According to the Centers for Disease Control and Prevention, 35.7% of American adults were obese in 2009-2010.¹ As the United States struggles to meet the health care demands of an increasingly overweight and obese population, health care providers must understand and adhere to medication dosage guidelines for these patients. Currently, body mass index (BMI) is used to categorize patients as underweight (BMI <18 kg/m²), normal weight (BMI = 18 – 24.9 kg/m²), overweight (BMI ≥25 – 29.9 kg/m²), obese (BMI ≥30 – 39.9 kg/m²), and morbidly obese (BMI ≥40 kg/m²). Despite the publication of the 2012 American Society of Clinical Oncology (ASCO) guidelines on chemotherapy dosing in obese patients,² which recommend that full weight–based cytotoxic chemotherapy doses be used to treat obese patients with cancer, significant confusion and misinformation persists in implementing appropriate dosing strategies.

Chemotherapy Dosing Strategies
Data was published 55 years ago supporting the use of body surface area (BSA) in dosing chemotherapy.³ Although this research focused on pediatric patients, the concept of using BSA as a main criterion for chemotherapy dosing quickly became the standard for dosing the majority of antineoplastic drugs in children and adults. Since that time, a number of methods for calculating BSA have been suggested, but none has been proven superior.⁴ BSA calculated with the various validated equations results in values within 10% of each other, an acceptable margin of error. The confusion in chemotherapy dosing for obese patients arises when deciding which weight (actual, adjusted, or ideal body weight) is used (see TABLE 1). 

Click here to view a larger version of this Table

The maximum tolerated dose for cancer drugs in humans is most commonly determined in phase I and phase II clinical trials. However, these studies often exclude overweight and obese individuals, and so clinical data supporting a maximum tolerated dose for these patients is limited. In the absence of data supporting the use of actual body weight in dosing obese patients, many practitioners have capped doses or used doses based on ideal body weight to minimize the possibility of toxicity.2 Unfortunately, the practice of using capped doses or doses based on ideal body weight has correlated with obese patients having worse outcomes, including lower rates of disease-free survival and overall survival, than normal weight patients.^2,5,6 

While underdosing is not the sole reason for the poorer outcomes obese cancer patients may experience, it is a contributing factor.^2,7 For example, current evidence demonstrates that increased adipose tissue may negatively influence the pathophysiology of many malignancies (eg, breast, colon, and ovarian cancers).² Additionally, hepatic drug clearance is often decreased in obese individuals due to fatty infiltration of the liver.⁸ Nevertheless, there is significant evidence that underdosing chemotherapy in obese patients negatively affects outcomes. 

Underdosing in Breast Cancer
The majority of data evaluating chemotherapy dosing for obese patients is found in the breast cancer literature. One study reported that 68% of overweight and obese patients with breast cancer received less than full body weight–based chemotherapy doses.⁵ Additionally, significant treatment dose variability was found in the over 900 practice sites included in the study. Interestingly, the rate of hospitalization for febrile neutropenia in overweight and obese patients who received full weight–based dosing was less than for their healthy weight counterparts. The lower rates of toxicity when utilizing full body weight–based dosing has been demonstrated repeatedly. A 2013 meta-analysis of 12 studies⁹ reported that full-dose chemotherapy based on actual body weight in obese patients did not result in increased rates of toxicity compared with healthy weight patients.

Clinical Guidelines for Dosing Chemotherapy in Obese Patients
As the body of evidence continues to demonstrate increased benefit and equal or lower risk of toxicity to dosing obese patients based on actual body weight, the use of capped chemotherapy doses or doses based on ideal weight is no longer being recommended for the majority of antineoplastic medications in obese patients (for exceptions, see TABLE 2). In 2012, ASCO published the first guidelines for dosing chemotherapy in obese adult patients, which recommend that full weight–based cytotoxic chemotherapy doses be used to treat obese patients with cancer.² However, these guidelines do not preclude the use of sound clinical judgment when dosing chemotherapy. Just like their normal weight counterparts, chemotherapy dosing for overweight and obese patients must take into account renal function, liver function, comorbid conditions, and any other compelling indications. Additionally, the management of toxicity (hematologic and/or nonhematologic) resulting in dose reductions should be based on the same clinically established management that applies to healthy-weight patients. Furthermore, dose reductions should not occur a priori based on fear of toxicity.



The ASCO guidelines address six clinical questions regarding the use of antineoplastic medications in overweight and obese patients with cancer2: 

• Is there evidence that full weight–based dosing increases toxicity in obese patients with cancer? There is no evidence that short- or long-term toxicity is increased when using full body weight dosing for chemotherapeutic agents. ASCO recommends using full body weight dosing for overweight, obese, and morbidly obese patients.
• Is there evidence that less than full weight–based dosing compromises efficacy in obese patients with cancer? Yes, there is evidence that certain outcomes, including disease-free and overall survival, are poorer when using less than full weight–based dosing.
• If an obese patient experiences high-grade toxicity, should chemotherapy doses or schedules be modified differently from modifications used for nonobese patients with cancer? No, clinicians should follow the same toxicity management protocols for overweight and obese patients that they follow for healthy weight patients. This includes hematologic and nonhematologic toxicities.
• Is the use of fixed-dose (dose prescribed independently of weight or BSA) cytotoxic chemotherapy ever justified? Are there unique dosing considerations for certain chemotherapeutic agents? Although the data is limited, ASCO recommends fixed-weight dosing for bleomycin, carboplatin, and vincristine.
• How should BSA be calculated? Specifically, what is the best formula to use for the obese patient with cancer? ASCO recommends the use of any of the validated BSA equations.
• What is the role of pharmacokinetic and/or pharmacogenetic factors when determining optimal chemotherapy dose and delivery (bolus, infusional, therapeutic drug monitoring) for obese patients with cancer? There is not enough data on the role of pharmacokinetic and/or pharmacogenetic factors to reject using full weight–based dosing for antineoplastic agents. ASCO recommends that more research be conducted for this patient population in this area.

Opportunities for Pharmacists as Educators
At the Dalton Oncology Clinic, part of the VCU Health System, pharmacy staff routinely check chemotherapy orders for appropriate dose, infusion time, and pre-medications. Since the publication of the ASCO guidelines for dosing chemotherapy in obese patients, a concerted effort has been made to adhere to the guidelines when preparing and dispensing chemotherapy. Since the pharmacy team was aware of the guidelines early on, we had the opportunity to educate our physician and nurse colleagues through group in-services and in patient-specific instances regarding the appropriate dosing of chemotherapy in overweight and obese patients. As an academic medical center, we routinely have student pharmacists, nurses, and physicians in our patient care areas. By exposing learners to evidence-based pharmacy practices and interdisciplinary team-based learning, we ensure that new practitioners are not only providing excellent evidence-based patient care, but that they are also experiencing the value pharmacy services can offer firsthand. 

Additionally, since pharmacists are by definition the drug experts, we should advocate for and participate in additional clinical studies that include overweight and obese patients in determining optimal dosing as new antineoplastic drugs are developed. 

Conclusion
The publication of the ASCO guidelines on chemotherapy dosing in obese patients is a positive first step in the clinical management of cancer in overweight and obese patients. More research is needed to evaluate not only the efficacy and safety of medications, but also to determine the pharmacokinetics, pharmacodynamics, and influence of genetics on the effects of new agents in overweight and obese patients. Until significant progress is made in identifying effective strategies to reverse the obesity epidemic in the US, these considerations will be paramount to ensure appropriate care of overweight and obese patients with cancer.

References

1. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of obesity in the United States, 2009-2010. NCHS Data Brief. Jan. 2012; 82. http://www.cdc.gov/nchs/data/databriefs/db82.pdf Accessed October 17, 2013.
2. Griggs, JJ, Mangu PB, Anderson H, et al. Appropriate chemotherapy dosing for obese adult patients with cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2012;30(13):1553-1561.
3. Pinkel D. The use of body surface area as a criterion of drug dosage in cancer chemotherapy. Cancer Res. 1958:18; 853-856.
4. Lyman GH, Sparreboom A. Chemotherapy dosing in overweight and obese patients with cancer. Nat Rev Clin Oncol. 2013;10(8):451-459.
5. Griggs JJ, Sorbero ME, Lyman G.H. Undertreatment of obese women receiving breast cancer chemotherapy. Arch Intern Med. 2005;165(11):1267-1273.
6. Protani M, Coory M, Martin JH. Effect of obesity on survival of women with breast cancer: systemic review and meta-analysis. Breast Cancer Res Treat. 2010;123(3):627-635.
7. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of US adults. N Engl J Med. 2003;348:1625-1638.
8. Cheymol G. Clinical pharmacokinetics of drugs in obesity. An update. Clin Pharmacokinet. 1993;25(2):103-114.
9. Hourdequin KC, Schpero WL, McKenna DR, Piazik BL, Larson RJ. Toxic effect of chemotherapy dosing using actual body weight in obese versus normal-weight patients: a systematic review and meta-analysis [published online ahead of print August 21, 2013]. Ann Oncol. doi:10.1093/annonc/mdt294  

Jennifer Neal, PharmD, BCOP, is an assistant professor of pharmacy at the Virginia Commonwealth University (VCU) School of Pharmacy, where she coordinates the oncology curriculum. In addition to her educational duties, she has a clinical practice site at the Dalton Oncology Clinic at the VCU Health System where she works with adult leukemia and lymphoma patients.