Flat-Fixed Dosing Versus Body Surface Area–Based Dosing of Anticancer Drugs in Adults: Does It Make a Difference?

Abstract

LEARNING OBJECTIVESAfter completing this course, the reader will be able to:1. Describe how and why BSA-based dosing was implemented into oncology. 2. Discuss if flat-fixed dosing of adults has advantages over BSA-based dosing in terms of interpatient pharmacokinetic variation of anticancer drugs, efficiency, and costs. 3. Explain which alternative dosing strategies for BSA-based dosing may have potential, leading to a minimum of adverse events and superior therapeutic outcome.Access and take the CME test online and receive 1 AMA PRA Category 1 Credit ™ at CME.TheOncologist.com CME CME ABSTRACTThe current practice of using body-surface area (BSA) in dosing anticancer agents was implemented in clinical oncology half a century ago. By correcting for BSA, it was generally assumed that cancer patients would receive a dose of a particular cytotoxic drug associated with an acceptable degree of toxicities without reducing the agent's therapeutic effect. More recently, doubt has arisen to this hypothesis, and for many drugs, the effects of BSA on the pharmacokinetics of these agents have therefore been studied retrospectively. In (by far) most cases, use of BSA does not reduce the interindividual variation in the pharmacokinetics of adults, and thus, a logical rationale for further use of this tool in dosing adults is lacking. As a result, alternative dosing strategies have been proposed in order to replace BSA-based dosing. Flat-fixed dosing regimens have been suggested, thereby avoiding potential dose calculation mistakes. As flat-fixed dosing does not typically lead to greater pharmacokinetic variability, it does not seem worse than using BSA-based dosing. While it provides a simplification, it can, however, be questioned whether to call this an improvement or not. Classic cytotoxic agents are known for their relatively narrow therapeutic window. This means that "low" doses of these drugs may not be effective, while "high" doses may be (very) toxic for the patient. Therefore, the optimal dose should be somewhere in between, thereby leading to the best possible treatment, which means yielding maximal therapeutic effect given tolerable and manageable toxicities. Based on the theory that large patients have a larger volume of distribution and a higher metabolizing capacity, it is assumed that those patients need to be dosed higher than smaller patients to reach equal drug concentrations. For this reason, traditionally, the administered dose is typically adjusted to the body-surface area (BSA) of the individual patient. BSA was originally calculated using a formula based on length and weight developed by DuBois and DuBois in 1916 [1] from an investigation that involved only nine individuals (Table 1) [1][2][3][4][5]. Although validation of the derived formula was not performed initially [3, 4], the use of BSA was incorporated into animal studies for the purpose of allometric scaling, and in the 1950s, BSA-based dosing was introduced into pediatric oncology [6,7]. Without further study, its use was also incorporated int...

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