Effets du topotécan, de la cytarabine, du carboplatin et du paclitaxel par infusion intra-artérielle dans le modèle pré-clinique F98-Fischer

Glioblastoma multiform (GBM) represent the most aggressive primary malignant cerebral tumor. The first line of treatment is well established with a maximal surgical resection followed by concomitant radio- and chemotherapy. However, the effects of this treatment remain modest with a median survival of 14.6 months (Stupp et al. 2005). Second line of treatment has not yet been established and varies from treatment center to another. At the Centre Hospitalier de l’Université de Sherbrooke, our team prioritizes the administration of chemotherapy agents by intra-arterial (IA) infusion (Fortin et al. 2019). This project has two distinct objectives: (1) to evaluate the maximum dose that can be administered without adverse effects using IA administration of four chemotherapeutic agents (topotecan, cytarabine and new formulations of carboplatin and paclitaxel); and (2) to determine their therapeutic efficacy using this route of administration compared with the conventional intravenous (IV) route. Healthy animals (without brain tumours) were used for part (1), while a syngeneic F98-Fischer model with a glial tumour was chosen for part (2). Only three agents were tested in arm (1), topotecan, cytarabine and paclitaxel, as carboplatin is already used clinically by this route with a known maximum tolerable dose (MTD) of 20 mg/kg (Charest et al., 2013; Côté et al., 2013). The MTDs (1) of topotecan and cytarabine were assessed at 4 mg/kg and 8.75 mg/kg, respectively. However, IA infusion of paclitaxel proved impossible due to its neurotoxicity. Encouraging results were demonstrated in terms of the therapeutic efficacy (2) of topotecan in the IA setting, with a significant increase in the survival rate in the IA group (29 days) compared with the IV group (23.5 days). For cytarabine, the results suggest a toxic trend, with survival in the IA group being lower than in the IV group (22.5 vs. 26.5 days). The new formulation of carboplatin proved significantly more effective than those commercially available, with median survival of 37.5 days versus 26 and 30 days, respectively (Charest et al., 2013; Côté et al., 2013). Finally, since paclitaxel cannot be administered IA, intratumoral infusion was tested. This proved ineffective with a non-significant median survival in the SHAM group compared to the treated group with respective survivals of 28.5 and 29 days. In conclusion, an increase in the therapeutic efficacy of topotecan and the new carboplatin formulation has been demonstrated, whereas cytarabine and paclitaxel have reported neurotoxicity with this route of administration.

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