PHARMACOKINETIC OPTIMIZATION OF CANCER-CHEMOTHERAPY - EFFECT ON OUTCOMES

Cancer chemotherapy doses are empirical in that the majority are admin istered at a fixed dose (mg/m(2) or mg/kg), One reason for this is the intrinsic sensitivity of the tumour or host cells to one particular c hemotherapy agent is unknown, Therefore, the likelihood of response or toxicity is unpredictable a priori. This contrasts with antimicrobial chemotherapy where sensitivity (minimum inhibitory concentration) can be determined for a specific bacterium, The pharmacokinetics of cance r chemotherapy agents is also highly variable between patients. In add ition, the small therapeutic index of these drugs, combined with the l ack of good surrogate markets of toxicity or response, adds to the emp iricism of the administration of cancer chemotherapy. In the past few years, numerous studies have established good relationships between sy stemic exposure to cancer chemotherapy and both response and toxicity. These relationships have been used to individualise chemotherapy dose administration a priori and a posteriori. Some examples of drugs whic h are individualised based on their pharmacokinetics are methotrexate, busulfan and carboplatin. Other examples of antineoplastic agents whi ch may eventually be individualised based on their pharmacokinetics ar e mercaptopurine, fluorouracil, etoposide and teniposide, topotecan an d suramin. New strategies are being investigated to improve the therap eutic index of cancer chemotherapy agents such as biomodulation, pharm acogenetics, circadian administration and the modification of drug sch eduling. Pharmacokinetic studies have also played a major role in thes e areas. Thus, despite the empiricism associate with cancer chemothera py administration, some progress has been made and shown to have an im pact on outcome. However, more studies are needed to improve cancer ch emotherapy administration.