Obesity in Dose Calculation: A Mouse or an Elephant?

Abstract

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 2 . 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][3][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

Dyslipidemia at diagnosis of childhood acute lymphoblastic leukemia

“…Overweight/obesity at time of ALL-diagnosis was associated to a poorer risk group stratification in our study indicating a poorer treatment outcome which previously have been shown by other studies [30,31]. Both interpatient variation of pharmacokinetics (over-and undertreatment) as well as protective mechanisms in adipocytes have been suggested to explain a worse therapy outcome in obese patients with ALL [30,45,46]. Furthermore, it has been discussed if obesity takes part in the' leukemogenesis' in adults, though it was not supported by our results [33,47,48].…”

Association of Body Composition with Outcome of Docetaxel Chemotherapy in Metastatic Prostate Cancer: A Retrospective Review

“…Gurney and Shaw eloquently discussed the dilemma of dose calculation for obese patients [ 36 ]. Obesity and body fat distribution are only two factors out of many that lead to inter-patient variability in pharmacokinetics [ 34 ].…”

Ultra-High-Precision, in-vivo Pharmacokinetic Measurements Highlight the Need for and a Route Toward More Highly Personalized Medicine

“…First, it is poorly correlated with the pharmacokinetics of many classes of drugs (Gurney, 1996; Dooley and Poole, 2000; Felici et al, 2002), often leading to suboptimal dosing (Sawyer and Ratain, 2001; Baker et al, 2002; Gao et al, 2008), including both inefficacious underdosing, and potentially lethal overdosing (Grochow et al, 1990). Second, BSA calculations fail to account for abnormal body sizes (Gurney and Shaw, 2007; Pai, 2012) or genetic variation across populations (Gurney, 1996, 2002). The field of pharmacogenetics seeks to overcome that latter factor by tailoring dosing to the specific genetic background of individual patients, but to date this is still poorly understood, lacks consistency in clinical outcomes, and has failed to adequately predict individual drug response (Shah and Shah, 2012).…”