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Journal of Clinical Oncology, Vol 24, No 10 (April 1), 2006: pp. 1489-1490 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.1607
Developing a New Framework for Dose CalculationDepartment of Medical Oncology and Department of Medicine, University of Sydney, Westmead Hospital, Westmead, Australia Drugs are to the medical oncologist what the scalpel is to the surgical oncologist. These are our basic tools, and using them correctly and deftly should be the most fundamental action in our day-to-day practice. Correct use of drugs with an extremely narrow therapeutic index is a key element that sets us apart from most other physicians. Critical decisions include the appropriateness and timing of treatment, which drugs to use, and at what dose. Appropriately, a lot of attention is given to the first two elements. However, as far as dose selection is concerned, often a dose is picked from a protocol, then set and forgotten, with the dose only changed if excessive toxicity occurs. Because of the nature of the drugs with which we deal, oncologists should understand drug disposition and dose selection better than any other medical specialists. We have known for some time that body surface area (BSA) -based dosing is inaccurate, on the whole favoring underdosing of individuals.1-3 The accumulated knowledge over the last decade indicates that we should move away from dose calculation based solely on BSA.3 Unfortunately, no practical alternative has been suggested, and we continue to use an imperfect system, each oncologist patching together a method that works to a degree for his or her patients.3,4 In the absence of a workable structure, how do we teach our trainees to calculate dose effectively? Dose calculation of chemotherapy could be described as more artistic than scientific, and therefore, a structure that is difficult to replicate. We must develop a new framework for dose calculation that is logical and that can be used in the clinic to form a foundation that can be further improved by clinical research.
In this issue of the Journal of Clinical Oncology, Loos et al5 propose such a framework using cisplatin as a model. This group of investigators had previously shown that BSA does not reduce the interpatient variation of cisplatin disposition and had recommended fixed dosing of this drug for patients of all body sizes.6 However, studies using fixed dosing of paclitaxel, irinotecan, cisplatin, epirubicin, or vinorelbine still show a wide variation in drug exposure and/or drug-induced neutropenia.3,6,7 In the study reported in this issue, the investigators refined their proposition regarding cisplatin by studying individuals at the extremes of BSA (males < 1.75 or > 2.05 m2; females < 1.60 or > 1.90 m2), treating patients with BSA-based or fixed doses for the first two cycles (or vice versa according to random assignment) and then comparing pharmacokinetic parameters of unbound platinum. Comparison of the first and second cycles in each patient showed an effect of BSA on area-under-the-curve (AUC) of unbound platinum. In high-BSA patients, BSA-based treatment led to a higher AUC than fixed doses. Conversely, in low-BSA patients, BSA-based treatment led to a lower AUC than fixed dosing. Comparison of clearance of unbound platinum between patient groups on the first cycle also showed a significant correlation with BSA in the study population. However, interpatient variability was extensive, and correction using BSA minimally reduced this variation (coefficient of variance, 20.8% v 17.1%). Additionally, a retrospective analysis of a larger group across all BSA values showed an association between body size and platinum clearance when examined in BSA clusters (
It is important to recognize that this study does not support the strict use of BSA for dose calculation of cisplatin. As with their previous study, BSA-based dose was associated with considerable variability in platinum clearance across all patients. However, the results suggested that fixed dosing for all patients might lead to excessive toxicity in small patients and underdosing in large patients. The authors maintained that fixed dose of cisplatin was a reasonable proposition, but in the presence of extremes of body size, BSA should be taken into account. This resulted in fixed-dose recommendations for BSA clusters. For example, for a protocol calling for a cisplatin dose of 70 mg/m2, all patients with BSA Although the link between drug exposure and body size is a tenuous one, it seems that extremes of body size do have an impact on the interaction between the drug and the recipient. A retrospective analysis of the International Breast Cancer Study Group showed that obese women with estrogen receptor–negative breast cancer treated with less than 85% of the BSA dose of adjuvant CMF (cyclophosphamide, methotrexate, fluorouracil) had a significantly worse survival compared with those receiving the protocol dose.8 Another retrospective analysis of 9,672 women with breast cancer treated with adjuvant doxorubicin and cyclophosphamide showed that overweight, obese, and severely obese patients were each significantly more likely to have first-cycle dose reductions. Importantly, the severely obese had a significantly lower incidence of neutropenic sepsis, even in those who received protocol doses.9 Additionally, body size may have an effect on the degree of myelosuppression, as shown in a recent study of fixed-dose vinorelbine, which may relate to an association between BSA and bone marrow volume.7 Without being defeatist, it is quite possible that we will never account for the complexities of drug elimination and drug effects to accurately calculate the correct dose for an individual patient every time. Drug elimination and normal tissue handling of drugs are bristling with nonlinear systems that change subtly, or even grossly on a day-to-day basis. We try to describe them by fitting linear models to estimate outcomes. However, can we ever hope to account for the myriad interactions of complex, changeable, and perhaps chaotic environmental and genetic factors? Currently, we need to accept that we don't fully understand how to adjust for all of these factors. For that reason, dose calculation must remain a continuous process in every individual. The narrower the therapeutic window, the more vigilant we must be to keep in the target range. Consequently, just as important as the method of dose selection is the practice of checking afterwards to ensure that the dose was correct. One way of doing this is to assume that normal and cancer cells respond similarly to a particular drug concentration. Given that a narrow therapeutic window exists for anticancer drugs, some toxicity or normal tissue effect needs to occur to be sure that the dose selected allowed an appropriate amount of drug to affect the cancer cells. This "toxicity-adjusted" dosing is a way of fine tuning the initial dose selection and should be a routine practice for both curative and palliative regimens.1 There is an important and growing body of evidence that lack of chemotherapy-induced toxicity (such as myelosuppression) is associated with worse outcome for cancers of the testis, breast, and ovary, and for non–small-cell lung cancer.10,11 We should embrace this new framework and extend it to drugs other than cisplatin after appropriate investigation. We can now start to put BSA in its place. It has some relevance, but not a lot. There are other parameters yet to be accurately defined that determine variability in drug disposition.12 By releasing the stranglehold of strict BSA dosing and adopting fixed doses of drug in BSA clusters, as suggested by Loos et al,5 our minds will be opened to other determinants of variability of drug disposition. We must actively investigate these factors and develop dosing strategies that account for these. We should vigorously examine dose effects and adjust dose up or down appropriately for every regimen, especially to minimize underdosing. Lastly, this framework should be tested in clinical trials to determine whether variability in drug effects can be reduced. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. Author Contributions
REFERENCES 1. Gurney H: Dose calculation of anticancer drugs: A review of the current practice and introduction of an alternative. J Clin Oncol 14:2590-2611, 1996[Abstract] 2. Baker SD, Verweij J, Rowinsky EK, et al: Role of body surface area in dosing of investigational anticancer agents in adults, 1991-2001. J Natl Cancer Inst 94:1883-1888, 2002 3. Sparreboom A: BSA-based dosing and alternative approaches. Clin Adv Hematol Oncol 3:448-450, 2005[Medline] 4. Gurney H: How to calculate the dose of chemotherapy. Br J Cancer 86:1297-1302, 2002[CrossRef][Medline] 5. Loos WJ, de Jongh FE, Sparreboom A, et al: Evaluation of an alternate dosing strategy for cisplatin in patients with extreme body surface area values. J Clin Oncol 24:1499-1506, 2006 6. 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 19:3733-3739, 2001 7. Wong M, Balleine RL, Blair EYL, et al: Predictors of vinorelbine pharmacokinetics and pharmacodynamics in patients with cancer. J Clin Oncol (in press) 8. Colleoni M, Li S, Gelber RD, et al: Relation between chemotherapy dose, oestrogen receptor expression, and body-mass index. Lancet 366:1108-1110, 2005[CrossRef][Medline] 9. Griggs JJ, Sorbero ME, Lyman GH: Undertreatment of obese women receiving breast cancer chemotherapy. Arch Intern Med 165:1267-1273, 2005 10. Gurney H: I don't underdose my patients do I? Lancet Oncol 6:637-638, 2005[CrossRef][Medline] 11. Di Maio M, Gridelli C, Gallo C, et al: Chemotherapy-induced neutropenia and treatment efficacy in advanced non-small-cell lung cancer: A pooled analysis of three randomised trials. Lancet Oncol 6:669-677, 2005[Medline] 12. Andersson T, Flockhart DA, Goldstein DB, et al: Drug-metabolizing enzymes: Evidence for clinical utility of pharmacogenomic tests. Clin Pharmacol Ther 78:559-581, 2005[CrossRef][Medline]
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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1.65 m2; 1.66-2.04 m2; 
2.05 m2). Although variability of platinum clearance within clusters remained high, mean clearance in the low-BSA group was 16% slower, and in the high-BSA group, 18% higher when compared with average-BSA patients. 
