Abstract
578 Background: Calcium and magnesium (Ca/Mg) infusions have been suggested as an effective intervention for preventing oxaliplatin-induced neurotoxicity, but the effects of Ca/Mg infusions on oxaliplatin pharmacokinetics, motor nerve hyperexcitability, and acute neurotoxicity symptoms are unclear. Methods: In this double-blind crossover study, colorectal cancer patients undergoing oxaliplatin-based chemotherapy were randomised to receive Ca/Mg (1g Ca Gluconate plus 1g MgSO4) on cycle 1 and placebo (vehicle alone) on cycle 2, or to receive the same treatments in the opposite sequence. Study endpoints included plasma pharmacokinetics of intact oxaliplatin and free platinum; electromyography (EMG) detection of abnormal spontaneous high-frequency motor unit action potential discharges; and patient-reported acute neurotoxicity symptoms and their preferred study treatment for reducing these symptoms. Results: The planned accrual target was achieved. Nineteen of 20 enrolled patients completed the study. Plasma pharmacokinetics of intact oxaliplatin and free platinum were similar when oxaliplatin was given with Ca/Mg or placebo (ratio of geometric means of AUC0-t with Ca/Mg or placebo: intact oxaliplatin, 0.95 (90% CI, 0.90 – 1.01); free platinum, 0.99 (90% CI, 0.94 – 1.05)). EMG motor nerve hyperexcitability scores were similar with Ca/Mg and placebo (mean difference in EMG score between Ca/Mg and placebo: -0.3 (95% CI, -2.2 – 1.6)). Patient-reported acute neurotoxicity symptoms were similar in frequency with Ca/Mg and placebo. For reducing neurotoxic symptoms, fewer patients preferred Ca/Mg than placebo or neither treatment (26% versus 74%; p < 0.01). Conclusions: Ca/Mg infusions do not alter the clinical pharmacokinetics of oxaliplatin and do not seem to reduce its acute neurotoxicity. Clinical trial information: ACTRN12611000738921.
Highlights
Calcium and magnesium (Ca/Mg) infusions have been suggested as an effective intervention for preventing oxaliplatin-induced neurotoxicity, but the effects of Ca/Mg infusions on oxaliplatin pharmacokinetics, motor nerve hyperexcitability and acute neurotoxicity symptoms are unclear
The plasma concentration values for free platinum appeared to be similar or slightly higher than those for intact oxaliplatin at each time point. Pharmacokinetic parameters of both intact oxaliplatin and free platinum were similar when oxaliplatin was given with Ca/Mg or placebo (Table 2)
We showed that Ca/Mg infusions do not alter the pharmacokinetics of either intact oxaliplatin or free platinum, and our evidence indicates that these infusions may provide no benefit in reducing acute oxaliplatin-induced neurotoxicity
Summary
Calcium and magnesium (Ca/Mg) infusions have been suggested as an effective intervention for preventing oxaliplatin-induced neurotoxicity, but the effects of Ca/Mg infusions on oxaliplatin pharmacokinetics, motor nerve hyperexcitability and acute neurotoxicity symptoms are unclear. Acute neurotoxicity occurs in a high proportion of patients shortly after oxaliplatin administration, but may resolve within a few hours or days, and is characterised by cold-related paresthesia, dysesthesia or allodynia, jaw stiffness, and muscle cramps [9]. These acute symptoms may reflect the induction of a state of acute peripheral nerve hyperexcitability detectable on electromyography (EMG) and other neurophysiological studies after oxaliplatin treatment [10,11,12]. Its recovery after discontinuation of oxaliplatin may be slow, improving gradually over many months or even years, and is incomplete in some patients
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