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CORRESPONDENCE
September 10, 2012

Body-Surface Area–Based Chemotherapy Dosing: Appropriate in the 21st Century?

Publication: Journal of Clinical Oncology

To the Editor:

The article by Griggs et al1 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 dose-intensity 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 DuBois2 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.3 However, there is no scientific basis for such use of BSA, and there is growing evidence that this approach is, in fact, invalid.4-10 BSA dosing is associated with high pharmacokinetic variability and is a poor indicator of optimal drug exposure. On this point, Baker et al4 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 al5 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 well-characterized for many chemotherapeutics. For carboplatin, fluorouracil, docetaxel, and paclitaxel, the levels of exposure beyond which unacceptable toxicity occurs have been identified.11-17 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 we are practicing personalized medicine by using a patient-specific metric. If anything, the calculations involved in determining the dose—no matter how simple—are likely to result in increased dosing errors. To provide our patients with the best care, we need to understand the issues and take the appropriate steps to ensure that the MTE is, in fact, achieved.
Presently, analytic technologies are routinely available in clinical chemistry laboratories, and we are able to pharmacokinetically guide dosing in the clinic. Such a guided approach is already routine with transplantation agents, antiepileptics, and antibiotics. In addition, this approach would deal with many of the issues acknowledged by Griggs et al.1 The extrapolation of the rather sparse published data from the obese subpopulations of trials to the extremes of morbid obesity and pharmacogenetic or other covariate effects on drug clearance would be of no concern if dose management were to be guided by pharmacokinetics.
Moving away from BSA-based dosing presents challenges, but we should realize the potential gains and initiate clinical studies to support the better alternative. Oncology has made great strides during the past 50 years. Let us hope that, in another 50 years, we are not still recommending BSA-based dosing and that we will have moved to dosing a patient with the right drug at whatever dose required to achieve the right exposure.

Acknowledgment

Supported by Grant No. U01-CA099168 from the National Institutes of Health.

Authors' Disclosures of Potential Conflicts of Interest

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Employment or Leadership Position: Salvatore J. Salamone, Saladax Biomedical (C) Consultant or Advisory Role: Jan H. Beumer, Saladax Biomedical (C); Edward Chu, Myriad Genetics (C), Saladax Biomedical (C) Stock Ownership: Edward Chu, Saladax Biomedical; Salvatore J. Salamone, Saladax Biomedical Honoraria: Jan H. Beumer, Saladax Biomedical; Edward Chu, Roche Research Funding: None Expert Testimony: None Other Remuneration: None

Reference

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O Capitain, A Asevoaia, M Boisdron-Celle, etal : Individual fluorouracil dose adjustment in FOLFOX based on pharmacokinetic follow-up compared with conventional body-area-surface dosing: A phase II, proof-of-concept study Clin Colorectal Cancer [epub ahead of print on June 8, 2012]

Information & Authors

Information

Published In

Journal of Clinical Oncology
Pages: 3896 - 3897
PubMed: 22965963

History

Published online: September 10, 2012
Published in print: November 01, 2012

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Authors

Affiliations

Jan H. Beumer [email protected]
University of Pittsburgh Cancer Institute; University of Pittsburgh School of Pharmacy, Pittsburgh, PA
Edward Chu
University of Pittsburgh Cancer Institute; University of Pittsburgh School of Medicine, Pittsburgh, PA
Salvatore J. Salamone
Saladax Biomedical, Bethlehem, PA

Notes

Corresponding author: Jan H. Beumer, PharmD, PhD, University of Pittsburgh Cancer Institute, Room G27E, Hillman Research Pavilion, 5117 Centre Avenue, Pittsburgh, PA 15213-1863; e-mail: [email protected].

Funding Information

National Institutes of Health: U01-CA099168

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Jan H. Beumer, Edward Chu, Salvatore J. Salamone
Journal of Clinical Oncology 2012 30:31, 3896-3897

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