported in the Journal of Clinical Oncology, Bielack et al found that the addition of postoperative pegylated interferon alfa-2b (Pegintron, Sylatron) to MAP (methotrexate, doxorubicin, and cisplatin) in patients with osteosarcoma showing good histologic response to preoperative MAP did not significantly improve event-free survival. A large proportion of patients randomly assigned to interferon never received the treatment or stopped it early.

Study Details

The open-label trial enrolled 2,260 patients aged ≤40 years with resectable high-grade osteosarcoma from 17 countries between April 2005 and June 2011. Eligibility criteria for randomization to postoperative MAP with or without interferon included at least two cycles of preoperative MAP, macroscopically complete surgery of primary tumor, < 10% viable tumor, and no disease progression.

Eligible patients were randomly assigned to four additional cycles of MAP with or without interferon at 0.5 to 1.0 µg/kg per week subcutaneously after chemotherapy until 2 years postregistration. The primary endpoint was event-free survival on intent-to-treat analysis.

Disposition of Interferon Group

Good histologic response was reported in 1,041 of the 2,260 registered patients. Of these, 716 consented to randomization to MAP plus interferon (n = 357) or MAP alone (n = 359). Of the 357 patients in the interferon group, 271 (76%) started interferon at a median of 23 weeks after randomization; at data freeze, 128 (47%) of these had completed protocol treatment, 105 (39%) had stopped early, and 38 (14%) were still receiving treatment.

Among patients who never started interferon treatment, refusal (78%) was the most common reason. Among patients who stopped interferon treatment early, toxicity (45%) was the most common reason. Among patients starting interferon treatment, the median duration of treatment was 67 weeks.

Event-Free Survival

At a median follow-up of 44 months, 3-year event-free survival among all 716 randomized patients was 77% (95% confidence interval [CI] = 72%–81%) in the interferon-MAP group and 74% (95% CI = 69%–79%) in the MAP group (HR = 0.83, P = .214). On an early estimate of overall survival, 5-year overall survival was 84% (95% CI = 78%–88%) in the interferon-MAP group vs 81% (95% CI = 74%–86%) in the MAP group (HR = 0.77, 95% CI = 0.50–1.19). Follow-up continues for overall survival.

The investigators noted that a meaningful as-treated analysis of event-free survival was precluded by the unexplained finding that patients randomly assigned to interferon who never started the drug had a worse outcome than patients randomized to MAP alone. 


Toxicity data for 268 of 271 patients starting interferon showed grade 4 adverse events in 12% (hematologic in 26 patients and left-ventricular systolic dysfunction in 4) and grade 3 adverse events in 38%. No fatal adverse events were reported.

The investigators concluded, “At the preplanned analysis time, MAP plus [interferon alfa-2b] was not statistically different from MAP alone. A considerable proportion of patients never started [interferon alfa-2b] or stopped prematurely. Long-term follow-up for events and survival continues.”

They noted, “Although we have reached the target number of [event-free survival] events, ongoing follow-up of patients is crucial and will permit the planned analysis of [overall survival]. The current [event-free survival] results, reported at the protocol-defined analytic endpoint, do not support the routine use of [interferon alfa-2b] maintenance after standard chemotherapy for osteosarcoma.”

Matthew R. Sydes, MSc, of MRC Clinical Trials Unit, University College London, is the corresponding author for the Journal of Clinical Oncology article.

The study was supported by governmental, nongovernmental, scientific, and charitable body funders in each participating country, with additional funding for pan-European trial coordination. Pegylated interferon alfa-2b was provided by Merck, which reviewed the study report. 

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.