PHILADELPHIATemozolomide (Temodar) appears to be an effective,
well-tolerated oral agent in the setting of recurrent malignant
glioma. Further testing is clearly warranted in this patient
population, and it is an attractive candidate to be evaluated in the
adjuvant setting for newly diagnosed patients, said Michael D.
Prados, MD, of the Brain Tumor Research Center, University of
California, San Francisco.
Speaking at the 90th annual meeting of the American Association for
Cancer Research, Dr. Prados reported the results of two major US
phase II multicenter clinical trials. Temozolomide, he
said, is a new orally administered second-generation
imidazotetrazine prodrug with essentially 100% bioavailability. In
preclinical testing, a broad spectrum of activity was noted that was
schedule dependent, with little toxicity.
The studies, Dr. Prados said, enrolled patients with glioblastoma
multiforme or anaplastic astrocytoma at the time of initial relapse
following standard treatment with surgery and external beam
radiotherapy. The primary objective was to evaluate
progression-free survival at 6 months and the safety of the drug
given over 5 days every 4 weeks, he said. Both studies had
quality of life assessments that included the European Organization
for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire
and the Brain Cancer Module 20 (BCM20).
Study C94-091, a multicenter, randomized, open-label phase II study,
compared temozolomide and procarbazine (Matulane) in the treatment of
patients with glioblastoma multiforme at first relapse. It included
225 patients with glioblastoma multiforme who were randomized to
temozolomide or procarbazine. Temozolomide was given orally at 200
mg/m²/day or 150 mg/m²/day if prior chemotherapy had been
given, for 5 days every 28 days. Procarbazine was given orally at 150
mg/m²/day or 125 mg/m²/day if prior chemotherapy had been
given, for 28 days every 56 days.
The results favored temozolomide, Dr. Prados said.
Six-month progression-free survival was significantly higher for
patients who received temozolomide (21%) than for those who received
procarbazine (8%) (P = .008). Median progression-free survival was
12.4 weeks for temozolomide vs 8.32 weeks for procarbazine (P =
.0063). The 6-month overall survival rate also favored temozolomide
(60% vs 44%, P = .019).
Study CI94-123 was a single-arm, multicenter, open-label phase II
trial of temozolomide in patients with anaplastic astrocytoma at
first relapse. Temozolo-mide was given orally at 200 mg/m²/day
or 150 mg/m²/day if prior chemotherapy had been given, for 5
days every 28 days. The intent-to-treat analysis included 162
patients, and the results include all patients enrolled. After
central pathology review, 111 patients were confirmed to have the
Progression-free survival at 6 months, was 46%. Median
progression-free survival was 5.4 months, and 24% of patients
remained progression free at 12 months. The objective response rate
was 35% (8% complete response, 27% partial response), with 27% of
patients achieving a stable disease classification.
In both studies, temozolomide toxicity was acceptable, with
only mild to moderate degrees of severity, Dr. Prados said. In
addition, the maintenance of progression-free survival and objective
response was associated with stable or improved quality of life as
measured by the EORTC QLC-C30 and BCM20 questionnaires.
Ongoing or planned studies of temozolomide in patients with recurrent
malignant gliomas are using the agent in combination with
nitrosoureas, platinum, and other agents. In addition, there are
plans to bring the drug up front in the adjuvant setting with a
large phase III study in newly diagnosed anaplastic
astrocytomas, Dr. Prados said.