Methotrexate, Doxorubicin, and Cisplatin (MAP) Plus Maintenance Pegylated Interferon Alfa-2b Versus MAP Alone in Patients With Resectable High-Grade Osteosarcoma and Good Histologic Response to Preoperative MAP: First Results of the EURAMOS-1 Good Response Randomized Controlled Trial

J Clin Oncol. 2015 Jul 10;33(20):2279-87. doi: 10.1200/JCO.2014.60.0734. Epub 2015 Jun 1.

Abstract

Purpose: EURAMOS-1, an international randomized controlled trial, investigated maintenance therapy with pegylated interferon alfa-2b (IFN-α-2b) in patients whose osteosarcoma showed good histologic response (good response) to induction chemotherapy.

Patients and methods: At diagnosis, patients age ≤ 40 years with resectable high-grade osteosarcoma were registered. Eligibility after surgery for good response random assignment included ≥ two cycles of preoperative MAP (methotrexate, doxorubicin, and cisplatin), macroscopically complete surgery of primary tumor, < 10% viable tumor, and no disease progression. These patients were randomly assigned to four additional cycles MAP with or without IFN-α-2b (0.5 to 1.0 μg/kg per week subcutaneously, after chemotherapy until 2 years postregistration). Outcome measures were event-free survival (EFS; primary) and overall survival and toxicity (secondary).

Results: Good response was reported in 1,041 of 2,260 registered patients; 716 consented to random assignment (MAP, n = 359; MAP plus IFN-α-2b, n = 357), with baseline characteristics balanced by arm. A total of 271 of 357 started IFN-α-2b; 105 stopped early, and 38 continued to receive treatment at data freeze. Refusal and toxicity were the main reasons for never starting IFN-α-2b and for stopping prematurely, respectively. Median IFN-α-2b duration, if started, was 67 weeks. A total of 133 of 268 patients who started IFN-α-2b and provided toxicity information reported grade ≥ 3 toxicity during IFN-α-2b treatment. With median follow-up of 44 months, 3-year EFS for all 716 randomly assigned patients was 76% (95% CI, 72% to 79%); 174 EFS events were reported (MAP, n = 93; MAP plus IFN-α-2b, n = 81). Hazard ratio was 0.83 (95% CI, 0.61 to 1.12; P = .214) from an adjusted Cox model.

Conclusion: At the preplanned analysis time, MAP plus IFN-α-2b was not statistically different from MAP alone. A considerable proportion of patients never started IFN-α-2b or stopped prematurely. Long-term follow-up for events and survival continues.

Publication types

  • Clinical Trial, Phase III
  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't
  • Webcast

MeSH terms

  • Adolescent
  • Adult
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Asia
  • Australia
  • Bone Neoplasms / mortality
  • Bone Neoplasms / pathology
  • Bone Neoplasms / therapy*
  • Chemotherapy, Adjuvant
  • Child
  • Child, Preschool
  • Cisplatin / administration & dosage
  • Disease Progression
  • Disease-Free Survival
  • Doxorubicin / administration & dosage
  • Europe
  • Female
  • Humans
  • Interferon alpha-2
  • Interferon-alpha / administration & dosage
  • Kaplan-Meier Estimate
  • Male
  • Methotrexate / administration & dosage
  • Neoadjuvant Therapy*
  • Neoplasm Grading
  • North America
  • Osteosarcoma / mortality
  • Osteosarcoma / pathology
  • Osteosarcoma / therapy*
  • Osteotomy* / adverse effects
  • Osteotomy* / mortality
  • Polyethylene Glycols / administration & dosage
  • Proportional Hazards Models
  • Recombinant Proteins / administration & dosage
  • Risk Factors
  • Time Factors
  • Treatment Outcome
  • Young Adult

Substances

  • Interferon alpha-2
  • Interferon-alpha
  • Recombinant Proteins
  • Polyethylene Glycols
  • Doxorubicin
  • peginterferon alfa-2b
  • Cisplatin
  • Methotrexate

Associated data

  • ISRCTN/ISRCTN67613327