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Received Dose and Dose-Intensity of Chemotherapy and Outcome in Nonmetastatic Extremity Osteosarcoma

From the St James’s University Hospital, Leeds; Cancer Division, Medical Research Council Clinical Trials Unit, London; and Department of Child Health, University of Newcastle upon Tyne, Newcastle upon Tyne; and United Kingdom Children’s Cancer Study Group, University of Leicester, Leicester, United Kingdom.

Address reprint requests to Simon Weeden, MSc, Cancer Division, Medical Research Council Clinical Trials Unit, 222 Euston Rd, London NW1 2DA, United Kingdom; email sw{at}ctu.mrc.ac.uk

PURPOSE: To examine the relationship between received dose, received dose-intensity (RDI), and survival in patients with osteosarcoma.

PATIENTS AND METHODS: Between 1983 and 1993, the European Osteosarcoma Intergroup (EOI) conducted two randomized trials involving patients with high-grade, nonmetastatic, biopsy-proven osteosarcoma of the extremity. These trials shared a common treatment arm of doxorubicin (DOX) 75 mg/m² and cisplatin (CDDP) 100 mg/m² planned for six cycles at 3-week intervals. Definitive surgery was scheduled at week 9, after three cycles. Survival time was calculated from 122 days, the scheduled end of chemotherapy.

RESULTS: A total of 287 patients randomized to DOX/CDDP received at least one cycle of chemotherapy, and 232 (81%) received all six cycles. On average, 79% of the intended dose of DOX and 80% of the intended dose of CDDP was given. Mean time to completion of chemotherapy was 1.27 times that specified by the protocol. Mean RDI was 0.64 for DOX (SD = 0.19) and 0.65 for CDDP (SD = 0.18). Progression-free survival was lower for those who received one to five cycles compared with those who completed all six cycles (hazards ratio, 1.69; 95% confidence interval, 1.03 to 2.78). Survival and progression-free survival were lowest for patients with RDI less than 0.6, although these differences were not statistically significant at the 5% level. There was no clear evidence of preoperative dose or dose-intensity influencing histologic response.

CONCLUSION: This analysis did not establish a clear survival benefit for increasing received dose or dose-intensity in the context of this two-drug regimen. The hypothesis that increasing dose-intensity may improve survival in osteosarcoma requires prospective evaluation.

The European Osteosarcoma Intergroup consists of the Bone Sarcoma Working Party of the United Kingdom Medical Research Council, the United Kingdom Children’s Cancer Study Group, the Société Internationale d’Oncologie Paedriatrique, and the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group.

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