The role of pharmacokinetic and pharmacodynamic studies in the planning ofprotocols for the treatment of childhood cancer

The chemosensitive nature of many childhood cancers means that chemotherapy has a greater role in therapy than in adult practice. However the present methods, schedules of administration and combinations have often been deriv ed form historical precedent rather than from pharmacological knowledge. Fo r many drugs, paediatric phase I and II studies have never been performed a nd reliance on adult studies will be inadequate as children may show differ ences in drug disposition or susceptibility to toxicity. In this review, we examine pharmacokinetic and pharmacodynamic studies as they relate to the treatment of a 'model' childhood cancer in the UK: acute lymphoblastic leuk aemia (ALL). Each of the drugs used is examined in the light of pharmacolog ical evidence. For the drugs L-asparaginase, methotrexate, cytarabine and t he thiopurines, this evidence suggests that the current use of these drugs is not optimal and that significant improvements in cure for ALL might be a chieved by pharmacologically guiding their use. We highlight an important r ecent study demonstrating a 10% increase in long-term survival in childhood ALL by the use of pharmacologically guided dosing compared to standard (by body surface area) dosing. Since significant improvements in survival may depend upon such effective use, we suggest that pharmacological studies bec ome an integral part of phase II and phase III trials of treatments for chi ldhood cancer.