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Deirdre R. Pachman, Charles L. Loprinzi, Axel Grothey, Lauren E. Ta
J. Clin. Invest. doi:10.1172/JCI73908.
This article Copyright © 2013, The American Society for Clinical Investigation
Oxaliplatin, a commonly used chemotherapeutic agent, is associated with both acute and chronic neurotoxicity. Chronic sensory neuropathy can be dose limiting and may have detrimental effects on patients’ quality of life. Preclinical studies provide an understanding of the pathophysiology of chemotherapy-induced peripheral neuropathy (CIPN) and may be important for developing effective preventative interventions. In this issue of the JCI, Coriat and colleagues used an animal model and a human pilot trial to evaluate the use of mangafodipir to reduce CIPN. Although many pilot clinical studies have reported promising data, larger clinical trials have repeatedly been unable to confirm these preliminary results. Thus, no agents are currently clinically recommended for the prevention of CIPN.
Romain Coriat, Jérôme Alexandre, Carole Nicco, Laurent Quinquis, Evelyne Benoit, Christiane Chéreau, Hervé Lemaréchal, Olivier Mir, Didier Borderie, Jean-Marc Tréluyer, Bernard Weill, Joel Coste, François Goldwasser and Frédéric Batteux
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.
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.
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 of 458 ± 207 mg/m2 cumulative dose of 1,426 ± 204 mg/m2 with those in nonresponders.
Our study suggests that mangafodipir can prevent and/or relieve oxaliplatin-induced neuropathy in cancer patients.