Randomised trial of two regimens of chemotherapy in operable osteosarcoma: a study of the European Osteosarcoma Intergroup

Summary

Background

A previous trial by the European Osteosarcoma Intergroup (EOI) suggested that a short intensive chemotherapy regimen with doxorubicin 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 undertook 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 doxorubicin 25 mg/m² on days 1–3 and cisplatin 100 mg/m² on day 1) or a multi-drug regimen (preoperatively vincristine, high-dose methotrexate, and doxorubicin; postoperatively bleomycin, cyclophosphamide, dactinomycin, 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 and progression-free survival were by intention to treat.

Findings

Of 407 randomised patients, 391 were eligible and have been followed up for at least 4 years (median 5–6 years). Toxic effects were qualitatively similar with the two regimens. However, 188 (94%) of 199 patients completed 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 regimens 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% Cl 0·69–1·27]). Progression-free survival at 5 years was 44% in both groups (hazard ratio 1·01 [0·77–1·33]).

Interpretation

We found no difference in survival between the two-drug and multi-drug regimens in operable, non-metastatic osteosarcoma. The two-drug regimen is shorter in duration 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 results.

Introduction

Although the survival of patients with operable osteosarcoma is improved by chemotherapy,1, 2 the optimum duration of treatment and the relative contributions of the constituent drugs have not been assessed in randomised trials. Such assessments are difficult in this rare disease, which each year affects only 1 in 200 000 of the population. The European Osteosarcoma Intergroup (EOI) was formed in 1982 to carry out randomised studies of sufficient size to allow investigation of important features of treatment. In the first EOI trial,³ 307 patients with osteosarcoma were randomly assigned one of two regimens of chemotherapy; a regimen of cisplatin and doxorubicin, given before and after surgery for a total of six cycles to patients with operable non-metastatic osteosarcoma, produced 5-year survival of 64% and progression-free survival of 57%. These results were similar with those of trials2, 4 in which chemotherapy was based on the T10 regimen introduced by Rosen et al.⁵

The T10 regimen has been the basis of much osteosarcoma chemotherapy. A report of the results of this and other similar regimens used at the Memorial Sloan-Kettering Cancer Centre showed that 65% of 279 patients were alive and free of disease at 8 years.⁶ Non-randomised studies of treatment do not allow an unbiased comparison of treatment outcomes. For this reason, the EOI undertook a formal comparison of a 44-week multi-drug T10-based regimen (multi-drug) with the 18-week cisplatin and doxorubicin (two-drug) regimen (the more effective of the two treatments compared previously in an EOI trial³). The primary hypothesis was that a short, two-drug regimen would produce equivalent survival to a long multi-drug regimen.