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Phase
III randomized study of postradiotherapy chemotherapy with combination
alpha-difluoromethylornithine-PCV versus PCV for anaplastic gliomas
Levin VA, Hess KR, Choucair A, Flynn PJ, Jaeckle KA, Kyritsis AP, Yung WK,
Prados MD, Bruner JM, Ictech S, Gleason MJ, Kim HW
Department of Neuro-Oncology, The University of Texas M.D.
Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
vlevin@mdanderson.org
Purpose. In the current study, we sought to determine whether the
addition of DFMO (alpha-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/m(2) 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.
PMID:
12631596 [PubMed - indexed for MEDLINE]
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