Intravenous calcium and magnesium for oxaliplatin-induced sensory neurotoxicity in adjuvant colon cancer: NCCTG N04C7

Abstract

Purpose: Cumulative sensory neurotoxicity (sNT) is the dose-limiting toxicity of oxaliplatin, which commonly leads to early discontinuation of oxaliplatin-based therapy in the palliative and adjuvant settings. In a nonrandomized, retrospective study, intravenous (IV) calcium/magnesium (Ca/Mg) was associated with reduced oxaliplatin-induced sNT.

Methods: Patients with colon cancer undergoing adjuvant therapy with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) were randomly assigned to Ca/Mg (1g calcium gluconate plus 1g magnesium sulfate pre- and post-oxaliplatin) or placebo, in a double-blinded manner. The primary end point was the percentage of patients with grade 2 or greater sNT at any time during or after oxaliplatin-based therapy by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; version 3) criteria. An oxaliplatin-specific sNT scale and patient questionnaires were also used to assess sNT. After 104 of 300 planned patients were enrolled, the study was closed. This was due to preliminary reports from another trial that suggested that Ca/Mg decreased treatment efficacy; these data were subsequently found to be incorrect.

Results: Overall, 102 patients were available for analysis. Ca/Mg decreased the incidence of chronic, cumulative, grade 2 or greater sNT, as measured by NCI CTCAE (P = .038) and also by the oxaliplatin-specific sNT scale (P = .018). In addition, acute muscle spasms associated with oxaliplatin were significantly reduced (P = .01) No effect on acute, cold-induced sNT was found. No substantial differences in adverse effects were noted between Ca/Mg and placebo.

Conclusion: Despite early termination and decreased statistical power, this study supports IV Ca/Mg as an effective neuroprotectant against oxaliplatin-induced cumulative sNT in adjuvant colon cancer.

Fig 1.

CONSORT flow diagram. AE, adverse event.

Fig 2.

Time to grade 2 or worse sensory neuropathy as measured by (A) Common Toxicity Criteria for Adverse Events or by (B) an oxaliplatin-specific scale. Ca, calcium; Mg, magnesium.

Fig 3.

Patient-reported outcomes regarding questions about (A) numbness in fingers/toes (P = .021) and (B) tingling in fingers/toes (P = .662). Open circles represent mean values for the placebo group; filled circles represent mean values for the calcium/magnesium (Ca/Mg) group. Vertical lines represent 95% CIs about the means.

Fig 4.

Acute symptoms regarding (A) sensitivities to touching cold items, (B) discomfort swallowing cold liquids, (C) throat discomfort, and (D) muscle cramps. Ca, calcium; Mg, magnesium.