Clin Cancer Res
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Randomized Controlled Trial Comparative Study Clinical Trial
Phase III randomized study of postradiotherapy chemotherapy with alpha-difluoromethylornithine-procarbazine, N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosurea, vincristine (DFMO-PCV) versus PCV for glioblastoma multiforme.
Although the efficacy of the nitrosourea-based combination chemotherapy procarbazine, N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosurea, and vincristine (PCV) has been previously demonstrated in the setting of anaplastic/intermediate-grade gliomas, the benefit for glioblastoma patients remains unproven. In the current study, we sought to determine whether the addition of alpha-difluoromethylornithine (eflornithine), an inhibitor of ornithine decarboxylase, which has shown encouraging results in the setting of recurrent glioma patients, to a nitrosourea-based therapy (PCV) would constitute a more effective adjuvant therapy in the treatment of glioblastoma multiforme patients in the postradiation therapy setting. Following conventional radiation therapy, 272 glioblastoma (GBM) patients were randomized to receive either alpha-difluoromethylornithine-PCV (DFMO-PCV; 134 patients) or PCV alone (138 patients), with survival and time to tumor progression being the primary endpoints. ⋯ The addition of DFMO to the nitrosourea-based PCV regimen in this phase III study demonstrated no additional benefit in glioblastoma patients, underscoring the resistance of glioblastoma multiforme tumors to alkylating agents. For patients with anaplastic (intermediate grade) gliomas, in which the previously demonstrated benefit of post-radiation chemotherapy is more substantial, the evaluation of DFMO-PCV vs. PCV is still ongoing and hopefully will yield more encouraging results.
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Clinical Trial
A phase I and pharmacologic evaluation of the DNA intercalator CI-958 in patients with advanced solid tumors.
5-[(2-Aminoethyl)amino]-2-[2-(diethylamino)ethyl]-2H-[1]benzothiopyra no[4,3,2-cd]-indazol-8-ol trihydrochloride (CI-958) is the most active member of a new class of DNA intercalating compounds, the benzothiopyranoindazoles. Because of its broad spectrum and high degree of activity as well as a favorable toxicity profile in preclinical models, CI-958 was chosen for further development. The Phase I study described here was undertaken to determine the toxicity profile, maximum tolerated dose, and pharmacokinetics of CI-958 given as an i.v. infusion every 21 days. ⋯ The percentage reduction in absolute neutrophil count from baseline was well predicted by AUC using a simple Emax model. The pharmacokinetically guided dose escalation saved five to six dose levels in reaching the maximum tolerated dose compared with a standard dose escalation scheme. This may represent the most successful application to date of this dose escalation technique.
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Intracerebral microinfusion (ICM) is an innovative technique of delivering therapeutic agents throughout large portions of the brain that circumvents the blood-brain barrier, minimizes systemic toxicity, and provides a homogeneous distribution of the infused agent. Temozolomide is a novel methylating agent with proven efficacy against malignant gliomas (MGs) after systemic administration but with dose-limiting myelotoxicity. Because MGs rarely metastasize, systemic drug delivery is unnecessary. ⋯ In addition, overall, 21.7% of rats treated by ICM with temozolomide survived for > 100 days without clinical or histological evidence of tumor. The dose of temozolomide delivered by ICM in this study was limited only by drug solubility, and no neurological or systemic toxicity could be attributed to ICM with temozolomide. Therefore, ICM of temozolomide may offer significant advantages in the treatment of MGs.