Introduction: Carboplatin is a potent putative anti-glioma agent in vitro. However, when delivered systemically, clinical efficacy is poor due to limited penetration across the blood-brain barrier (BBB). Direct convection-enhanced delivery (CED) of carboplatin has been used to bypass the BBB and successfully treat malignant glioma in rodent models. This phase I clinical trial was conducted to assess the feasibility and safety of CED carboplatin in recurrent malignant glioma patients.
Methods: Cohorts of 3 patients with recurrent WHO grade III or IV glioma were treated with escalating doses of CED carboplatin delivered via catheters (1-2 µg in 54 mL over 72 hours) placed at the time of surgical resection of recurrent tumor. Primary outcome measure was toxicity to establish the maximum tolerated dose (MTD). Secondary outcome measures included overall survival (OS), progression-free survival (PFS) and radiographic correlation.
Results: A total of 7 patients have completed treatment (infusion dose of carboplatin, 1 µg, 1.3 µg, and 2 µg). Total planned volume of infusion was 54 mL for each patient. All patients had previously received surgery and chemoradiation. Histology at treatment include GBM (n = 6) and anaplastic oligodendroglioma (n = 1). Median KPS was 90 (range, 70 to 100) at time of treatment. Median OS was 9.7 months after completion of CED. A single adverse event possibly related to treatment was noted (generalized seizure).
Conclusions: CED of carboplatin is feasible and safe at doses up to 2 microgram in 54 mL over 72 hours in malignant glioma patients. Further studies will determine the maximum tolerate dose and potential efficacy.
Patient Care: Efficacious therapeutic options for recurrent high-grade gliomas are limited, and many systemic treatments are associated with significant toxicities in addition to poor tumor response. Identifying novel delivery methods of chemotherapies that enhance tumor penetration and decrease systemic toxicity is essential for improving patient outcomes after progression and recurrence of their initial tumors. This trial identifies convection-enhanced delivery of carboplatin as a feasible and safe mechanism to achieve these goals and may help others to build on this work.
Learning Objectives: By the conclusion, participants should be able to:
1. Describe the limitations of systemic administration of carboplatin to treat recurrent high-grade gliomas.
2. Describe the aspects of convection-enhanced delivery of carboplatin that help overcome these previously identified limitations.
3. Identify potential future trials and therapies that would expand the use of convection-enhanced delivery of carboplatin in recurrent high-grade gliomas.