Optimising the treatment of childhood cancer patients through adaptive dosing and the generation of evidence-based dosing guidelines

Background: Obtaining the right balance between efficacy and toxicity is particularly challenging when dosing childhood cancer patients requiring modified drug doses, including neonates and infants, children with poor kidney function and obese patients. For the vast majority of widely used anticancer drugs, current dose recommendations for these patient groups show wide variation between protocols and treatment centres and are based on limited scientific rationale. We have established a national therapeutic drug monitoring (TDM) programme of work in the United Kingdom, providing individual patient drug exposure data in real-time, to support dosing decisions for particularly hard to treat childhood cancer patients across all treatment centres. In addition, data generated have allowed us to propose evidence-based dosing regimens for specific drugs and patient groups. Methods: A national TDM study (ISRCTN10139334) has recruited >450 patients across 18 centres. Within this study, samples for pharmacokinetic analysis from a total of 241 neonates and infants, 50 patients receiving high dose chemotherapy and 20 obese patients have been collected and analysed across a range of widely used anticancer drugs including carboplatin, vincristine, etoposide, fludarabine and imatinib. Where significant numbers of patients have been recruited for a particular patient population and study drug, population pharmacokinetic models have been developed. Collation of dosing information, alongside quantification of individual patient drug concentrations, allows drug exposures to be determined and compared between groups and dosing regimens. Results: Data generated form the study to date have identified clear correlations between potentially subtherapeutic drug exposures in neonates and infants and the use of commonly used body weight-based dosing regimens for commonly used drugs carboplatin, vincristine and mitoxantrone. Due to an observed marked variability in drug exposures in patients <1 year of age, with the potential for marked changes in drug clearance within the first weeks and months of life, therapeutic drug monitoring and adaptive dosing approaches have become gold standard for many drugs in the UK. The data generated have allowed us to define dosing regimens based on a sound pharmacological rationale for drugs including carboplatin, where a dose of 6.0 mg/kg/day in all neonates and infants has now replaced previous dosing regimens of 4.4 mg/kg/day in patients <5kg and 6.6 mg/kg/day in patients between 5-10kg, and vincristine. Conclusions: The current study shows the feasibility and benefits of utilizing a TDM approach for the treatment of challenging patient populations, with currently used dosing regimens potentially leading to sub-therapeutic drug exposures in many patients. Pharmacokinetic data generated in neonate and infant patients have facilitated the calculation of evidence-based dosing regimens for the widely used drugs carboplatin and vincristine. Additional analysis is now ongoing for additional drugs and patient subpopulations including obese patients, with a view to identifying appropriate dosing regimens for future use.