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

Victor A. Levin, Joon H. Uhm, Kurt Jaeckle, Ali Choucair, Patrick J. Flynn, W. K.Alfred Yung, Michael D. Prados, Janet M. Bruner, Susan M. Chang, Athanassios P. Kyritsis, Mary Jo Gleason, Kenneth R. Hess

Research output: Contribution to journalArticle

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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 either α-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 described. 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.

Original languageEnglish (US)
Pages (from-to)3878-3884
Number of pages7
JournalClinical Cancer Research
Volume6
Issue number10
StatePublished - Jan 1 2000

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Procarbazine
Eflornithine
Vincristine
Glioblastoma
Drug Therapy
Glioma
Survival
Neoplasms
Radiotherapy
Therapeutics
Tinnitus
Alkylating Agents
Gadolinium
Combination Drug Therapy
Proportional Hazards Models
Nausea
Vomiting
Diarrhea
Radiation

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Levin, Victor A. ; Uhm, Joon H. ; Jaeckle, Kurt ; Choucair, Ali ; Flynn, Patrick J. ; Yung, W. K.Alfred ; Prados, Michael D. ; Bruner, Janet M. ; Chang, Susan M. ; Kyritsis, Athanassios P. ; Gleason, Mary Jo ; Hess, Kenneth R. / 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. In: Clinical Cancer Research. 2000 ; Vol. 6, No. 10. pp. 3878-3884.
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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 either α-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 described. 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.",
author = "Levin, {Victor A.} and Uhm, {Joon H.} and Kurt Jaeckle and Ali Choucair and Flynn, {Patrick J.} and Yung, {W. K.Alfred} and Prados, {Michael D.} and Bruner, {Janet M.} and Chang, {Susan M.} and Kyritsis, {Athanassios P.} and Gleason, {Mary Jo} and Hess, {Kenneth R.}",
year = "2000",
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language = "English (US)",
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pages = "3878--3884",
journal = "Clinical Cancer Research",
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Levin, VA, Uhm, JH, Jaeckle, K, Choucair, A, Flynn, PJ, Yung, WKA, Prados, MD, Bruner, JM, Chang, SM, Kyritsis, AP, Gleason, MJ & Hess, KR 2000, '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', Clinical Cancer Research, vol. 6, no. 10, pp. 3878-3884.

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. / Levin, Victor A.; Uhm, Joon H.; Jaeckle, Kurt; Choucair, Ali; Flynn, Patrick J.; Yung, W. K.Alfred; Prados, Michael D.; Bruner, Janet M.; Chang, Susan M.; Kyritsis, Athanassios P.; Gleason, Mary Jo; Hess, Kenneth R.

In: Clinical Cancer Research, Vol. 6, No. 10, 01.01.2000, p. 3878-3884.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 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

AU - Levin, Victor A.

AU - Uhm, Joon H.

AU - Jaeckle, Kurt

AU - Choucair, Ali

AU - Flynn, Patrick J.

AU - Yung, W. K.Alfred

AU - Prados, Michael D.

AU - Bruner, Janet M.

AU - Chang, Susan M.

AU - Kyritsis, Athanassios P.

AU - Gleason, Mary Jo

AU - Hess, Kenneth R.

PY - 2000/1/1

Y1 - 2000/1/1

N2 - 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 either α-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 described. 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.

AB - 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 either α-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 described. 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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