Temozolomide versus procarbazine, lomustine, and vincristine in recurrent high-grade glioma.
OBJECTIVE
Temozolomide (TMZ) is an alkylating agent licensed for treatment of high-grade glioma (HGG). No prospective comparison with nitrosourea-based chemotherapy exists. We report, to our knowledge, the first randomized trial of procarbazine, lomustine, and vincristine (PCV) versus TMZ in chemotherapy-naive patients with recurrent HGG.


METHODS
Four hundred forty-seven patients were randomly assigned to PCV (224 patients) or TMZ (sub-random assignment: TMZ-5 [200 mg/m(2) for 5 days, 112 patients] or TMZ-21 [100 mg/m(2) for 21 days, 111 patients]) for up to 9 months or until progression. The primary outcomes were survival (PCV v TMZ) and 12-week progression-free survival (PFS; TMZ-5 v TMZ-21). This study is registered as ISRCTN83176944.


RESULTS
Percentages of patients completing 9 months of treatment in the PCV, TMZ-5, and TMZ-21 arms were 17%, 26%, and 13%, respectively. Major toxicity was similar across all three groups. With a median follow-up time of 12 months and 382 deaths, there was no clear survival benefit when comparing PCV with TMZ (hazard ratio [HR], 0.91; 95% CI, 0.74 to 1.11; P = .350). For TMZ-5 versus TMZ-21, 12-week PFS rates were similar (63.6% and 65.7%, respectively; P = .745), but TMZ-5 improved overall PFS (HR, 1.38; 95% CI, 1.05 to 1.82; P = .023), survival (HR, 1.32; 95% CI, 0.99 to 1.75; P = .056), and global quality of life (49% v 19% improved > 10 points at 6 months, respectively; P = .005).


CONCLUSIONS
Although TMZ (both arms combined) did not show a clear benefit compared with PCV, comparison of the TMZ schedules demonstrated that the 21-day schedule was inferior to the 5-day schedule in this setting. This challenges the current understanding of increasing TMZ dose-intensity by prolonged scheduling.
Brada
Michael
M
The Institute of Cancer Research and The Royal Marsden National Health Service Foundation Trust, Sutton, Surrey, United Kingdom. Michael.Brada@icr.ac.uk
Stenning
Sally
S
Gabe
Rhian
R
Thompson
Lindsay C
LC
Levy
David
D
Rampling
Roy
R
Erridge
Sara
S
Saran
Frank
F
Gattamaneni
Rao
R
Hopkins
Kirsten
K
Beall
Sarah
S
Collins
V Peter
VP
Lee
Siow-Ming
SM
D000328:Adult; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D016009:Chi-Square Distribution; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D006801:Humans; D053208:Kaplan-Meier Estimate; D008130:Lomustine / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011344:Procarbazine / Q000008:administration & dosage / Q000009:adverse effects; D016016:Proportional Hazards Models; D011788:Quality of Life; D012008:Recurrence; D018570:Risk Assessment; D012307:Risk Factors; D000077204:Temozolomide; D013997:Time Factors; D016896:Treatment Outcome; D006113:United Kingdom; D014750:Vincristine / Q000008:administration & dosage / Q000009:adverse effects
D018906:Antineoplastic Agents, Alkylating; D011344:Procarbazine; D014750:Vincristine; D008130:Lomustine; D003606:Dacarbazine; D000077204:Temozolomide