IV Calcium/Magnesium Has No Effect on Oxaliplatin-Induced Neuropathy

Intravenous calcium plus magnesium given before or after adjuvant FOLFOX chemotherapy has absolutely no effect on the development of sensory neurotoxicity induced by oxaliplatin.

Axel Grothey, MD

Intravenous calcium plus magnesium (IV CaMg) given before or after adjuvant FOLFOX chemotherapy has absolutely no effect on the development of sensory neurotoxicity induced by oxaliplatin, new research shows. Findings were presented July 6, 2013 during the European Society for Medical Oncology 15th World Congress on Gastrointestinal Cancer in Barcelona.

Axel Grothey, MD, professor of Oncology at the Mayo Clinic in Rochester, Minnesota, and multicenter colleagues found that IV CaMg has no effect on any aspect of sensory neuropathy commonly seen in patients who receive oxaliplatin-based chemotherapy relative to placebo controls.

“We actually surveyed oncologists around the world and more or less 50% of them said they use IV CaMg based on non-definitive data because there was such an unmet need,” Grothey told OncLive. “For oncologists like myself who believed it could work, this study changes our standard of care, because now we know IV CaMg doesn’t work. It’s unfortunate, but it shows that even negative trials can be very informative for clinical practice.”

The N08CB prospective, randomized, phase III study enrolled 362 patients with colon cancer who were undergoing adjuvant FOLFOX chemotherapy. Patients were randomized to one of three treatment arms. The first arm received IV CaMg (1 g calcium gluconate and 1 g magnesium sulfate) before and after chemotherapy. The second group received IV placebo before and after chemotherapy, and the third received IV CaMg prior to chemotherapy but placebo after chemotherapy.

The primary endpoint was cumulative sensory neurotoxicity as repeatedly measured by the sensory subscale of the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire—Chemotherapy-Induced Peripheral Neuropathy (EORTC QLQ-CIPN20) scale. Secondary endpoints using the Common Terminology for Adverse Events (CTCAE 4.0) and an oxaliplatin-specific neurotoxicity scale were also assessed. Acute neuropathy data were also collected for 5 days following each oxaliplatin dose.

The curves mirroring the overall incidence of sensory neuropathy in each of the three treatment arms were virtually superimposable across 12 treatment cycles, Grothey said.

Time to the development of grade 2 sensory neuropathy was also not significantly different between the three treatment arms. Changes in measurements reflecting sensitivity to touching cold items as well as discomfort swallowing cold liquids were also similar across all treatment groups, Grothey reported, as were scores measuring throat discomfort and muscle cramps.

Importantly, there were no significant differences between arms regarding the doses of oxaliplatin administered or discontinuation rates from chemotherapy, and no substantial differences in acute neuropathy scores or side effects were seen between the three study arms.

“Neurotoxicity is actually the dose-limiting toxicity of oxaliplatin—the longer we treat patients with it, the more likely they will develop neurotoxicity, and it can be disabling,” Grothey said.

Unlike other chemotherapy-induced side effects, such as diarrhea and hair loss, “neurotoxicity can also stick around for months and sometimes years, and some patients never recover from it, particularly when we are treating in a palliative setting,” he added.

Whereas other chemotherapy agents are associated with neurotoxicity, certain types of neuropathy associated with oxaliplatin are unique to the drug. For example, some patients develop sensitivity to cold which can be quite burdensome. Patients can also develop jaw spasms and throat discomfort that are again unique to oxaliplatin, Grothey continued.

The use of IV CaMg emerged a number of years ago based on the premise that the neurotoxicity of oxaliplatin was related to the chelating effect it had on calcium ion channels. Magnesium was added in an attempt to prevent the jaw spasms that some patients also develop, Grothey explained. There also were several nonrandomized trials—one of which was carried out by Grothey himself—which at least initially gave a perception of benefit from using IV CaMg to prevent oxaliplatin-induced neurotoxicity.

“There were a lot of trials showing an inconsistent effect, so there was a need to have a definitive study,” said Grothey. “We now have that definitive study, and it shows IV CaMg does not work to prevent oxaliplatin-induced neurotoxicity. This should be the nail in the coffin for using IV CaMg as a neuroprotectant against oxaliplatin-induced acute and chronic neurotoxicity.”

Grothey A, et al. Phase III randomized, placebo-controlled, double-blind study of intravenous calcium/magnesium (CaMg) to prevent oxaliplatin-induced sensory neurotoxicity, N08CB: an alliance for clinical trials in oncology study. Presented at: ESMO 15th World Congress on Gastrointestinal Cancer; July 3-6, 2013; Barcelona, Spain. Abstract 0-0032.


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