Grothey, A., Nikcevich, D.A., Sloan, J.A., Kugler, J.W., Silberstein, P.T., Dentchev, T., . . . Loprinzi, C.L. (2011). Intravenous calcium and magnesium for oxaliplatin-induced sensory neurotoxicity in adjuvant colon cancer: NCCTG N04C7. Journal of Clinical Oncology, 29, 412–427.

The purpose of the study was to determine whether calcium and magnesium infusions would prevent or ameliorate neurotoxity associated with oxaliplatin, enable a larger cumulative oxaliplatin dose delivered, ameliorate acute neuropathy associated with oxaliplatin, and whether any adverse events occurred.

Patients were randomly assigned to receive either IV calcium gluconate plus magnesium sulfate, 1 g each in 100 ml D5W for 30 minutes immediately before and after each dose of oxaliplatin, or an identical-looking placebo. Patients underwent a physical examination at study entry and before each two-week chemotherapy cycle, including an assessment for adverse events and toxicity as well as laboratory testing. Patients completed daily questionnaires before each dose of FOLFOX and for five days after completion of each cycle.

• The total sample consisted of 102 participants with a majority being men (53%) and older than age 65 (64%).
• All participants had stage II or III adenocarcinoma of the colon and were scheduled to receive six months of oxaliplatin-based FOLFOX chemotherapy.
• Exclusion criteria included a preexisting peripheral neuropathy of any grade, hypercalcemia, and having received prior neurotoxic chemotherapy.

The study was conducted in multiple outpatient settings throughout the United States.

• Active treatment
• Late effects

The study was a double-blind, placebo-controlled randomized clinical trial.

• The National Cancer Institute's Common Terminology Criteria for Adverse Events, verion 3.0
• A patient questionnaire using a 0–10 scale for sensitivity, discomfort swallowing, and muscle cramps.
• The North Central Cancer Treatment Group patient-reported outcome questionnaire to detect onset of neurotoxicity symptoms.

The study accrual was stopped before the original goal because of a data monitoring committee report regarding a similar trial in patients receiving palliative FOLFOX treatment in which interim analysis showed lower response rates in patients receiving calcium and magnesium. However, subsequent independent analysis of the data showed that initial interpretations were incorrect and that antitumor response was lower in that study's placebo group.

Results of the current study showed that the incidence of grade 2 or higher sensory neurotoxicity was significantly lower in the calcium and magnesium group on two different measurement scales (p < 0.04). In addition, onset of grade 2 or higher was significantly delayed in patients who received calcium and magnesium (p = 0.03). Patient report of numbness also was lower in the calcium and magnesium group (p = 0.021). The study intervention did not appear to have an effect of oxaliplatin-specific symptoms such as muscle cramps, throat discomfort, and cold sensitivity toxicities. No patients developed hypercalcemia.

The findings provide some support for the hypothesis that calcium and magnesium infusions can decrease oxaliplatin-related cumulative sensory neurotoxicity. The results suggest that some types of neurotoxic effects may be reduced, while no obvious effect on other symptoms is apparent.

• The study may have been underpowered because of premature closure to subject accrual.
• No information is provided regarding whether or not there were any FOLFOX dose reductions or discontinuations that also may have affected study findings.
• The authors stated that this was because of early study closure; however, why this would prevent providing any such data is unclear.

Calcium and magnesium infusion may reduce neurotoxicity associated with chemotherapy agents. Additional research in this area is needed to determine if both elements are required and what is the most effective dosages, timing, and efficacy with agents other than oxaliplatin. Research would further clarify the role of this intervention with specific neuropathic symptoms and whether this intervention is effective with various chemotherapeutic agents.