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

Abstract

PurposeEURAMOS-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 MethodsAt 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).ResultsGood 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.ConclusionAt 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.

EURO-B.O.S.S.: A European study on chemotherapy in bone-sarcoma patients aged over 40: Outcome in primary high-grade osteosarcoma

“…This may be related to the suggested primary chemotherapy regimen. In our protocol, MTX was not used preoperatively and the doses per cycle of CDP and ADM were lower than those adopted in younger patients (3,5). At the same time we cannot exclude that agerelated pharmacokinetics changes (13-15) may be responsible for the reduced activity of the drugs in this subset of patients.…”

“…Methotrexate (MTX), doxorubicin (Adriamycin [ADM]), cisplatin (CDP), and ifosfamide (IFO) are considered the drugs with proven efficacy against osteosarcoma (1) and have been used according to different schedules in chemotherapy protocols adopted in large studies (2-7). The peak incidence of osteosarcoma is in the second decade of life (1) and most of the studies with dose intensive chemotherapy include only patients up to the age of 40 years (2,3,5,6).…”

Has the Level of Evidence of Podium Presentations at the Musculoskeletal Tumor Society Annual Meeting Changed Over Time?

“…In addition, with limited patient enrollment, statistically significant endpoints are difficult to obtain [6]. Despite these obstacles, multicenter (Children's Oncology Group) and international (European and American Osteosarcoma Study Group) pediatric and medical oncology collaborations have completed sarcoma RCTs, the results of which have improved clinical practice [5,47,48].…”

Treatment of high-grade osteoblastic osteosarcoma of the humerus in a 5-year-old boy with cystic fibrosis: A case report

“…Prior to treatment, antibiotic prophylaxis with cefuroxime (20 mg/kg body weight per day, twice daily) was initiated to avoid pulmonary infections. Neoadjuvant chemotherapy (the EURAMOS-1 trial) (8) following two cycles of MAP, i.e., 10 weeks following the start of the chemotherapy (9). The first febrile episode of unknown origin (FUO) during neutropenia occurred at the ninth week.…”