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

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 Multiforme1

Departments of Neuro-Oncology [V. A. L., J. H. U., K. A. J., W. K. A. Y., A. P. K., M. J. G.], Pathology, Section of Neuropathology [J. M. B.], and Biomathematics [K. R. H.], University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030; Marshfield Clinic, Marshfield, Wisconsin 54449-5777 [A. C.]; Metro-Minnesota, Community Cancer Oncology Program, St. Louis Park, Minnesota 55416 [P. J. F.]; and University of California, San Francisco, Neuro-Oncology Services, San Francisco, California 94143-0372 [M. D. P., S. M. C.]

Abstract

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/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; 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.

Footnotes

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵1 Supported in part by NIH Grant CA55261.
↵2 To whom requests for reprints should be addressed, at Department of Neuro-Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 100, Houston, Texas 77030. Phone: (713) 792-8297; Fax: (713) 794-4999; E-mail: vlevin{at}mdanderson.org
↵3 Present address: Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905.
↵4 The abbreviations used are: DFMO,α -difluoromethylornithine (eflornithine); CCNU, N-(2-chloroethyl)-N′-cyclohexyl-N-nitrosurea; PCV, procarbazine, CCNU, vincristine; GBM, glioblastoma multiforme; ODC, ornithine decarboxylase; MTP, median-time(s)-to-tumor progression; MS, median survival; KPS, Karnofsky performance status; BCNU, 1,3-bis(2-chloroethyl)-1-nitrosurea, MDACC, M. D. Anderson Cancer Center; CI, confidence interval; MRI, magnetic resonance imaging; CT, computed tomography; NCI, National Cancer Institute; CR, complete response; PR, partial response; MR, minor response.
↵5 Eflornithine, dl-α-difluoromethyl-2,5-diaminopentanoic acid hydrochloride, monohydrate.
- Accepted July 13, 1900.
- Received March 30, 1900.
- Revision received July 10, 1900.