Objective: The objective of this study was to determine whether weekly intravenous administration of a novel Vitamin E paclitaxel emulsion to rats at clinically relevant doses for the treatment of metastatic breast cancer would result in reduced neurotoxicity when compared to the approved products; docetaxel, cremophor paclitaxel and albumin-bound paclitaxel.
Methods: Ten male CRL: CD (SD) rats/group were treated with either saline, vitamin E paclitaxel 50 or 100 mg/m2, docetaxel 40 mg/m2, cremophor paclitaxel 50 mg/m2 or albumin-bound paclitaxel 125 mg/m2. Doses were intravenously administered once per week for 6 weeks, followed by a 4 week recovery period. The cremophor paclitaxel dose was limited to 50 mg/m2, the MTD in rats. Endpoints included: mortality, clinical observations, body weights, thermal paw latency, rota-rod, sensory and motor nerve conduction velocity assays, and neurohistopathology.
Results: There were five test article related deaths. Clinical findings were consistent with the known cytotoxicity of taxanes. Half the animals in the albumin-bound paclitaxel treatment group developed impaired hind limb function. Body weight changes were most severe in the docetaxel 40 mg/m2 > albumin-bound paclitaxel 125 mg/m2 > vitamin E paclitaxel 100 mg/m2 > cremophor paclitaxel 50 mg/m2 > vitamin E paclitaxel 50 mg/m2. The thermal paw latency assay and motor nerve conduction velocity showed no definitive treatment effect. Rota-rod times were shortened and sensory nerve conduction velocity decreased during treatment. At week 10, docetaxel and albumin-bound paclitaxel-treated animals demonstrated less recovery in these parameters than either vitamin E paclitaxel or cremophor paclitaxel-treated animals. Histologically, nerve fiber degeneration, in the peripheral nerves and/or spinal nerve roots, was observed in varying degrees across the treatment groups (Saline Control < (Slight) vitamin E paclitaxel 50 mg/m2 < cremophor paclitaxel 50 mg/m2 = docetaxel 40 mg/m2 < vitamin E paclitaxel 100 mg/m2 < albumin-bound paclitaxel 125 mg/m2). Multifocal areas of neuronal (gray matter) necrosis, many progressing to cavitation, in the brain were pronounced in the cremophor paclitaxel group. Minimal to mild nerve fiber degeneration in the optic chiasm/optic tract and spinotrigeminal tract in the medulla oblongata was present in the albumin-bound paclitaxel group. There were no treatment-related brain lesions in the vitamin E paclitaxel groups.
Conclusions: Clear differences in neurotoxicity were noted across treatment groups. Vitamin E paclitaxel emulsion treatment (50 mg/m2) resulted in less nerve fiber degeneration than docetaxel, cremophor paclitaxel or albumin-bound paclitaxel.
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA