Phase III Randomized Study of Postradiotherapy Chemotherapy with α-Difluoromethylornithine-Procarbazine, N-(2-Chloroethyl)-N′-cyclohexyl-N-nitrosurea, Vincristine (DFMO-PCV) Versus PCV for Glioblastoma Multiforme
2000
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 α-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 post-radiation therapy setting. Following conventional radiation therapy, 272 glioblastoma (GBM)
patients were randomized to receive eitherα
-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/m 2 p.o. q8h for 14 days before and after treatment with
N -(2-chloroethyl)- N -cyclohexyl- N -nitrosurea;
PCV was administered as previously described 1 . 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; PCV, 11.1; MTP (months):
DFMO-PCV, 4.6; PCV, 4.4]. 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.
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