Enhanced chemotherapy delivery by intraarterial infusion and blood‐brain barrier disruption in malignant brain tumors

Abstract

BACKGROUND.The treatment of malignant brain tumors is hampered by the presence of the blood-brain barrier, which limits chemotherapy penetration to the central nervous system (CNS). In recent years, different strategies have been designed to circumvent this physiologic barrier. The osmotic blood-brain barrier disruption (BBBD) procedure is one such strategy, and has been studied extensively in preclinical and clinical studies. The authors detail their experience so far with the procedure in the context of an open Phase II study in the treatment of malignant brain tumors. METHODS.Patients with histologically proven malignant gliomas, primitive neuroectodermal tumors, primary CNS lymphomas, and metastatic disease to the brain were eligible. Patients enrolled were treated every 4 weeks (1 cycle) for Յ 12 cycles.A methotrexate-based regimen was offered to patients with lymphomas, whereas a carboplatin-based regimen was offered to patients with all other histologies. Before intraarterial chemotherapy infusion, patients were submitted to an osmotic BBBD procedure. RESULTS.Seventy-two patients were included in the current report. The overall median survival times (MST) from treatment initiation for glioblastoma multiforme (GBM), anaplastic oligodendrogliomas, primary CNS lymphomas, and metastases were, respectively, 9.1, 13.9, not reached, and 9.9 months, whereas time to disease progression was 4.1, 9.2, 12.3, and 3.3 months. The MST from diagnosis was 32.2 months for GBM. CONCLUSIONS.These encouraging results prompted the authors to further refine their knowledge of the potential contribution of this procedure in the treatment of brain tumors. These authors designed a randomized Phase III study for patients with GBM that is now open.

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

“…The Centre Hospitalier Universitaire de Sherbrooke (CHUS) neuro-oncology group joined the consortium in 2000 and has recently reported results with the BBBD procedure combined with the administration of a carboplatinbased tri-drug regimen (58). We observed a prolonged median survival of 32.2 months in the treatment of glioma, more than double the reported median survivals of 9 to 14 months with standard therapeutic modalities (59)(60)(61)(62).…”

Convection-enhancement delivery of platinum-based drugs and LipoplatinTM to optimize the concomitant effect with radiotherapy in F98 glioma rat model

“…The prognosis of patients with glioblastomas remains dismal. A substantial number of clinical trials involving platinum-based antineoplastic drugs (cisplatin, carboplatin) for glioma have been carried out [1][2][3][4][5][6]. Whereas cisplatin showed no or limited improvements in patients with glioblastoma [1,2], carboplatin, especially delivered via an intra-arterial route, has demonstrated the drug's efficacy to improve median survival [3][4][5][6].…”

Impact of Drug Size on Brain Tumor and Brain Parenchyma Delivery after a Blood–Brain Barrier Disruption

“…12 The procedure has been shown to increase the survival of newly diagnosed GBM patients, with a median survival of 32.2 months. 10 One major weakness of this therapeutic strategy remains the intersubject variability in the BBB permeability; this is accompanied by an inherent difficulty in predicting and evaluating the extent of this permeability. 13 The extent of BBBD in preclinical studies has traditionally been studied with ex vivo brain samples using an Evan's blue staining technique, and consequently do not allow the follow-up of the animals.…”