Pharmacological determinants of oxaliplatin neurotoxicity in patients undergoing cancer chemotherapy

Abstract

Oxaliplatin-based chemotherapy has become the standard treatment for gastrointestinal cancers. Oxaliplatin-induced neurotoxicity often compromises treatment delivery and causes long-lasting neurological deficits that negatively impact upon patient's quality of life. Calcium and magnesium (Ca/Mg) infusions had been suggested as an effective intervention for preventing oxaliplatin neurotoxicity. In a prospective randomised double-blind placebo-controlled cross-over study, the effects of Ca/Mg infusions on the pharmacokinetics, motor nerve hyperexcitability and acute neurotoxicity symptoms of oxaliplatin in patients were evaluated. The impact of calcium and magnesium ions on the in vitro degradation of oxaliplatin was also studied. A separate prospective observational cohort study was conducted to explore potential associations between neurotoxicity outcomes and clinical and pharmacological variables measured at baseline or during initial treatment in patients undergoing oxaliplatin-based therapy. Calcium and magnesium ions accelerated oxaliplatin degradation in vitro by interacting with the oxalate ring-opened oxaliplatin intermediate. In the clinical study, however, Ca/Mg infusions had no significant effect on the pharmacokinetics of oxaliplatin. An in vitro-in vivo extrapolation method was shown to predict effects of these infusions on the in vivo clearance of oxaliplatin. Ca/Mg infusions also had no effect on the motor nerve hyperexcitability or acute neurotoxicity symptoms, and fewer patients preferred the cycle with Ca/Mg infusions than without. Based on this clinical study, a superior phase Ib trial design was developed for future clinical studies evaluating new therapeutics for prevention of oxaliplatin neurotoxicity. The cohort study showed that nearly half of the patients developed treatment-limiting neurotoxicity and 82% had persisting neurotoxicity 3 months after the last dose of oxaliplatin. Cumulative oxaliplatin dose correlated with neurotoxicity outcomes, and shorter treatment interval appeared to be more neurotoxic. No other clinical and pharmacological variables correlated with neurotoxicity outcomes. In conclusion, calcium and magnesium were found to accelerate in vitro oxaliplatin degradation, however, Ca/Mg infusions had no significant effects on the pharmacokinetics of oxaliplatin in patients. They had no protective effects against oxaliplatin neurotoxicity, which is a major treatment-limiting side effect and causes persisting neurotoxicity in patients. Development of preventative interventions and predictive markers for oxaliplatin neurotoxicity represents an urgent unmet need in clinical oncology.