Zosia Chustecka

June 03, 2013

CHICAGO, Illinois — The common practice of administering intravenous calcium and magnesium along with oxaliplatin to reduce the side effect of neuropathy should be stopped, experts say.

The first placebo-randomized phase 3 trial of this practice has shown no benefit. The results were presented here at the 2013 Annual Meeting of the American Society of Clinical Oncology (ASCO®) by Charles Loprinzi, MD, from the Mayo Clinic in Rochester, Minnesota.

The trial was conducted in 353 patients with colon cancer undergoing adjuvant therapy with FOLFOX (5-fluorouracil, oxaliplatin, and leucovorin), who were randomized to receive intravenous CaMg (1g calcium gluconate, 1 g magnesium sulfate) or placebo before and after oxaliplatin. There was also a third arm in the trial, in which patients received CaMg before and placebo after the oxaliplatin.

The results showed no differences between the groups in either acute neurotoxicity or cumulative sensory neurotoxicity, as assessed both by patient and physician questionnaires.

"This study did not demonstrate any activity of IV CaMg as a neuroprotectant against oxaliplatin-induced neurotoxicity," the researchers concluded.

"This practice should now be stopped," Dr. Loprinzi told Medscape Medical News in an interview .

The study was described as "practice changing" by Richard Wilson, MD, from Queen's University Belfast, in Northern Ireland, speaking at a "highlights of the Day" session.

"The results were very clear," he said.

There was "no difference whatsoever" in either acute or chronic oxaliplatin-induced neuropathy between patients who received CaMg and those who did not.

"This does no good," he said. "Stopping this practice will free up chair time and patient time," he said.

Chair time refers to the time spent in the intravenous-infusion clinic receiving the CaMg, which takes about half hour, and both before and after administration of oxaliplatin, Dr. Loprinzi explained.

Lesson Learned: Earlier Trial Was Too Small

The lesson learned here, Dr. Wilson suggested, is that the small study that had suggested a benefit, reported in 2004, should have been considered as hypothesis-generating data that would inform clinical trials, but should not have led immediately to a change in clinical practice, he said.

That original report (Gamelin et al, Clin Cancer Res. 2004;10[12 Pt 1]:4055-4061) on the benefits of intravenous CaMg was based on a study of 160 prospective patients. The authors compared the results in this series of patients with historical controls, and found that the rate of neurotoxicity with oxaliplatin was reduced by half, Dr. Loprinzi explained. This was not a randomized study, he noted, but the report led to an enthusiastic uptake of this practice.

Dr. Loprinzi said that at medical meetings, when he has asked audiences how many of them use intravenous Ca/Mg, more than half of the clinicians have said they do. He suspects that it may be even more in Europe, as the original report came from French researchers.

There is some rationale behind the practice, he said. Oxaliplatin is metabolized to oxalate, and this binds to calcium and magnesium, so there is less in the nerves; adding more was hoped to prevent the development of neuropathy, he explained.

Neuropathy is a big problem with oxaliplatin, he said. It affects a large number of patients, and while many improve, in some it last for years and is a major problem, he said. The neuropathy is mainly sensory, and it mostly affects the hands and feet with stinging burning pain.

There have been several other trials that have attempted to address this issue, but 2 were stopped prematurely after concern was raised over the possibility that CaMg was interfering with chemotherapy efficacy. However, a subsequent review of the data showed that this was not in fact the case, and efficacy was not altered. The study (N08CB) by Dr. Loprinzi and colleagues set out to "definitively test whether IV CaMg significantly decreases cumulative oxaliplatin-related sensory neurotoxicity."

The results show that it does not. "It's taken us nearly a decade, but we now have definitive data on this," he commented.

American Society of Clinical Oncology Annual Meeting: Abstract 3501, presented June 1.

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