Toxicity and Efficacy of Carboplatin and Etoposide in Conjunction with Disruption of the Blood-Brain Tumor Barrier in the Treatment of Intracranial Neoplasms

Abstract

CARBOPLATIN AND ETOPOSIDE have been investigated in preclinical studies and a limited toxicity study in 13 patients; these studies have established carboplatin and etoposide as a tolerable combination when administered with blood-brain barrier disruption. The studies also found a predictable dose-limiting toxicity of myelosuppression. Subsequently, a broad efficacy trial of this regimen was carried out. A total of 34 patients, ranging in age from 7 to 72 years, underwent a combination chemotherapy regimen of carboplatin (200 mg/m2 administered intra-arterially) and etoposide (200 mg/m2 administered intravenously) administered with blood-brain barrier disruption on each of 2 consecutive days every 28 days. The diagnoses included glioblastoma multiforme (n = 3), malignant astrocytoma (n = 8), malignant astrocytoma-oligodendroglioma (n = 1), primitive neuroectodermal tumor (n = 4), disseminated germ cell tumor of the central nervous system (CNS) (n = 6), CNS lymphoma (n = 7), and metastatic carcinoma (n = 5). The major toxicity observed in patients treated with multiple courses of this regimen was the expected reversible myelosuppression and an unexpected, irreversible high-frequency hearing loss. Of these 34 patients, 22 had measurable disease, and 9 radiographic responses (50% or more decrease in enhancing tumors) were observed in these patients. Carboplatin and etoposide with blood-brain barrier disruption is an active regimen in the treatment of malignant astrocytomas and has shown dramatic responses in primitive neuroectodermal tumors and CNS lymphoma. Additionally, the durability of responses in patients with disseminated CNS germ cell tumors is encouraging. However, such therapy is associated with unexpected high-frequency hearing loss; even so, on the basis of the favorable responses in patients with primitive neuroectodermal tumors, germ cell tumors, and lymphomas, the study of this regimen for those tumors is being extended in a multiinstitutional trial that also includes cytoxan to further evaluate the potential enhanced drug delivery.

Recent Advances in Blood–Brain Barrier Disruption as a CNS Delivery Strategy

“…The procedure has been applied in the treatment of different brain tumor types. Williams et al reported on the use of BBBD in conjunction with a regimen composed of intra-arterial carboplatin and intra-venous etoposide in 34 patients with various histologies (57). Of these 34 patients, 22 had measurable disease, and nine radiographic responses (50% or more decrease in enhancing tumors) were observed in these patients.…”

Novel Drug Delivery Strategies in Neuro-Oncology

“…Animal studies suggest that this method is able to increase concentrations of chemotherapeutic agents in the brain parenchyma up to 90-fold. 8 Methotrexate delivery to CNS is enhanced four-to seven-fold when administered IA after osmotic BBB disruption compared with IA administration without blood brain barrier disruption (BBBD). 9 The ability of BBBD to improve therapeutic efficacy of chemotherapy has been variable in humans.…”

<i>D</i>-Methionine Attenuates Inner Hair Cell Loss in Carboplatin-Treated Chinchillas

“…However, some cancer treatment regimens require doses of carboplatin high enough to be ototoxic to humans [Kennedy et al, 1990]. Highfrequency hearing loss has been reported in many patients receiving carboplatin for malignant brain tumors [Williams et al, 1995]. Thus, methods of preventing carboplatin ototoxicity could improve its clinical efficacy, and enhance the quality of life for patients.…”