Phase III randomized study of postradiotherapy chemotherapy with combination α-difluoromethylornithine-PCV versus PCV for anaplastic gliomas

Victor A. Levin, Kenneth R. Hess, Ali Choucair, Patrick J. Flynn, Kurt Jaeckle, Athanassios P. Kyritsis, W. K.Alfred Yung, Michael D. Prados, Janet M. Bruner, Sandra Ictech, Mary Jo Gleason, Hyung Woo Kim

Research output: Contribution to journalArticle

94 Citations (Scopus)

Abstract

Purpose: In the current study, we sought to determine whether the addition of DFMO (α-difluoromethyl ornithine; eflornithine), an inhibitor of ornithine decarboxylase, to a nitrosourea-based therapy procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, vincristine (PCV) would be more effective as a postirradiation adjuvant therapy for anaplastic gliomas (AG) than PCV alone. Patients and Methods: After conventional radiation therapy, 249 AG patients were randomized to receive either DFMO-PCV (125 patients) or PCV alone (124 patients), with survival being the primary endpoint and progression-free survival being an important secondary endpoint. The starting dosage of DFMO was 3 grams/m2 p.o.q. 8 h for 14 days before and 4 weeks after 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea; PCV was administered as described previously (1). Clinical and radiological (gadolinium-enhanced magnetic resonance imaging) 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 hematological and other adverse effects were at 2-week intervals. Results: In the DFMO-PCV arm, there were 114 evaluable patients with 78.1% anaplastic astrocytoma (AA), 3.5 % anaplastic oligoastrocytoma (AOA), 14% anaplastic oligodendroglioma (AO), and 4.4% other malignant gliomas. These histological groupings were comparable with those of the 114 patients in the PCV arm: (a) 69.3% AA; (b) 7% AOA; (c) 21.1% AO; and (d) 2.6% malignant gliomas. Although improved survival estimates for the DFMO-PCV treatment group persisted over the course of the study, analysis of survival differences over the entire follow-up period did not yield significance (P = 0.11). However, careful analysis of the corresponding hazard and hazard ratio functions indicated that the real treatment difference was limited to the first 24 months of follow-up (P = 0.02). The median progression-free survival for the two treatment groups, as measured from postradiotherapy registration, was 71.1 months for the DFMO-PCV arm and 37.5 months for the PCV-only arm. Median survival, measured from registration, was 75.8 and 61.1 months, respectively, for the DFMO-PCV and PCV arms. The treatment effect persisted when the AA histology was separated from AO and AOA histologies. This effect persisted even after adjusting for the covariates of age, Karnofsky performance status, and extent of surgery. There was a statistically significant increase in grade 3 adverse events for diarrhea and anemia associated with DFMO-PCV. Grade 3 or 4 adverse events of nausea, ototoxicity, and thrombocytopenia were not significantly increased among groups. Conclusions: The addition of DFMO to the nitrosourea-based PCV regimen in this Phase III study demonstrated a sustained benefit in survival probabilities for AG patients but not in the corresponding hazard rates. Survival analysis from registration found a DFMO-PCV median survival of 6.3 years (49 of 114 events), whereas that for PCV alone was 5.1 years (55 of 114 events). The hazard function demonstrated a difference over the first 2 years of study (hazard ratio 0.53, P = 0.02) but not after 2 years (hazard ratio 1.06, P = 0.84), supporting the conclusion that DFMO adds to the survival advantage of PCV chemotherapy for AG patients by direct temporal interaction with PCV.

Original languageEnglish (US)
Pages (from-to)981-990
Number of pages10
JournalClinical Cancer Research
Volume9
Issue number3
StatePublished - Mar 1 2003

Fingerprint

Eflornithine
Combination Drug Therapy
Glioma
Oligodendroglioma
Survival
Astrocytoma
Survival Analysis
Disease-Free Survival
Histology
Therapeutics
Procarbazine
Karnofsky Performance Status
Ornithine
Gadolinium
Vincristine
Thrombocytopenia
Nausea
Anemia
Diarrhea
Radiotherapy

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Levin, V. A., Hess, K. R., Choucair, A., Flynn, P. J., Jaeckle, K., Kyritsis, A. P., ... Kim, H. W. (2003). Phase III randomized study of postradiotherapy chemotherapy with combination α-difluoromethylornithine-PCV versus PCV for anaplastic gliomas. Clinical Cancer Research, 9(3), 981-990.
Levin, Victor A. ; Hess, Kenneth R. ; Choucair, Ali ; Flynn, Patrick J. ; Jaeckle, Kurt ; Kyritsis, Athanassios P. ; Yung, W. K.Alfred ; Prados, Michael D. ; Bruner, Janet M. ; Ictech, Sandra ; Gleason, Mary Jo ; Kim, Hyung Woo. / Phase III randomized study of postradiotherapy chemotherapy with combination α-difluoromethylornithine-PCV versus PCV for anaplastic gliomas. In: Clinical Cancer Research. 2003 ; Vol. 9, No. 3. pp. 981-990.
@article{8179ed6e98c446348029ed1c4088fc19,
title = "Phase III randomized study of postradiotherapy chemotherapy with combination α-difluoromethylornithine-PCV versus PCV for anaplastic gliomas",
abstract = "Purpose: In the current study, we sought to determine whether the addition of DFMO (α-difluoromethyl ornithine; eflornithine), an inhibitor of ornithine decarboxylase, to a nitrosourea-based therapy procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, vincristine (PCV) would be more effective as a postirradiation adjuvant therapy for anaplastic gliomas (AG) than PCV alone. Patients and Methods: After conventional radiation therapy, 249 AG patients were randomized to receive either DFMO-PCV (125 patients) or PCV alone (124 patients), with survival being the primary endpoint and progression-free survival being an important secondary endpoint. The starting dosage of DFMO was 3 grams/m2 p.o.q. 8 h for 14 days before and 4 weeks after 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea; PCV was administered as described previously (1). Clinical and radiological (gadolinium-enhanced magnetic resonance imaging) 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 hematological and other adverse effects were at 2-week intervals. Results: In the DFMO-PCV arm, there were 114 evaluable patients with 78.1{\%} anaplastic astrocytoma (AA), 3.5 {\%} anaplastic oligoastrocytoma (AOA), 14{\%} anaplastic oligodendroglioma (AO), and 4.4{\%} other malignant gliomas. These histological groupings were comparable with those of the 114 patients in the PCV arm: (a) 69.3{\%} AA; (b) 7{\%} AOA; (c) 21.1{\%} AO; and (d) 2.6{\%} malignant gliomas. Although improved survival estimates for the DFMO-PCV treatment group persisted over the course of the study, analysis of survival differences over the entire follow-up period did not yield significance (P = 0.11). However, careful analysis of the corresponding hazard and hazard ratio functions indicated that the real treatment difference was limited to the first 24 months of follow-up (P = 0.02). The median progression-free survival for the two treatment groups, as measured from postradiotherapy registration, was 71.1 months for the DFMO-PCV arm and 37.5 months for the PCV-only arm. Median survival, measured from registration, was 75.8 and 61.1 months, respectively, for the DFMO-PCV and PCV arms. The treatment effect persisted when the AA histology was separated from AO and AOA histologies. This effect persisted even after adjusting for the covariates of age, Karnofsky performance status, and extent of surgery. There was a statistically significant increase in grade 3 adverse events for diarrhea and anemia associated with DFMO-PCV. Grade 3 or 4 adverse events of nausea, ototoxicity, and thrombocytopenia were not significantly increased among groups. Conclusions: The addition of DFMO to the nitrosourea-based PCV regimen in this Phase III study demonstrated a sustained benefit in survival probabilities for AG patients but not in the corresponding hazard rates. Survival analysis from registration found a DFMO-PCV median survival of 6.3 years (49 of 114 events), whereas that for PCV alone was 5.1 years (55 of 114 events). The hazard function demonstrated a difference over the first 2 years of study (hazard ratio 0.53, P = 0.02) but not after 2 years (hazard ratio 1.06, P = 0.84), supporting the conclusion that DFMO adds to the survival advantage of PCV chemotherapy for AG patients by direct temporal interaction with PCV.",
author = "Levin, {Victor A.} and Hess, {Kenneth R.} and Ali Choucair and Flynn, {Patrick J.} and Kurt Jaeckle and Kyritsis, {Athanassios P.} and Yung, {W. K.Alfred} and Prados, {Michael D.} and Bruner, {Janet M.} and Sandra Ictech and Gleason, {Mary Jo} and Kim, {Hyung Woo}",
year = "2003",
month = "3",
day = "1",
language = "English (US)",
volume = "9",
pages = "981--990",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "3",

}

Levin, VA, Hess, KR, Choucair, A, Flynn, PJ, Jaeckle, K, Kyritsis, AP, Yung, WKA, Prados, MD, Bruner, JM, Ictech, S, Gleason, MJ & Kim, HW 2003, 'Phase III randomized study of postradiotherapy chemotherapy with combination α-difluoromethylornithine-PCV versus PCV for anaplastic gliomas', Clinical Cancer Research, vol. 9, no. 3, pp. 981-990.

Phase III randomized study of postradiotherapy chemotherapy with combination α-difluoromethylornithine-PCV versus PCV for anaplastic gliomas. / Levin, Victor A.; Hess, Kenneth R.; Choucair, Ali; Flynn, Patrick J.; Jaeckle, Kurt; Kyritsis, Athanassios P.; Yung, W. K.Alfred; Prados, Michael D.; Bruner, Janet M.; Ictech, Sandra; Gleason, Mary Jo; Kim, Hyung Woo.

In: Clinical Cancer Research, Vol. 9, No. 3, 01.03.2003, p. 981-990.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Phase III randomized study of postradiotherapy chemotherapy with combination α-difluoromethylornithine-PCV versus PCV for anaplastic gliomas

AU - Levin, Victor A.

AU - Hess, Kenneth R.

AU - Choucair, Ali

AU - Flynn, Patrick J.

AU - Jaeckle, Kurt

AU - Kyritsis, Athanassios P.

AU - Yung, W. K.Alfred

AU - Prados, Michael D.

AU - Bruner, Janet M.

AU - Ictech, Sandra

AU - Gleason, Mary Jo

AU - Kim, Hyung Woo

PY - 2003/3/1

Y1 - 2003/3/1

N2 - Purpose: In the current study, we sought to determine whether the addition of DFMO (α-difluoromethyl ornithine; eflornithine), an inhibitor of ornithine decarboxylase, to a nitrosourea-based therapy procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, vincristine (PCV) would be more effective as a postirradiation adjuvant therapy for anaplastic gliomas (AG) than PCV alone. Patients and Methods: After conventional radiation therapy, 249 AG patients were randomized to receive either DFMO-PCV (125 patients) or PCV alone (124 patients), with survival being the primary endpoint and progression-free survival being an important secondary endpoint. The starting dosage of DFMO was 3 grams/m2 p.o.q. 8 h for 14 days before and 4 weeks after 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea; PCV was administered as described previously (1). Clinical and radiological (gadolinium-enhanced magnetic resonance imaging) 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 hematological and other adverse effects were at 2-week intervals. Results: In the DFMO-PCV arm, there were 114 evaluable patients with 78.1% anaplastic astrocytoma (AA), 3.5 % anaplastic oligoastrocytoma (AOA), 14% anaplastic oligodendroglioma (AO), and 4.4% other malignant gliomas. These histological groupings were comparable with those of the 114 patients in the PCV arm: (a) 69.3% AA; (b) 7% AOA; (c) 21.1% AO; and (d) 2.6% malignant gliomas. Although improved survival estimates for the DFMO-PCV treatment group persisted over the course of the study, analysis of survival differences over the entire follow-up period did not yield significance (P = 0.11). However, careful analysis of the corresponding hazard and hazard ratio functions indicated that the real treatment difference was limited to the first 24 months of follow-up (P = 0.02). The median progression-free survival for the two treatment groups, as measured from postradiotherapy registration, was 71.1 months for the DFMO-PCV arm and 37.5 months for the PCV-only arm. Median survival, measured from registration, was 75.8 and 61.1 months, respectively, for the DFMO-PCV and PCV arms. The treatment effect persisted when the AA histology was separated from AO and AOA histologies. This effect persisted even after adjusting for the covariates of age, Karnofsky performance status, and extent of surgery. There was a statistically significant increase in grade 3 adverse events for diarrhea and anemia associated with DFMO-PCV. Grade 3 or 4 adverse events of nausea, ototoxicity, and thrombocytopenia were not significantly increased among groups. Conclusions: The addition of DFMO to the nitrosourea-based PCV regimen in this Phase III study demonstrated a sustained benefit in survival probabilities for AG patients but not in the corresponding hazard rates. Survival analysis from registration found a DFMO-PCV median survival of 6.3 years (49 of 114 events), whereas that for PCV alone was 5.1 years (55 of 114 events). The hazard function demonstrated a difference over the first 2 years of study (hazard ratio 0.53, P = 0.02) but not after 2 years (hazard ratio 1.06, P = 0.84), supporting the conclusion that DFMO adds to the survival advantage of PCV chemotherapy for AG patients by direct temporal interaction with PCV.

AB - Purpose: In the current study, we sought to determine whether the addition of DFMO (α-difluoromethyl ornithine; eflornithine), an inhibitor of ornithine decarboxylase, to a nitrosourea-based therapy procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, vincristine (PCV) would be more effective as a postirradiation adjuvant therapy for anaplastic gliomas (AG) than PCV alone. Patients and Methods: After conventional radiation therapy, 249 AG patients were randomized to receive either DFMO-PCV (125 patients) or PCV alone (124 patients), with survival being the primary endpoint and progression-free survival being an important secondary endpoint. The starting dosage of DFMO was 3 grams/m2 p.o.q. 8 h for 14 days before and 4 weeks after 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea; PCV was administered as described previously (1). Clinical and radiological (gadolinium-enhanced magnetic resonance imaging) 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 hematological and other adverse effects were at 2-week intervals. Results: In the DFMO-PCV arm, there were 114 evaluable patients with 78.1% anaplastic astrocytoma (AA), 3.5 % anaplastic oligoastrocytoma (AOA), 14% anaplastic oligodendroglioma (AO), and 4.4% other malignant gliomas. These histological groupings were comparable with those of the 114 patients in the PCV arm: (a) 69.3% AA; (b) 7% AOA; (c) 21.1% AO; and (d) 2.6% malignant gliomas. Although improved survival estimates for the DFMO-PCV treatment group persisted over the course of the study, analysis of survival differences over the entire follow-up period did not yield significance (P = 0.11). However, careful analysis of the corresponding hazard and hazard ratio functions indicated that the real treatment difference was limited to the first 24 months of follow-up (P = 0.02). The median progression-free survival for the two treatment groups, as measured from postradiotherapy registration, was 71.1 months for the DFMO-PCV arm and 37.5 months for the PCV-only arm. Median survival, measured from registration, was 75.8 and 61.1 months, respectively, for the DFMO-PCV and PCV arms. The treatment effect persisted when the AA histology was separated from AO and AOA histologies. This effect persisted even after adjusting for the covariates of age, Karnofsky performance status, and extent of surgery. There was a statistically significant increase in grade 3 adverse events for diarrhea and anemia associated with DFMO-PCV. Grade 3 or 4 adverse events of nausea, ototoxicity, and thrombocytopenia were not significantly increased among groups. Conclusions: The addition of DFMO to the nitrosourea-based PCV regimen in this Phase III study demonstrated a sustained benefit in survival probabilities for AG patients but not in the corresponding hazard rates. Survival analysis from registration found a DFMO-PCV median survival of 6.3 years (49 of 114 events), whereas that for PCV alone was 5.1 years (55 of 114 events). The hazard function demonstrated a difference over the first 2 years of study (hazard ratio 0.53, P = 0.02) but not after 2 years (hazard ratio 1.06, P = 0.84), supporting the conclusion that DFMO adds to the survival advantage of PCV chemotherapy for AG patients by direct temporal interaction with PCV.

UR - http://www.scopus.com/inward/record.url?scp=0037342691&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037342691&partnerID=8YFLogxK

M3 - Article

VL - 9

SP - 981

EP - 990

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 3

ER -