Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial

Abstract

SummaryBackgroundWe designed the EURAMOS-1 trial to investigate whether intensified postoperative chemotherapy for patients whose tumour showed a poor response to preoperative chemotherapy (≥10% viable tumour) improved event-free survival in patients with high-grade osteosarcoma.MethodsEURAMOS-1 was an open-label, international, phase 3 randomised, controlled trial. Consenting patients with newly diagnosed, resectable, high-grade osteosarcoma aged 40 years or younger were eligible for randomisation. Patients were randomly assigned (1:1) to receive either postoperative cisplatin, doxorubicin, and methotrexate (MAP) or MAP plus ifosfamide and etoposide (MAPIE) using concealed permuted blocks with three stratification factors: trial group; location of tumour (proximal femur or proximal humerus vs other limb vs axial skeleton); and presence of metastases (no vs yes or possible). The MAP regimen consisted of cisplatin 120 mg/m2, doxorubicin 37·5 mg/m2 per day on days 1 and 2 (on weeks 1 and 6) followed 3 weeks later by high-dose methotrexate 12 g/m2 over 4 h. The MAPIE regimen consisted of MAP as a base regimen, with the addition of high-dose ifosfamide (14 g/m2) at 2·8 g/m2 per day with equidose mesna uroprotection, followed by etoposide 100 mg/m2 per day over 1 h on days 1–5. The primary outcome measure was event-free survival measured in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00134030.FindingsBetween April 14, 2005, and June 30, 2011, 2260 patients were registered from 325 sites in 17 countries. 618 patients with poor response were randomly assigned; 310 to receive MAP and 308 to receive MAPIE. Median follow-up was 62·1 months (IQR 46·6–76·6); 62·3 months (IQR 46·9–77·1) for the MAP group and 61·1 months (IQR 46·5–75·3) for the MAPIE group. 307 event-free survival events were reported (153 in the MAP group vs 154 in the MAPIE group). 193 deaths were reported (101 in the MAP group vs 92 in the MAPIE group). Event-free survival did not differ between treatment groups (hazard ratio [HR] 0·98 [95% CI 0·78–1·23]); hazards were non-proportional (p=0·0003). The most common grade 3–4 adverse events were neutropenia (268 [89%] patients in MAP vs 268 [90%] in MAPIE), thrombocytopenia (231 [78% in MAP vs 248 [83%] in MAPIE), and febrile neutropenia without documented infection (149 [50%] in MAP vs 217 [73%] in MAPIE). MAPIE was associated with more frequent grade 4 non-haematological toxicity than MAP (35 [12%] of 301 in the MAP group vs 71 [24%] of 298 in the MAPIE group). Two patients died during postoperative therapy, one from infection (although their absolute neutrophil count was normal), which was definitely related to their MAP treatment (specifically doxorubicin and cisplatin), and one from left ventricular systolic dysfunction, which was probably related to MAPIE treatment (specifically doxorubicin). One suspected unexpected serious adverse reaction was reported in the MAP group: bone marrow infarction due to methotrexate.InterpretationEURAMOS-1 results do not s...

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

“…Approximately one-third of patients experienced 1 or more episodes of nephrotoxicity, mostly G1, but in 1 case dialysis was required. The incidence of nephrotoxicity was higher than that reported for younger patients (3,5,6), probably reflecting an age-related decreased renal function not detected by the laboratory tests recommended in the protocol.…”

“…The incidence of chemotherapy-induced peripheral neuropathy exceeded the frequency reported for younger patients treated with higher cumulative doses of CDP and ADM (3,5,6). However, it is similar to reported levels in adult patients with other CDP-treated cancers, who are more prone to this side effect (24,25).…”

Team Approach: Osteosarcoma of the Distal Part of the Femur in Adolescents

“…42,43 The addition of etoposide and ifosfamide in the adjuvant setting for patients with a poor histologic response has been evaluated and does not improve overall or event-free survival. 44 Inadequate surgical margins lead to a higher risk of local recurrence which is associated with poor prognosis.…”

Pharmacogenomics of Second-Line Drugs Used for Treatment of Unresponsive or Relapsed Osteosarcoma Patients

“…Event-free survival did not differ between the two treatment arms. Intensification of postoperative treatment with ifosfamide and etoposide was associated with more frequent grade 4 nonhematological toxicity [52]. The authors concluded that these results do not support the addition of ifosfamide and etoposide to the first-line chemotherapy in HGOS patients with poor response to preoperative treatment [52].…”

“…In this intercontinental treatment protocol, which enrolled 2260 patients with resectable HGOS from 326 centers across 17 countries, preoperative chemotherapy included doxorubicin, methotrexate and cisplatin. Poor responders to pre operative chemotherapy (patients with ≥10% viable cells in the resected tumor tissue) were randomized and were postoperatively treated with doxorubicin, methotrexate and cisplatin with or without ifosfamide and etoposide [51,52]. Event-free survival did not differ between the two treatment arms.…”