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
Authors: Bielack Stefan S. , Smeland Sigbjørn , Whelan Jeremy S. , Marina Neyssa , Jovic Gordana , Hook Jane M. , Krailo Mark D. , Gebhardt Mark , Pápai Zsuzsanna , Meyer James , Nadel Helen , Randall R. Lor , Deffenbaugh Claudia , Nagarajan Rajaram , Brennan Bernadette , Letson G. Douglas , Teot Lisa A. , Goorin Allen , Baumhoer Daniel , Kager Leo , Werner Mathias , Lau Ching C. , Sundby Hall Kirsten , Gelderblom Hans , Meyers Paul , Gorlick Richard , Windhager Reinhard , Helmke Knut , Eriksson Mikael , Hoogerbrugge Peter M. , Schomberg Paula , Tunn Per-Ulf , Kühne Thomas , Jürgens Heribert , van den Berg Henk , Böhling Tom , Picton Susan , Renard Marleen , Reichardt Peter , Gerss Joachim , Butterfass-Bahloul Trude , Morris Carol , Hogendoorn Pancras C.W. , Seddon Beatrice , Calaminus Gabriele , Michelagnoli Maria , Dhooge Catharina , Sydes Matthew R. , Bernstein Mark 
Published: June 2015

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.