Prevention of Oxaliplatin-Related Neurotoxicity by Calcium and Magnesium Infusions: A Retrospective Study of 161 Patients Receiving Oxaliplatin Combined with 5-Fluorouracil and Leucovorin for Advanced Colorectal Cancer Laurence Gamelin, 4 Michele Boisdron-Celle, 1,2 Remy Delva, 1 Ve ´ronique Gue ´rin-Meyer, 1 Norbert Ifrah, 3 Alain Morel, 1,2 and Erick Gamelin 1,2 1 Department of Medical Oncology and Oncopharmacology, 2 INSERM U564, Anticancer Centre Paul Papin, and 3 Department of Hematology, and 4 Antipoison Center, University Hospital, Angers Cedex, France ABSTRACT Purpose: Oxaliplatin is active in colorectal cancer. Sen- sory neurotoxicity is its dose-limiting toxicity. It may come from an effect on neuronal voltage-gated Na channels, via the liberation one its metabolite, oxalate. We decided to use Ca and Mg as oxalate chelators. Experimental Design: A retrospective cohort of 161 pa- tients treated with oxaliplatin  5-fluorouracil and leuco- vorin for advanced colorectal cancer, with three regimens of oxaliplatin (85 mg/m 2 /2w, 100/2w, 130/3w) was identified. Ninety-six patients received infusions of Ca gluconate and Mg sulfate (1 g) before and after oxaliplatin (Ca/Mg group) and 65 did not. Results: Only 4% of patients withdrew for neurotoxic- ity in the Ca/Mg group versus 31% in the control group (P  0.000003). The tumor response rate was similar in both groups. The percentage of patients with grade 3 distal par- esthesia was lower in Ca/Mg group (7 versus 26%, P  0.001). Acute symptoms such as distal and lingual paresthe- sia were much less frequent and severe (P  10 -7 ), and pseudolaryngospasm was never reported in Ca/Mg group. At the end of the treatment, 20% of patients in Ca/Mg group had neuropathy versus 45% (P  0.003). Patients with grade 2 and 3 at the end of the treatment in the 85 mg/m 2 oxali- platin group recovered significantly more rapidly from neu- ropathy than patients without Ca/Mg. Conclusions: Ca/Mg infusions seem to reduce incidence and intensity of acute oxaliplatin-induced symptoms and might delay cumulative neuropathy, especially in 85 mg/m 2 oxaliplatin dosage. INTRODUCTION Oxaliplatin combined with 5-fluorouracil (5FU) is now considered a standard treatment for metastatic colorectal cancer (1, 2) and is also under evaluation in the adjuvant setting (3). Its overall safety profile is good, but neurotoxicity is a frequent dose-limiting toxicity. The peculiar acute neurotoxicity of ox- aliplatin (including cold-related dysesthesia and sometimes ac- companied by muscle contractions), which may occur shortly after drug administration, differs greatly from cisplatin neuro- toxicity and is not explained by morphological damage of the nerve (3, 4). These clinical manifestations of this acute neuro- toxicity resemble those described in patients with congenital myotonia or tetany (5). Therefore, we hypothesized that oxali- platin had a unique direct effect on nerve excitability. We suspected that oxalate, one of the oxaliplatin metabolites, re- sponsible for acute neurotoxic effects of ethylene glycol poi- soning (6) and known chelator of both Ca and Mg, might be involved in this acute neurotoxic effect via Ca and/or Mg chelation. We tested the effectiveness of both Ca and Mg infusions in several oxaliplatin-treated patients who developed the manifestations of acute neurotoxicity (including those with pseudolaryngospasm). The immediate and important improve- ment in both the pseudolaryngospasm and other acute neuro- toxicities we observed prompted us to extend that approach to their preventive treatment, and we began to administer Ca and Mg before and just after oxaliplatin infusion to prevent the acute neurological manifestations that can occur during or within the hours following oxaliplatin administration. We recently demonstrated in in vitro models that the acute (and possibly chronic) neurotoxicity associated with oxaliplatin may be either directly or indirectly linked (via the chelation of calcium by oxalate) to an effect on neuronal voltage-gated sodium (Na + ) channels (7, 8). Therefore, since 1996, when oxaliplatin was made widely available for patients with advanced colorectal cancer, we em- pirically started treating patients receiving oxaliplatin for ad- vanced colorectal cancer with Ca and Mg infusions. After sev- eral years of empirical use, the very encouraging results, described by the nurses, the patients, and the treating physicians of our department prompted us to review these data and conduct a retrospective analysis of our patients’ experiences after ap- proval by our institutional Review Board to perform that study. Received 12/2/03; revised 2/3/04; accepted 2/23/04. Grant support: Comite ´ De ´partemental du Maine et Loire de la Ligue Nationale contre le Cancer. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Note: This work as been presented in part at the 2002 American Society for Clinical Oncology Meeting. Requests for reprints: Erick Gamelin, Head Department of Medical Oncology and Oncopharmacology, Anticancer Centre Paul Papin, 2 rue Moll, 49033 Angers Cedex, France. Fax: 00-33-2-41-48-31-90; E-mail: e.gamelin@unimedia.fr. 4055 Vol. 10, 4055– 4061, June 15, 2004 Clinical Cancer Research Downloaded from http://aacrjournals.org/clincancerres/article-pdf/10/12/4055/1952468/zdf01204004055.pdf by guest on 18 June 2022