Treatment of oxaliplatin-induced peripheral neuropathy by intravenous mangafodipir

Abstract

Background: The majority of patients receiving the platinum-based chemotherapy drug oxaliplatin develop peripheral neurotoxicity. Because this neurotoxicity involves ROS production, we investigated the efficacy of mangafodipir, a molecule that has antioxidant properties and is approved for use as an MRI contrast enhancer.

Methods: The effects of mangafodipir were examined in mice following treatment with oxaliplatin. Neurotoxicity, axon myelination, and advanced oxidized protein products (AOPPs) were monitored. In addition, we enrolled 23 cancer patients with grade ≥ 2 oxaliplatin-induced neuropathy in a phase II study, with 22 patients receiving i.v. mangafodipir following oxaliplatin. Neuropathic effects were monitored for up to 8 cycles of oxaliplatin and mangafodipir.

Results: Mangafodipir prevented motor and sensory dysfunction and demyelinating lesion formation. In mice, serum AOPPs decreased after 4 weeks of mangafodipir treatment. In 77% of patients treated with oxaliplatin and mangafodipir, neuropathy improved or stabilized after 4 cycles. After 8 cycles, neurotoxicity was downgraded to grade ≥ 2 in 6 of 7 patients. Prior to enrollment, patients received an average of 880 ± 239 mg/m2 oxaliplatin. Patients treated with mangafodipir tolerated an additional dose of 458 ± 207 mg/m2 oxaliplatin despite preexisting neuropathy. Mangafodipir responders managed a cumulative dose of 1,426 ± 204 mg/m2 oxaliplatin. Serum AOPPs were lower in responders compared with those in nonresponders.

Conclusion: Our study suggests that mangafodipir can prevent and/or relieve oxaliplatin-induced neuropathy in cancer patients. Trial registration. Clinicaltrials.gov NCT00727922. Funding. Université Paris Descartes, Ministère de la Recherche et de l'Enseignement Supérieur, and Assistance Publique-Hôpitaux de Paris.

Figure 1. In vivo study of oxaliplatin-induced neurotoxicity.

Experimental mice received oxaliplatin (10 mg/kg) weekly and mangafodipir (10 mg/kg) 3 times a week for 8 weeks. Evaluation of hyperalgesia required two 5-day cycles of daily oxaliplatin (3 mg/kg). Control mice received either oxaliplatin or vehicle alone. Locomotor disturbances, cold hypoesthesia, nociception, or cold hyperalgesia were evaluated using rotarod testing, cold plate testing at +4°C, von Frey tests, or cold plate testing at –4°C, respectively (A–D). MnTBAP (10 mg/kg) or vitamin B6 (10 mg/kg), two components of mangafodipir, were substituted for mangafodipir, and mice were tested under the same experimental conditions (E–H). Data are presented as the means ± SEM of 8 different mice under each condition. *P < 0.05 and **P < 0.01 versus vehicle.

Figure 2. Morphological characterization of single myelinated nerve fibers isolated from the sciatic nerves of mice injected with vehicle, oxaliplatin, oxaliplatin plus mangafodipir (Ox + M), or mangafodipir (M) for 44 days.

(A) Typical confocal microscopic images under each condition of single nerve fibers acquired by transmitted light (left panels) and of 3D reconstructions by projections of a series of optical sections from single nerve fibers stained with FM1-43 (right panels). The circles indicate the nodes of Ranvier examined. Original magnification, ×3,500. (B) Schematic representation of a single myelinated axon showing the measured morphological parameters: internodal diameter (Di), nodal diameter (Dn), and nodal length (Ln).

Figure 3. CONSORT statement flow diagram of patients included in the study. n, number of patients.

Figure 4. Sensory neurotoxicity improves with cumulative oxaliplatin plus mangafodipir treatment.

(A) Biological changes in the sera of patients treated with oxaliplatin plus mangafodipir. Plasma manganese changes (B). Oxidative stress markers prior to chemotherapy for serum levels of AOPPs (C), plasma SOD activity (D), GR (E), and thiols (F).

Figure 5. Survival rates of patients treated with oxaliplatin plus mangafodipir.

Progression-free survival (A) and overall survival (B). Cumulative doses of oxaliplatin administered to patients in each group (C).