Radiation therapy and hydroxyurea followed by
the combination of 6-thioguanine and BCNU for the treatment of primary malignant
Prados MD, Larson DA, Lamborn K, McDermott MW, Sneed PK, Wara WM, Chang SM,
Mack EE, Krouwer HG, Chandler KL, Warnick RE, Davis RL, Rabbitt JE, Malec M,
Levin VA, Gutin PH, Phillips TL, Wilson CB
Department of Neurosurgery, University of California San
Purpose. This study was designed to evaluate a combined modality
treatment for malignant gliomas using radiation therapy with a radiosensitizer
and an adjuvant chemotherapy regimen designed to modify resistance to
and Materials. Patients were eligible if they were 15 years of age or older,
and had newly diagnosed glioblastoma multiforme (GBM), or anaplastic glioma
Treatment consisted of external beam radiotherapy given to a dose of 60 Gy using
a single daily fraction Monday to Friday.
Concurrent hydroxyurea at a dose of 300 mg/m2 every 6 h every other day was
given during radiation.
Following radiotherapy, patients were then treated with BCNU and 6-Thioguanine
The 6-TG was given by mouth every 6 h for 12 doses prior to BCNU.
Patients were initially treated with 60 mg/m2/dose of 6TG, with escalation to a
maximum dose of 100 mg/m2/dose.
The primary study end points were time to tumor progression and survival.
A total of 245 eligible patients were enrolled from 1/18/88 to 12/26/91.
The histologic subtypes included 135 GBM, and 110 with AG (103 with anaplastic
astrocytoma, 7 with high-grade mixed oligoastrocytoma).
For the GBM group, the median time to tumor progression (TTP) and median
survival were 33 (95% CI 26, 39) and 56 (95% CI 49, 69) weeks,
For the AG group the median TTP was 282 weeks (95% lower confidence bound = 155
Median survival for this group has not been reached (95% lower confidence bound
= 284 weeks) with a median follow-up for surviving patients of 298 weeks.
A proportional hazards model was used to look at potential prognostic factors
for survival, including initial Karnofsky Performance Scale (KPS), age, and
extent of surgery, as well as dose of 6TG.
Higher KPS, and lower age, predicted for longer survival (p < 0.01, <
0.001) in GBM patients; lower age was significant (p = 0.05) for AG cases.
A higher (greater than 95 mg/m2) or lower dose of 6TG was not statistically
significant in this model.
This therapy was no more effective in patients with GBM than other reported
In patients with malignant gliomas other than GBM, prolonged progression-free
and overall survival is noted, without a median survival reached at the time of
In this subset of AG patients, survival is comparable to recent studies using
halogenated prymidines during radiation and Procarbazine, CCNU, and Vincristine
(PCV) as adjuvant chemotherapy.
PMID: 9422558 [PubMed - indexed for MEDLINE]