Dosing Chemotherapy in Obese Patients, Still Not Answered

Obesity rates in adults have been increasing in the United States since the 1980s.¹ The Centers for Disease Control and Prevention reported that in 2018 (the latest data available), 42% of Americans were considered obese.² Cancer is also increasing in numbers over time, and obesity has been identified as a risk factor for the development of several types of cancer.^3,4 Thus, as obesity in the population increases, we can expect that the number of patients with cancer who are overweight or obese will also increase.

This raises the question of the routine chemotherapy dosing conventions. Because clinicians are concerned with overdosing obese patients, they are routinely tasked with questions such as—Should we use actual body weight, ideal body weight, or something in between? Overdosing patients is a concern for all clinicians, but underdosing may be just as problematic. Therefore, we must consider the questions related to dose reduction of chemotherapy based on multiple reports in the medical literature indicating that such reductions may compromise patient outcomes.^5-11 Although many clinicians would argue that this question has been answered, and we have published guidelines outlining how to manage dosing in obese patients,^12,13 the questions keep re-emerging.

The goal in bone marrow transplantation is to use high doses of chemotherapy in an attempt to kill the tumor while overcoming the adverse event of bone marrow suppression by supplying stem-cell rescue. This allows clinicians to bypass the initial dose-limiting adverse reactions to many chemotherapy agents. Although high doses of chemotherapy are part of the treatment plan, dose reductions are still being used in obese patients, for fear that using the patient’s actual weight will increase the adverse effects compared with using an adjusted weight; but this also means that as clinicians we worry about compromising the patient’s response or survival, by “short-changing” the patient regarding the chemotherapy dose.

In this issue of the Journal of Hematology Oncology Pharmacy, Zink and colleagues present a retrospective analysis of the use of an adjusted body weight based on a 25% adjustment between the patient’s ideal and actual weight for dosing busulfan and fludarabine in patients undergoing a transplant.¹⁴ The authors applied this dose adjustment to all patients, not just to those defined as obese. They examined the time to disease relapse and overall survival at 6 months and at 1 year.

The authors recognized that the dose was not the sole factor in predicting disease relapse and used the Disease Risk Index (DRI) score to help them adjust for the confounding factors that affect disease relapse in patients undergoing a transplant. Characteristic to such studies, this study involves a small sample size from a single institution. A total of 56 (41.4%) patients were categorized as obese, defined as a body mass index >30 kg/m², and 51% of the patients were in the intermediate-risk DRI category. The patients had a significant difference in actual body weight and body surface area (BSA); however, no difference was found in the adjusted body weight parameters between obese and nonobese patients. Furthermore, busulfan’s pharmacokinetics were not reported.¹⁴

The authors reported no difference in the outcome measures of disease relapse or overall survival at 6 months and 1 year. Although this is statistically correct, the hazard ratio for disease relapse at 6 months was 1.85 for all patients and 2.35 in the patients with intermediate-risk DRI; these 2 hazard ratios had very large confidence intervals as a result of the small sample size.¹⁴

If the goal of this study was to analyze early disease relapse, this would suggest that perhaps there is a potential problem. Although not statistically significant, many clinicians would be uncomfortable with an 85% chance of disease relapse. This is not to suggest that chemotherapy dosing based on actual body weight would have produced better results, which we cannot say about this type of a study. And with the overall relapse rate at 1 year and the overall survival data not being different between the 2 groups, it is hard to know what to make of these data. To answer that question fully, a better comparison needed to be done between actual body weight dosing and adjusted body weight dosing in obese patients, but this was not possible, given the retrospective nature of the study.

Many clinicians spend too much time agonizing about the doses of chemotherapy. The assumption is that because we individualize doses for a patient, the result is a more exact dose calculation. The reality is, however, that all the dosing calculations are based on an estimate, either because of the dose-escalation nature of phase 1 clinical trials, or because of the body measurements used for dose calculations, or both.

For example, BSA, which is the most common method used to calculate chemotherapy doses, consists of measured parameters (ie, height and weight) that are then applied to a population-derived equation to arrive at an estimate. Developed in the 1950s as a method to translate dosing in animals into humans, the use of BSA for dosing chemotherapy was never intended to become the standard by which chemotherapy is being dosed.¹⁵

No scientific study has yet proved that BSA is a better dosing measurement than body weight or even fixed doses of chemotherapy. In fact, studies have shown that the pharmacokinetics parameters do not correlate with BSA.¹⁶ Some researchers have even suggested that flat dosing of some chemotherapy agents based on population parameters is just as effective as a dosing strategy.^16-19 At the same time, a growing body of evidence suggests that chemotherapy dosing in obese patients based on actual body weight is not associated with increased adverse events.^20-23 Like BSA, adjusted body weight uses a measured value and creates an estimate based on some arbitrary adjustment—as was used in this study, at 25%¹⁴—which results in a dose that is as much of a guess as it is individualized.

Studies often focus on the pharmacokinetics of dosing patients with different body weights or BSA,^24,25 but given the lack of correlation, the true question is the effect of dosing strategies on patient outcomes, which is the refreshing part of the study by Zink and colleagues.¹⁴ Most studies focus on the adverse events associated with weight-based dosing strategies,²³ whereas Zink and colleagues focused on the end points of disease relapse and overall survival,¹⁴ which could give us a hint as to whether the reducing of doses is harming patients. The problem is, however, that the true comparison, as the authors correctly pointed out in their limitations section,¹⁴ is not obese versus nonobese patients, but should rather be dosing based on actual body weight versus adjusted body weight in obese patients. Only then will we be able to tell if the dose reduction leads to differences in outcomes.

The current study by Zink and colleagues suggests that for obese patients, an adjusted body weight dose reduction of high-dose chemotherapy in the transplant setting does not adversely affect outcomes compared with a similar dosing strategy in nonobese patients.¹⁴ Yet as is the case with other studies on dosing in obese patients, this study leaves us with as many questions as it answers. So, we still do not know the answers to the question—Should we use actual body weight, ideal body weight, or something in between?

References

1. Hales CM, Fryar CD, Carroll MD, et al. Trends in obesity and severe obesity prevalence in US youth and adults by sex and age, 2007-2008 to 2015-2016. JAMA. 2018;319:1723-1725.
2. Centers for Disease Control and Prevention. Adult obesity facts. Updated June 7, 2021. www.cdc.gov/obesity/data/adult.html. Accessed October 29, 2021.
3. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin. 2021;71:7-33. Erratum in: CA Cancer J Clin. 2021;71:359.
4. De Pergola G, Silvestris F. Obesity as a major risk factor for cancer. J Obes. 2013;2013:291546. doi: 10.1155/2013/291546.
5. Bonadonna G, Valagussa P, Moliterni A, et al. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. N Engl J Med. 1995;332:901-906.
6. Bonneterre J, Roché H, Kerbrat P, et al. Epirubicin increases long-term survival in adjuvant chemotherapy of patients with poor-prognosis, node-positive, early breast cancer: 10-year follow-up results of the French Adjuvant Study Group 05 randomized trial. J Clin Oncol. 2005;23:2686-2693.
7. Budman DR, Berry DA, Cirrincione CT, et al; for the Cancer and Leukemia Group B. Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. J Natl Cancer Inst. 1998;90:1205-1211.
8. Lepage E, Gisselbrecht C, Haioun C, et al; for the GELA. Prognostic significance of received relative dose intensity in non-Hodgkin’s lymphoma patients: application to LNH-87 protocol. Ann Oncol. 1993;4:651-656.
9. Griggs JJ, Sorbero MES, Lyman GH. Undertreatment of obese women receiving breast cancer chemotherapy. Arch Intern Med. 2005;165:1267-1273.
10. Mayers C, Panzarella T, Tannock IF. Analysis of the prognostic effects of inclusion in a clinical trial and of myelosuppression on survival after adjuvant chemotherapy for breast carcinoma. Cancer. 2001;91:2246-2257.
11. Lyman GH. Impact of chemotherapy dose intensity on cancer patient outcomes. J Natl Compr Canc Netw. 2009;7:99-108.
12. 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;30:1553-1561.
13. Bubalo J, Carpenter PA, Majhail N, et al. Conditioning chemotherapy dose adjustment in obese patients: a review and position statement by the American Society for Blood and Marrow Transplantation Practice Guideline Committee. Biol Blood Marrow Transplant. 2014;20:600-616.
14. Zink KA, Stein J, Ten Eyck P, Ginn M. Impact of using adjusted body surface area in obese patients receiving ablative busulfan plus fludarabine conditioning regimen before hematopoietic stem-cell transplant. J Hematol Oncol Pharm. 2021;11(6):306-311.
15. Pinkel D. The use of body surface area as a criterion of drug dosage in cancer chemotherapy. Cancer Res. 1958;18:853-856.
16. Felici A, Verweij J, Sparreboom A. Dosing strategies for anticancer drugs: the good, the bad and body-surface area. Eur J Cancer. 2002;38:1677-1684.
17. Ekhart C, Rodenhuis S, Schellens JHM, et al. Carboplatin dosing in overweight and obese patients with normal renal function, does weight matter? Cancer Chemother Pharmacol. 2009;64:115-122.
18. Ekhart C, de Jonge ME, Huitema ADR, et al. Flat dosing of carboplatin is justified in adult patients with normal renal function. Clin Cancer Res. 2006;12:6502-6508.
19. Mathijssen RHJ, de Jong FA, Loos WJ, et al. Flat-fixed dosing versus body surface area–based dosing of anticancer drugs in adults: does it make a difference? Oncologist. 2007;12:913-923.
20. Lopes-Serrao MD, Gressett Ussery SM, Hall RG II, Shah SR. Evaluation of chemotherapy-induced severe myelosuppression incidence in obese patients with capped dosing. J Oncol Pract. 2011;7:13-17.
21. Field KM, Kosmider S, Jefford M, et al. Chemotherapy dosing strategies in the obese, elderly, and thin patient: results of a nationwide survey. J Oncol Pract. 2008;4:108-113.
22. Shayne M, Culakova E, Wolff D, et al. Dose intensity and hematologic toxicity in older breast cancer patients receiving systemic chemotherapy. Cancer. 2009;115:5319-5328.
23. Hourdequin KC, Schpero WL, McKenna DR, et al. Toxic effect of chemotherapy dosing using actual body weight in obese versus normal-weight patients: a systematic review and meta-analysis. Ann Oncol. 2013;24:2952-2962.
24. Green B, Duffull SB. What is the best size descriptor to use for pharmacokinetic studies in the obese? Br J Clin Pharmacol. 2004;58:119-133.
25. 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. 2002;94:1883-1888.