Cautious Arguments in Favor of Body Surface Area–Based Dosing
Authors: Ulrich Schuler, Alex Sparreboom, Felix de Jongh, Jaap Verweij
Journal: Journal of Clinical Oncology (2002)

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2002.99.160 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 12377974 Cautious Arguments in Favor of Body Surface Area–Based Dosing Ulrich SchulerxUlrich SchulerSearch for articles by this author Alex SparreboomxAlex SparreboomSearch for articles by this author , Felix de JonghxFelix de JonghSearch for articles by this author , Jaap VerweijxJaap VerweijSearch for articles by this author Show More Medizinische Klinik und Poliklinik I, Dresden, GermanyErasmus MC-Daniel den Hoed Cancer Center, Rotterdam, the Netherlands https://doi.org/10.1200/JCO.2002.99.160 First Page Full Text PDF Figures and Tables © 2002 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse15102002In Reply:We thank Dr Schuler for his interest and comments on our article that was published in the September 1, 2001 issue of the Journal of Clinical Oncology.1 As pointed out, this article indeed contains an error in the equation that relates body-surface area (BSA) to the clearance (CL) of the unbound (free) fraction of cisplatin. Erroneously, the reported values for slope (a) and intercept (b) were derived from the same data with BSA as a function of CL [ie, BSA = (a × CL) + b]. The correct formula with the coefficients (± SE) from the linear-regression analysis is as follows (Fig 1): CL free (in L/h) = (31.80 ± 4.225) × BSA (in m2) + (−1.985 ± 7.897). Fig 1. Relationship between BSA and the CL of unbound cisplatin (CL free) in a group of 268 adult cancer patients. The raw data are plotted with each symbol representing an individual patient, and the fitted line represents a linear-regression analysis.The curvefit coefficients show 95% confidence limits of −17.53 to 13.56 (P = .802) for the intercept and 23.48 to 40.11 (P < .0001) for the slope, with an r value of 0.42 (R2 = 0.176). In line with our original conclusions, this suggests that despite the significant slope, BSA accounts for only a small percentage of the observed kinetic variability.We agree that there is no general consensus on optimal study designs to relate BSA-based dosing to pharmacodynamic outcome and that cutoff levels for significance and r still remain arbitrarily defined. Arguably, the best setting to test this relationship is a randomized comparative analysis with BSA-based versus flat-fixed dosing with appropriate attention to pharmacologic end points, as performed recently for paclitaxel.2 Unfortunately, for the vast majority of agents used in today’s clinical practice no data are available on the use of non-BSA–based dosing, with the exception of agents that do not induce any relevant degree of acute side effects (eg, bleomycin and novel target-based cytostatic drugs).3 Therefore, the issue of whether non-BSA dosing might offer any improvement cannot be evaluated. However, it can be anticipated that implementation of such concepts as flat-fixed dosing would have significant economic implications. The ability to manufacture a unit dose has obvious benefits for the pharmaceutical company involved. Similarly, reconstituting a fixed dose without subsequent individualization for different patients is more efficient and cost-effective than preparing individualized doses, and would eliminate a significant source of error in attempting to obtain precise dosing.4 In addition, and in contrast to the comment that BSA-based dosing is not dangerous, drug administration errors are very common in oncology and are usually the result of systematic error (eg, inaccuracy of the calculation algorithms) and inevitable convergence error (eg, use of inaccurate height and weight for BSA calculation).5Although a large number of studies have appeared in the literature that clearly question the routine use of BSA in drug dose calculation, the message seems not to have been heard or understood, and many clinicians are still concerned. This concern is based on the intuitive belief that patients with a larger BSA necessarily require more drug to induce the same drug effects. In this context, the statement “put a drug into a bigger volume and the concentration will decrease” is a remarkable and unnecessary oversimplification. Furthermore, there is ample evidence that for some water-soluble agents (eg, doxorubicin and irinotecan) CL actually decreases with an increase in BSA, presumably as a result of poor distribution to adipose tissue.6,7 A recent retrospective investigation involving 33 different drugs and 1,650 adult cancer patients shows that dosing strategies based on BSA may be relevant clinically only in very exceptional cases (Baher et al, manuscript submitted for publication). This is when drug disposition characteristics are confined to the central blood compartment (eg, temozolomide), and to a lesser extent, when renal function plays a principal role in drug elimination (eg, troxacitabine). This can be explained, in part, by known relationships between body size and blood volume and BSA and glomerular filtration rate, respectively.8,9 In any event, we hope that performing exploratory analyses of BSA-CL relationships, such as that performed previously for cisplatin, will encourage investigators to adequately define and optimize dosing strategies for other agents.1. De Jongh FE, Verweij J, Loos WJ, et al: Body-surface area-based dosing does not increase accuracy of predicting cisplatin exposure. J Clin Oncol 19:: 3733,2001-3739, Link, Google Scholar2. Smorenburg SM, Sparreboom A, Bontenbal M, et al: Randomized-crossover evaluation of body-surface area-based dosing versus flat-fixed dosing of paclitaxel. J Clin Oncol (in press) Google Scholar3. Felici A, Verweij J, Sparreboom A: Dosing strategies for anticancer agents: The good, the bad and body-surface area. Eur J Cancer 38:: 1674,2002-1681, Google Scholar4. 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