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Dosing of anticancer agents in adults

Keith D Eaton, MD, PhD
Gary H Lyman, MD, MPH, FASCO, FACP, FRCP (Edin)
Section Editor
Paul J Hesketh, MD
Deputy Editor
Sadhna R Vora, MD


Most anticancer agents have a steep dose response relationship and a narrow therapeutic index. Small variations in the administered dose can lead to severe and life-threatening toxicity in some individuals and underdosing in others, which may compromise cancer outcomes. Proper dose selection is of great importance, particularly in individuals with potentially curable diseases such as lymphoma or testicular cancer, and in the setting of adjuvant treatment (eg, breast and colon cancer). Selection of the right dose is complicated by the fact that individuals have a highly variable capacity to metabolize and eliminate drugs.

The most relevant pharmacokinetic parameter for drug exposure is the area under the curve (AUC) of plasma concentration x time following a single dose. During drug development, drug level sampling at multiple time points helps define the relationship between drug administration and the AUC. The AUC is influenced by external factors such as drug dose and schedule, as well as patient-specific factors such as age, gender, height, weight, concomitant medications and habits, genetics (inherited variations in drug metabolizing enzymes, drug transporters, and/or drug targets), and clearance (which depends upon renal and hepatic function). As a result, there is much interindividual variation in the AUC following a single dose of a drug [1]. For most anticancer agents, attempts to minimize interindividual variation have been limited to normalizing doses based on body size (weight, body surface area [BSA]).

This topic will address issues related to dosing of anticancer agents in adults, including BSA-based dosing, which is used for most cytotoxic agents, weight-based dosing (eg, as is done for some cytotoxic agents such as melphalan and several therapeutic monoclonal antibodies), fixed dose prescribing (as is done for oral targeted agents such as tyrosine kinase inhibitors [TKIs]), AUC-based dosing (as is done for carboplatin), and pharmacogenetic as well as pharmacokinetic-guided dosing, including therapeutic drug monitoring. Dosing of anticancer agents in patients with renal or hepatic failure, and issues pertinent to dosing in the elderly are discussed in detail elsewhere. (See "Chemotherapy-related nephrotoxicity and dose modification in patients with renal insufficiency" and "Chemotherapy hepatotoxicity and dose modification in patients with liver disease" and "Systemic chemotherapy for cancer in elderly persons".)


Conventional cytotoxic agents — Appropriate dosing for cytotoxic anticancer agents has been largely determined from prospective and retrospective studies in which the goal was to maximize efficacy and minimize toxicity. The starting dose for conventional cytotoxic agents in phase I studies has generally been based upon animal studies, where doses are usually escalated until the LD10 is reached (the dose that results in lethality in 10 percent of the treated animals). By convention, in human phase I studies, the first dose employed has been one-tenth of the LD10.

Based upon the theory and intuitive belief that larger patients have a larger volume of distribution and a higher metabolizing capacity, it has been assumed that they require more drug to induce the same effects. In an attempt to minimize interindividual variation, dosing for most anticancer agents has generally been normalized using mg of drug per m2 of body surface area (BSA), which is calculated using a patient's height and weight.


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