Dose intensity of chemotherapy for osteosarcoma and outcome in the cooperative osteosarcoma study group (COSS) trials

Background: The prognostic relevance of dose intensity in the treatment of osteosarcoma is still under discussion. The aim of this study was to investigate whether higher dose intensities of chemotherapy correlated with better outcomes. Procedure: This study contains 917 consecutive Cooperative Osteosarcoma Study Group (COSS) patients < 40 years with primary, high-grade central, nonmetastatic osteosarcoma of the extremities, who were in complete remission at least until day 200 after the start of chemotherapy. All COSS-protocols were based on a uniform treatment concept of aggressive polychemotherapy and definitive surgery. Chemotherapy dose intensity in the first 200 days of treatment (DI200) and possible correlations to overall and event-free survival were investigated. The study focused on methotrexate, doxorubicin, cisplatin, and ifosfamide, which are considered to be the most active drugs against osteosarcoma. Multivariate analyses including well-known prognostic factors were added to complete this investigation. Results: Until day 200, patients received 80.7 +/- 26.1 g/m(2) methotrexate (MTX); 242 +/- 69 mg/m(2) doxorubicin (DOX); 324 +/- 133 mg/m(2) cisplatin (DDP); and 13.9 +/- 9.8 g/m(2) ifosfamide (IFO) (mean +/- SD). Median follow-up from day 200 was 6.6 (0.02-22.1) years. There was no correlation between a higher DI200 of any one drug and better outcomes in uni- or multi-variate analyses. Total treatment intensity did not show such correlations either. Conclusions: In an overall setting of intensive multidrug treatment of osteosarcoma, we could not prove that higher dose intensities correlate with better outcomes.