Although the efficacy of the nitrosourea-based
combination chemotherapy procarbazine, N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosurea, and
vincristine (PCV) has been previously demonstrated in the setting of anaplastic/intermediate-grade
gliomas, the benefit for
glioblastoma patients remains unproven. In the current study, we sought to determine whether the addition of
alpha-difluoromethylornithine (
eflornithine), an inhibitor of
ornithine decarboxylase, which has shown encouraging results in the setting of recurrent
glioma patients, to a nitrosourea-based
therapy (PCV) would constitute a more effective adjuvant
therapy in the treatment of
glioblastoma multiforme patients in the postradiation
therapy setting. Following conventional
radiation therapy, 272
glioblastoma (GBM) patients were randomized to receive either
alpha-difluoromethylornithine-PCV (DFMO-PCV; 134 patients) or PCV alone (138 patients), with survival and time to
tumor progression being the primary endpoints. The starting dosage of DFMO was 3.0 g/m2 p.o. q8h for 14 days before and
after treatment with N-(2-chloroethyl)-N-cyclohexyl-N-nitrosurea; PCV was administered as previously described1. Clinical and radiological (
Gadolinium-enhanced MRI) follow-ups were 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 effects were at 2 week intervals. There was no difference in median survival or median time-to-
tumor progression between the two treatment groups, as measured from day of commencement of postradiotherapy
chemotherapy [MS (months): DFMO-PCV, 10.5; Overall survival, as measured from time of
tumor diagnosis at first surgery, was 13.3 and 14.2 months at the median and 6.2 and 8.7% at 5 years, respectively, for the DFMO-PCV and PCV arms. 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 consisted of gastrointestinal (
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, underscoring the resistance of
glioblastoma multiforme tumors to
alkylating agents. For patients with anaplastic (intermediate grade)
gliomas, in which the previously demonstrated benefit of post-radiation
chemotherapy is more substantial, the evaluation of DFMO-PCV vs. PCV is still ongoing and hopefully will yield more encouraging results.