Phase III randomized study of postradiotherapy chemotherapy with alpha-difluoromethylornithine-procarbazin N-(2-chloroethyl)-N '-cyclohexyl-N-nitrosurea, vincristine (DFMO-PCV) versus PCV for glioblastoma multiforme

;Although the efficacy of the nitrosourea-based combination chemotherapy pr ocarbazine, N-(2-chloroethyl)-N'-cyclohexryl-N-nitrosurea, and vincristine (PCV) has been previously demonstrated in the setting of anaplastit/interme diate-grade gliomas, the benefit for glioblastoma patients remains unproven , In the current study, we sought to determine whether the addition of alph a-difluoromethylornithine (eflornithine), an inhibitor of ornithine decarbo xyIase, which has shown encouraging results in the setting of recurrent gli oma patients, to a nitrosourea-based therapy (PCV) would constitute a more effective adjuvant therapy in the treatment of glioblastoma multiforme pati ents in the postradiation therapy setting. Following conventional radiation therapy, 272 glioblastoma (GBM) patients w ere randomized to receive either alpha-difluoromethylornifhine-PCV (DFMO-PC V; 134 patients) or PCV alone (138 patients), with survival and time to tum or progression being the primary endpoints, The starting dosage of DFMO was 3.0 g/m(2) p.o. q8bh for 14 days before and after treatment with N-(2-chlo roethyl)-N-cyclohexgl-N-nitrosurea: PCV was administered as previously desc ribed(1). Clinical and radiological (Gadolinium-enhanced MRI) follow-ups we re nominally at the end of each 6 or 8 week cycle (PCV at 6 weeks; DFMO-PCV at 8 weeks), Laboratory evaluations for hematologic and other adverse effe cts were at 2 week intervals, There was no difference in median survival or median time-to-tumor progress ion between the two treatment groups, as measured from day of commencement of postradiotherapy chemotherapy [MS (months): DFMO-PCV, 10.5; PCV, 11.1; M TP (months): DFMO-PCV, 4.6; PCV, 4.4] Overall survival, as measured from ti me of tumor diagnosis at first surgery, was 13.3 and 14.2 months at the med ian and 6.2 and 8.7% at 5 years, respectively, for the DFMO-PCV and PCV arm s. The treatment effect was unchanged after adjustment for age, performance status (KPS), extent of surgery, and other factors using the multivariate Cox proportional hazard model. Adverse effects associated with DFMO consist ed of gastrointestinaI (diarrhea nausea/vomiting), cytopenias, and minimal ototoxicity (limited to tinnitus) at the dose range tested, The addition of DFMO to the nitrosourea-based PCV regimen in this phase III study demonstrated no additional benefit in glioblastoma patients, undersc oring the resistance of glioblastoma multiforme tumors to alkylating agents . For patients with anaplastic (intermediate grade) gliomas, in which the p reviously demonstrated benefit of post-radiation chemotherapy is more subst antial, the evaluation of DEWO-PCV vs. PCV is still ongoing and hopefully w ill yield more encouraging results.