Treatment > Temozolomide Investigations

Abstract

Temozolomide: A Review of its Use in the Treatment of Malignant Gliomas, Malignant Melanoma and Other Advanced Cancers

M.J.M. Darkes, G.L. Plosker, B. Jarvis

Temozolomide is a cytotoxic prodrug that, when hydrolyzed, inhibits DNA replication by methylating nucleotide bases. In preclinical testing, temozolomide has shown a broad spectrum of antineoplastic activity.
In patients with malignant glioma, the objective response (complete or partial response) rate ranged from 11 to 47% in noncomparative studies. The highest objective response rate was observed in newly diagnosed patients. Progression-free survival (PFS) at 6 months was consistently >20%.
In patients with relapsing anaplastic astrocytoma who were treated with temozolomide, the objective response and 6-month PFS rates ranged from 11 to 35% and 22 to 49%, respectively, in noncomparative studies. All patients with progression-free disease at 6 months had either similar or better scores in the seven health-related quality-of-life (HR-QOL) domains when compared with baseline. In contrast, patients with disease progression reported statistically significant deterioration in five of seven domain scores at 6 months. Of the patients with an objective response, 92 and 82% of those achieved an HR-QOL response in one or more and three or more domains, respectively.
In patients with glioblastoma multiforme, temozolomide produced a greater 6-month PFS rate than that of patients who were treated with procarbazine (21 vs 8%) in a randomized, multicenter study. Survival at 6 months was also greater in the temozolomide-treated group (60 vs 44%). Moreover, the temozolomide-treated population scored consistently higher in all HR-QOL domains measured.
In a randomized phase III trial involving patients with advanced malignant melanoma, temozolomide produced an objective response rate of 13.5% compared with 12.1% in the dacarbazine group. Temozolomide produced a modest increase in PFS time compared with dacarbazine (1.9 vs 1.5 months). There was a statistically significant difference in favor of the temozolomide-treated group in the physical functioning and cognitive functioning domains.
Temozolomide produced low objective response rates in patients with advanced soft tissue sarcoma, non-Hodgkin's lymphoma, hormone-refractory prostate cancer, pancreatic cancer, advanced nasopharyngeal carcinoma and brain metastases in small noncomparative trials.
Temozolomide is generally well tolerated. Mild to moderate myelosuppression is the primary dose-limiting adverse effect of temozolomide, which is reversible and noncumulative. Nausea and vomiting, although common, are usually mild.
Conclusion: Temozolomide has demonstrated similar clinical responses to procarbazine and dacarbazine in malignant glioma and melanoma, respectively. Although initial studies have not demonstrated an overall survival advantage associated with temozolomide in either disease, the drug has demonstrated clinically significant HR-QOL benefits when compared with either procarbazine or dacarbazine. The favorable HR-QOL scores confirm its acceptable tolerability profile. Temozolomide's oral formulation allows patients to be treated in the home setting.