Body-Surface Area–Based Chemotherapy Dosing: Appropriate in the 21st Century?
Authors: Jan H. Beumer, Edward Chu, Salvatore J. Salamone
Journal: Journal of Clinical Oncology (2012)

The article by Griggs et al 1 gave guidelines for appropriate dosing for obese adult patients that use body-surface area (BSA) to determine dose.The oncology community is in general agreement that patients should be given an optimal dose that results in clinical benefit and that a reduction in "dose-intensity may compromise disease-free survival (DFS) and overall survival (OS) in the curative setting." 1(p1553) Historically, dosing of obese patients has been problematic, and to date, there has been no standardized approach.Although Griggs et al propose the use of BSA to determine dose, it seems that this recommendation lacks true level-one evidence.The new recommendation aims to achieve the same maximum doseintensity in the obese, arguing for full weight-based calculation of BSA to determine doses as opposed to using a reduced weight metric or dose capping.However, there is growing evidence that there are significant limitations with respect to BSA-based dosing.BSA dosing was originally derived, in 1916 using eight patients, by DuBois and DuBois 2 to adjust for basal metabolic rates in estimating the human starting dose from animal doses.This formula was used by Freireich in the 1960s to achieve uniformity in dosing patients who were being treated with phase I cytotoxics. 3However, there is no scientific basis for such use of BSA, and there is growing evidence that this approach is, in fact, invalid. 4-10BSA dosing is associated with high pharmacokinetic variability and is a poor indicator of optimal drug exposure.On this point, Baker et al 4 reviewed 33 investigational agents and found that BSA-based dosing reduced interpatient variability for only five (15%).Moreover, the reduction in clearance variability was between 15% and 35%, which indicates that only up to one third of the variability was explained by BSA.Felici et al 5 reported the variability in clearance of the most commonly used cytotoxics to be between 25% and 70%, with most drugs showing variability above 35%.They concluded: "BSA failed to individualize the effects of the majority of agents explored." 5(p1677) More recently, the exposure effect relationship has been wellcharacterized for many chemotherapeutics.For carboplatin, fluorouracil, docetaxel, and paclitaxel, the levels of exposure beyond which unacceptable toxicity occurs have been identified. [11][2][13][14][15][16][17] These maximum tolerated exposures (MTEs) have generally been derived from biologic effects correlated to exposure levels after BSA-based dosing.The exposure for fluorouracil varies 30-to 100-fold and for docetaxel up to seven-fold.This variability reflects differences in the way individual patients clear drugs, which underscores the need for an alternative to BSA-based dosing.It would be more appropriate to titrate an individual patient's dose to an MTE by means of therapeutic drug monitoring.In this regard, the most widely used measure of exposure is area under the concentration curve.Some may argue that there is insufficient evidence proving the benefit of therapeutic drug monitoring.Yet, have such rigorously controlled randomized trials been performed to prove the benefit of BSA-based dosing?In fact, the literature shows that BSA-based dosing does not achieve its goal of reducing pharmacokinetic variability and that it is merely used as a matter of convenience.It gives the false impression that wearepracticingpersonalizedmedicinebyusingapatient-specificmetric.If anything, the calculations involved in determining the dose-no matter how simple-are likely to result in increased dosing errors.To