Medulloblastoma and primitive neuroectodermal tumors (PNETs) are childhood brain tumors where about 40% of patients die due to early tumor recurrence. Cyclophosphamide is an alkylating agent that is used as part of the chemotherapy regimen for these tumors following surgery and radiation therapy. However, significant inter-patient variations in response and toxicity still exist. Relationships between outcomes (e.g., response, toxicity) and the systemic exposure of cyclophosphpamide and its active metabolite hydroxycyclophosphamide (HCY) have not been analyzed in medulloblastoma patients, mostly due to analytical constraints that were overcome during the past decade. Although few studies have previously described cyclophosphamide pharmacokinetics in children, none have used recently developed, highly sensitive analytical techniques to assess inter- and intra-patient variability in cyclophosphamide exposure. In fact, intra-patient variability in cyclophosphamide exposure has not been addressed thoroughly by any means in pediatric patients. Since cyclophosphamide is a prodrug that undergoes extensive hepatic metabolism to form pharmacologically-active HCY, and since this metabolism is under genetic control, variation in patient genetic composition may directly influence the variability in cyclophosphamide exposure, response, and toxicity. Thus, in this study we propose the following specific aims: (1) Develop a population pharmacokinetic model to assess inter-patient and intra-patient variability in pharmacokinetic parameters of CTX and its metabolite 4-OHCTX, using a recently developed LC-MS/MS analytical method. Determine the extent of auto-induction within courses;(2) Evaluate the effect of CTX and 4-OHCTX pharmacokinetics upon the outcomes of event-free survival (EFS) and CTX-related hematologic and hepatic toxicities;(3) Assess the relationship between genetic polymorphisms in drug metabolizing enzymes and drug transporters and the pharmacokinetics of CTX and its metabolite 4-OHCTX. Examine whether these polymorphisms are predictive of EFS or CTX-related toxicities.
The information this study will provide will allow us to better predict the toxicity and anti-tumor response to cyclophosphamide treatment in children with medulloblastoma or PNETs. We can then adjust the dosage of cyclophosphamide based on patient characteristics to obtain an optimal response to therapy.
