Introduction: Glioblastoma multiforme, a remarkably aggressive brain tumor, is effectively protected by the presence of the blood brain barrier with regards to efficacious systemic delivery of chemotherapuetics (1). To overcome this obstacle, and therefore achieve higher intratumoral concentrations of therapeutics, a novel single thermo-setting biodegradable paste based on poly(lactic-co-glycolic acid)/poly(ethylene glycol) (PLGA/PEG) microparticles has been developed and evaluated in vivo by our group (2). The main advantages of this novel formulation over rigid polymeric discs are its extreme malleability and the optimized adherence to the resection cavity margin, two factors that potentially greatly improve the delivery of chemotherapeutics to diffuse malignant glioma cells in the brain parenchyma.

Methods: 70 F344 rats were implanted with intracranial 9L gliosarcoma, assigned to ten cohorts, randomized and treated at day 5 with different combinations of surgery, radiation therapy, oral temozolamide (TMZ) and intracranial administration of a PLGA/PEG paste containing either TMZ, etoposide (ETOP) or a combination of these molecules. Long-term survivors were euthanised at day 120, and histologic evaluation was performed.

Results: Animals treated with ETOP paste or a combination of surgery/radiation therapy/TMZ-ETOP paste achieved the most remarkable increase in terms of median and overall survival when compared to controls and rats treated with surgery/blank polymer, surgery/oral TMZ, surgery/XRT, surgery/XRT/oral TMZ, surgery/ETOP-TMZ paste, surgery/TMZ paste and surgery/XRT/oral TMZ/TMZ-ETOP paste. Long-term survival (over 120 days from tumor implantation) was reached in more than 57% of the animals implanted with the combination of TMZ-ETOP paste and surgery-XRT (p=0.0085 vs controls).

Conclusions: This experiment demonstrates the importance and efficacy of localized drug delivery by means of a PLGA/PEG-based thermosensitive paste, and confirms the synergistic mechanisms of action of TMZ and ETOP in gliosarcoma models, paving the way for the clinical application of this promising formulation.

Patient Care: Thise paste is capable of adhering better to the margins of tumor resection cavities, improving the diffusion of therapeutics to the surrounding brain parenchyma.

Learning Objectives: By the conclusion of this session, participants should be able to: 1) Describe the importance of local delivery of combination therapy of temozolamide and etoposide, 2) Discuss, in small groups the importance of a thermosensitive paste for glioblastoma treatment, 3) Identify an effective treatment for those glioblastoma cells that invade the healthy brain parenchyma.

References: (1) B. Engelhardt, L. Sorokin. The blood–brain and the blood–cerebrospinal fluid barriers: function and dysfunction. Semin. Immunopathol. 31, 497– 511, (2009). (2) C.V. Rahman et al., Adjuvant chemotherapy for brain tumors delivered via a novel intra-cavity moldable polymer matrix, PLoS One 8, (2013).