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Journal of Clinical Oncology, Vol 25, No 30 (October 20), 2007: pp. 4703-4704 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.1078
Obesity in Dose Calculation: A Mouse or an Elephant?Department of Medical Oncology, Westmead Hospital, New South Wales, Australia How many of us give a "full" dose of chemotherapy to an obese patient—even in the curative setting? Dose calculation in the obese is a confusing but important puzzle for the oncologist and is becoming a more frequent issue because of the obesity epidemic in Western societies. Although it is clear that body size plays only a minor role in interpatient variability of systemic exposure, it is an easily defined parameter and probably gains more significance at the extremes of body size. Imagine this scenario: You need to prescribe adjuvant chemotherapy for an otherwise well woman with high-risk breast cancer and who has a body surface area (BSA) of 2.3 m2. Your pen is poised over the order sheet. Do you grit your teeth and prescribe 170 mg of docetaxel, 115 mg of doxorubicin, and 1,150 mg of cyclophosphamide? You understand that this is the correct thing to do. Studies have shown that obese patients with breast cancer frequently receive a reduced dose of chemotherapy because of a desire to avoid toxicity.1,2 If anything, obese patients seem to be less likely to develop neutropenic sepsis, even if actual body weight (ABW) is used.2-4 Furthermore, obese patients who receive arbitrary dose reductions have a worse outcome.4,5 However, 170 mg of docetaxel is a big dose in anyone's book and it is a drug that can be unforgiving. You do not want your patient to succumb to overwhelming sepsis. So maybe your courage falters so you cap her BSA at 2.0 or 2.1 or something else? Perhaps you decide that, today, ideal body weight has its merits after all? Let's be honest —we all do it. In our department, we have a weekly chemotherapy write-up in which all the consultants and trainees meet together to order the treatment for the coming week. When a trainee proceeds to calculate a treatment dose for an obese patient, the inevitable discussion ensues, often in hushed tones, regarding what the dose should be. It is sobering to listen to the conversation between an experienced oncologist, the oncology pharmacist and trainee as they struggle with a solution that never seems to have a satisfactory answer—and one that may change from week to week. There is still a persistent reluctance for medical oncologists to prescribe doses based on actual body weight for obese patients even though this has been shown to be safe.4,5 The article by Sparreboom et al,6 in this issue of the Journal of Clinical Oncology gives us further insight into dose calculation in the obese. The investigators tackled this problem by reevaluating data subsets from previously published studies of eight anticancer drugs and compared results for patients with a body mass index (BMI) of more than 30 (obese patients) to those with a BMI of less than 25 (lean patients). Using actual area under the curve (AUC) in lean patients as the target standard, they compared a raft of theoretical AUCs derived from actual clearance (CL) in obese patients using a number of alternate weight measures. They calculated data using the formula [Theoretical AUC = theoretical dose / actual CL]. The theoretical dose was based on the various weight descriptors (ideal weight [IDW], ABW, lean body mass, and others). The aim was to define the weight descriptor in obese patients that gives the same AUC in an obese patient as that in a lean patient. The authors confirm that arbitrary capping of dose in obese patients is not supported for any of the eight drugs. They also broadly conclude that there is no support for the practice of dose reduction because of obesity. The study also supports the use of ABW rather some other weight permutation for dose calculation of the drugs studied. This analysis by no means gives us all the answers, and some of the results go against findings from other studies. For example, the authors found that doxorubicin clearance was significantly reduced in obese women compared with lean women, implying that obese woman should receive a lower dose of doxorubicin not a higher dose. But this is contrary to what has been found in retrospective studies of breast cancer patients mentioned previously herein.2,5 The authors correctly pointed out there are obviously other factors at play besides drug clearance. For example, Wong et al7 have shown a relationship between BSA and vinorelbine-induced neutropenia that was not related to drug CL and hypothesized that BSA reflects a patient's bone marrow reserve. Body distribution of drug is another possible factor. Sparreboom et al defined obesity as a BMI of more than 30 according to the WHO definition. However, BMI, although a predictor of obesity, is not in itself a definition of the condition. There may be a difference in drug disposition in patients of different body composition but with a BMI of more than 30. For example, a tall, muscular patient with little body fat may have a very different drug disposition from another patient with significant central obesity from metabolic syndrome. That is a question that could be readily answered with an appropriate pharmacokinetic study. It is important to remember that the results of the study by Sparreboom et al, as well as others examining dose calculation, are based on averages of a population and can be regarded only as general recommendations. On average, a patient with a high BSA needs a larger dose. Generally speaking, an obese patient should have his or her dose based on actual weight. But just like median survival figures, these recommendations weaken when it comes down to an individual. Other factors need to be considered. Every oncologist knows that the published median survival figure of 24 months for metastatic colon cancer is meaningless for an obese patient who is bed bound and with severe liver dysfunction from extensive liver metastases. Likewise, a general recommendation for using ABW alone for dose calculation of oxaliplatin for the same patient should rightly be ignored by the treating oncologist. In the same way, the presence of obesity does not override the presence of a UGT1A1*28 polymorphism in a patient receiving irinotecan or another patient with dihydropyrimidine dehydrogenase deficiency treated with fluouracil.8,9 Obesity alone does not prevail over the CYP3A4 inhibiting effect of ritonavir in a patient receiving doxorubicin.10 Most importantly, obesity may not be the dominating factor in dose calculation for a patient who, for other undefined reasons, has reduced drug elimination. In other words, it is important to realize that drug elimination for all drugs varies widely between individuals, obese or otherwise, and often this variation eclipses any contribution body size has to drug disposition. In many individuals, accounting for obesity is the "mouse" compared with the "elephant" of interpatient variation in drug effect. Obesity is probably important only if the patient has "average" drug metabolism and elimination. So what recommendations can be given regarding dose calculation in the obese? Clearly, we need prospective trials using end points other than systemic drug exposure, such as toxicity and survival. Ideally, patients with a high BSA who are obese, compared with those with high BSA and are lean, should be differentiated. In the meantime, we have to use the information we have to reach a consensus based on data, pragmatism, and clinical experience. In our department, we have rules that we follow that can now be further refined on the basis of the article by Sparreboom et al. In our view, obesity, and body size in general, needs to be taken into account...but only a little. We calculate a protocol dose using BSA and regard it as a "dose to be considered" but not actually given. We round the dose mercilessly for safety and cost considerations which, in practice, results in a range of fixed doses. Generally speaking, patients with a higher BSA will get a higher dose than will those with a smaller BSA. However, we take other known considerations such as concomitant drugs, performance status, previous treatment, as well as renal and hepatic function, into account and adjust dose if needed. Most importantly, because we know that we will be wrong at least 50% of the time, after the treatment is given, we adjust dose up and down in the absence or presence of toxicity.11 We should not be afraid to increase doses above those generally used, such as in a person with a high BSA who is otherwise healthy or in a patient who seems to have fast drug elimination that has been detected because of the lack of toxicity from treatment. A few studies have shown the utility of toxicity-adjusted dose,12,13 and further prospective trials are underway. Now, on the basis of the current article, further rules can be added. (1) BSA should not be capped at an arbitrary value. (2) When using BSA as a starting dose "guestimate as described herein, ABW should be used, not some other measure such as IDW. (3) Some drugs have special considerations, such as carboplatin, where it appears that an average of ABW and IDW is the best predictor of CL within the Chatelut formula that uses serum creatinine to calculate dose.14 This study helps clarify what is known about drug dosing for obese patients, but also highlights important areas that need further investigation. It confirms that actual body weight is currently the most accurate and safe way to calculate anticancer drug doses for obese patients. The use of other weight descriptors carries the significant risk of underdosing patients with the potential for suboptimal treatment outcomes. Appreciating the different body shapes and sizes that contribute to a high BSA (or BMI) cannot be overemphasized. Pharmacokinetic studies are required to determine whether these subgroups have different drug dispositions. Obesity does seem to affect the pharmacokinetics of some drugs. Despite this, it is really the elephant of interpatient variation in drug metabolism and elimination (which obesity may also affect) that has a much more powerful influence on drug effect. Further research into interpatient variations in anticancer drug metabolism will be another step toward the ultimate goal of individualized cancer therapy. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Conception and design: Howard Gurney Manuscript writing: Howard Gurney, Rachel Shaw Final approval of manuscript: Howard Gurney, Rachel Shaw REFERENCES
1. Griggs J, Culakova E, Sorbero MES, et al: Effect of patient socioeconomic status and body mass index on the quality of breast cancer adjuvant chemotherapy. J Clin Oncol 25:277-284, 2007 2. Griggs J, Sorbero MES, Lyman GH: Undertreatment of obese women receiving breast cancer chemotherapy. Arch Intern Med 165:1267-1273, 2005 3. Jenkins P, Elyan S, Freeman S: Obesity is not associated with increased myelosuppression in patients receiving chemotherapy for breast cancer. Eur J Cancer 43:544-548, 2007[CrossRef][Medline] 4. Rosner GL, Hargis JB, Hollis DR, et al: Relationship between toxicity and obesity in women receiving adjuvant chemotherapy for breast cancer: Results from Cancer and Leukemia Group B study 8541. J Clin Oncol 14:3000-3008, 1996[Abstract] 5. 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] 6. Sparreboom A, Wolff AC, Mathijssen RH, et al: Evaluation of alternate size descriptors for dose calculation of anticancer drugs in the obese. J Clin Oncol 25:4707-4713, 2007 7. Wong M, Balleine RL, Blair EY, et al: Predictors of vinorelbine pharmacokinetics and pharmacodynamics in patients with cancer. J Clin Oncol 24:2448-2455, 2006 8. Ramchandani RP, Wang Y, Booth BP, et al: The role of SN-38 exposure, UGT1A1*28 polymorphism, and baseline bilirubin level in predicting severe irinotecan toxicity. J Clin Pharmacol 47:78-86, 2007 9. Morel A, Boisdron-Celle M, Fey L, et al: Clinical relevance of different dihydropyrimidine dehydrogenase gene single nucleotide polymorphisms on 5-fluorouracil tolerance. Mol Cancer Ther 5:2895-2904, 2006 10. Bower M, McCall-Peat N, Ryan N, et al: Protease inhibitors potentiate chemotherapy-induced neutropenia. Blood 104:2943-2946, 2004 11. 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] 12. Bergh J, Wiklund T, Erikstein B, et al: Tailored fluorouracil, epirubicin, and cyclophosphamide compared with marrow-supported high-dose chemotherapy as adjuvant treatment for high-risk breast cancer: A randomized trial. Lancet 356:1384-1391, 2000[CrossRef][Medline] 13. Gurney H: I don't underdose my patients, Do I? Lancet Oncol 6:637-638, 2005[Medline] 14. Bénézet S, Guimbaud R, Chatelut E, et al: How to predict carboplatin clearance from standard morphological and biological characteristics in obese patients. Ann Oncol 8:607-609, 1997
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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