Estimating the Value of Intravenous Calcium and Magnesium in Ameliorating Oxaliplatin-Induced Neuropathy

TO THE EDITOR: The purpose of the N08CB trial (Calcium Gluconate and Magnesium Sulfate in Preventing Neurotoxicity in Patients With Colon Cancer or Rectal Cancer Receiving OxaliplatinBased Combination Chemotherapy) was to confirm the clinically significant effect of calcium and magnesium supplementation in ameliorating oxaliplatin-induced neurotoxicity that was reported in the only other fully published, randomized, placebo-controlled trial of this approach, namely N04C7 (Calcium Gluconate and Magnesium Sulfate in Preventing Neurotoxicity Caused By Oxaliplatin in Patients Receiving Combination Chemotherapy for Stage II, Stage III, or Stage IV Colorectal Cancer That Has Been Completely Removed By Surgery). How are we to reconcile the seemingly contradictory results of these two trials? The primary end point of N04C7 was the incidence of grades 2 to 3 neuropathy according to the National Cancer Institute Common Terminology Criteria for Adverse Events. Given that this end point was also measured in N08CB, it is helpful to compare the 95% CIs for the difference in this measure between the treatment and placebo groups in both trials (ignoring the group in N08CB that received no supplements after oxaliplatin, because this represents a different treatment). Although this statistic was not provided in either report, it is easily calculated from the data provided. In N04C7, the primary end point was recorded in 22% of patients receiving active treatment and 41% receiving placebo for an absolute difference of 19% (95% CI, 1% to 37%). In N08CB, this end point was recorded in 43% of patients receiving active treatment and 46% receiving placebo for an absolute difference of 3% (95% CI, 10 to 16%). Note that these data are compatible with each other, that is, both trials are consistent with an absolute reduction of neurotoxicity that is between 1% and 16%. The authors’ suggestion that the benefit seen in N04C7 was an artifact that resulted from early stopping is not cogent. Results may be exaggerated when trials are stopped early because of a finding of treatment effect, but this bias would not be introduced when a trial is stopped because of concern about off-target effects, as was the case with N04C7. The data from N08CB improve our estimate of the magnitude of benefit to expect from the use of calcium and magnesium supplementation in ameliorating oxaliplatin-induced neurotoxicity. A much larger trial would be required to exclude type II error and decisively show a lack of benefit. Oncologists and patients will need to decide whether the clinical benefit that is suggested by the combined data of N08CB and N04C7 is sufficient to warrant the time and expense of the additional treatment with calcium and magnesium.