Introduction: Glioblastoma (GBM), the most aggressive and common brain tumor in adults, is uniquely resistant to therapies and is highly invasive. Local delivery of therapeutics was developed as a strategy to increase intratumoral concentration of cytotoxic agents. A novel polymer with zero-order release kinetics was loaded with bis-chloroethylnitrosourea (BCNU) and temozolomide (TMZ) and tested in vivo (1, 2).
Methods: Female F344 rats (n=45) were intracranially implanted with 9L gliosarcoma. Five days later animals were randomized to receive an intracranial implantation of an empty blank polymer, BCNU polymer, TMZ polymer, BCNU-TMZ polymer, or oral TMZ, 50 mg/kg (qd, Days 5-9). We compared these results with those obtained from an untreated control group. A group that received the blank polymer was included to investigate this new polymer for toxicities and adverse events. Brain samples were analyzed for tumor growth and inflammation.
Results: Oral TMZ and polymers loaded with BCNU and TMZ resulted in a significant increase in median survival as compared to controls. Animals with the BCNU/TMZ polymer had a stronger benefit. The gradual release of therapeutics exposed malignant cells to effective cytotoxic levels of therapeutics for a londer period of time, hampering tumor proliferation and invasion. No evidence of local or systemic toxicity was found, and wafers were eroded by the end of the study.
Conclusions: Local chemotherapy is an efficient and safe strategy for targeting glioblastoma. This new formulation addressed combination therapy capable of overcoming mechanisms of mutation typical of these tumors, resulted in significantly prolonging survival in this animal model. The formulation of this polymeric wafer actively supported the efficacy of TMZ and BCNU by releasing these therapeutics in a gradual and temporal fashion. Further studies are needed to assess the clinical role of this promising polymeric matrix, possibly adding a valuable tool to the neurosurgeon’s armamentarium.
Patient Care: TMZ-BCNU combination therapy overcomes resistances to chemotherapy and allows a longer survival benefit than single-agent therapies, while zero-order kinetics polymers guarantee a more constant release of cytotoxic agents.
Learning Objectives: By the conclusion of this session, participants should be able to: 1) Describe the importance of polymers with zero-order release kinetics, 2) Discuss, in small groups, the beneficial synergistic effect of Temozolamide and Camurstine, 3) Identify an effective treatment for resistant high-grade gliomas.
References: (1) Pan E et al., A retrospective study of the safety of BCNU wafers with concurrent temozolomide and radiotherapy and adjuvant temozolomide for newly diagnosed glioblastoma patients. Journal of Neuro-oncology 88(3):353-357, (2008).
(2) LaRocca RV et al. A phase II study of radiation with concomitant and then sequential temozolomide (TMZ) in patients with newly diagnosed supratentorial high-grade malignant glioma who have undergone surgery with carmustine (BCNU) wafer insertion (abstract TA-28). Neurooncology 8:445, (2006).