Obesity in Dose Calculation: A Mouse or an Elephant?
Authors: Howard Gurney, Rachel Shaw
Journal: Journal of Clinical Oncology (2007)

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 m. 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. If anything, obese patients seem to be less likely to develop neutropenic sepsis, even if actual body weight (ABW) is used. Furthermore, obese patients who receive arbitrary dose reductions have a worse outcome. 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. The article by Sparreboom et al, 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. The authors correctly pointed out there are obviously other factors at play besides drug clearance. For example, Wong et al have shown a relationship between BSA and vinorelbineinduced 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 JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 25 NUMBER 30 OCTOBER 2