A phase 3 randomized study of radiotherapy plus procarbazine, CCNU, and vincristine (PCV) with or without BUdR for the treatment of anaplastic astrocytoma: A preliminary report of RTOG 9404

Purpose: This study was an open label, randomized Phase 3 trial in newly di agnosed patients with anaplastic glioma comparing radiotherapy plus adjuvan t procarbazine, CCNU, and vincristine (PCV) chemotherapy with or without br omodeoxyuridine (BUdR) given as a 96-hour infusion each week of radiotherap y. Methods and Materials: Only patients 18 years or older with newly diagnosed anaplastic glioma were eligible; central pathology review was accomplished , but was not mandated prior to registration. The study had initially opene d as a Northern California Oncology Group (NCOG) trial in 1991, becoming an Intergroup RTOG, SWOG, and NCCTG study in July 1994. Total accrual of 293 patients was planned as the sample size, using survival and time to tumor p rogression as the primary endpoints. The experiment arm (RT/BUdR plus PCV) was to be compared to the control arm (RT plus PCV) using an alpha = 0.05, one-tailed, with a power of 85% for detecting an increase in median surviva l from 160 to 240 weeks, assuming a 3-year follow-up after completion of en rollment. Results: As of July 1996, 281 patients had been randomized; 53 (20%) were i neligible, primarily based upon central pathology review, and another 39 ca ses were canceled. In total, 30% of cases were excluded from analysis. The treatment arms were well balanced despite this rate of exclusion. The RTOG Data Monitoring Committee recommended suspension of enrollment in July 1996 based upon a stochastic curtailment analysis which strongly suggested that the addition of BUdR would not be associated with increased survival. In F ebruary 1997, the study was closed prior to full enrollment. At that time, the 1-year survival estimates were 82% versus 68% for RT plus PCV and RT/BU dR plus PCV respectively (one-sided, p = 0.96). The conditional power analy sis indicated that even with an additional 12 months of additional accrual and follow-up the probability of detecting the prespecified difference was less than 0.01%. The differences in the two arms seem td be due to early de aths in the BUdR arm, not related to toxicity of the treatment. Conclusions: Despite encouraging Phase 2 results with BUdR, it is unlikely that a survival benefit will be seen. A final study analysis will not be do ne for at least 3 more years. (C) 1999 Elsevier Science Inc.