RANDOMIZED TRIAL OF 2 REGIMENS OF CHEMOTHERAPY IN OPERABLE OSTEOSARCOMA - A STUDY OF THE EUROPEAN OSTEOSARCOMA INTERGROUP

Background A previous trial by the European Osteosarcoma Intergroup (E OI) suggested that a short intensive chemotherapy regimen with doxorub icin and cisplatin might produce survival of operable, non-metastatic osteosarcoma similar to that obtained with complex and longer-duration drug regimens based on the widely used T10 multi-drug protocol. We un dertook a randomised multicentre trial to compare these two approaches . Methods 407 patients with operable, non-metastatic osteosarcoma were randomly assigned the two-drug regimen (six cycles [18 weeks] of doxo rubicin 25 mg/m(2) on days 1-3 and cisplatin 100 mg/m(2) on day 1) or a multi-drug regimen (preoperatively vincristine, high-dose methotrexa te, and doxorubicin; postoperatively bleomycin, cyclophosphamide, dact inomycin, vincristine, methotrexate, doxorubicin, and cisplatin; this protocol took 44 weeks). Surgery was scheduled for week 9 for the two- drug group and week 7 for the multi-drug group. Analyses of survival a nd progression-free survival were by intention to treat. Findings Of 4 07 randomised patients, 391 were eligible and have been followed up fo r at least 4 years (median 5.6 years). Toxic effects were qualitativel y similar with the two regimens. However, 188 (94%) of 199 patients co mpleted the six cycles of two-drug treatment, whereas only 97 (51%) of 192 completed 18 or more of the 20 cycles of the multi-drug regimen. The proportion showing a good histopathological response (>90% tumour necrosis) to preoperative chemotherapy was about 29% with both regimen s and was strongly predictive of survival. Overall survival was 65% at 3 years and 55% at 5 years in both groups (hazard ratio 0.94 [95% CI 0.69-1.27]). Progression-free survival at 5 years was 44% in both grou ps (hazard ratio 1.01[0.77-1.33]). Interpretation We found no differen ce in survival between the two-drug and multi-drug regimens in operabl e, non-metastatic osteosarcoma. The two-drug regimen is shorter in dur ation and better tolerated, and is therefore the preferred treatment. However, 5-year survival is still unsatisfactory and new approaches to treatment, such as dose intensification, are needed to improve result s.