Clinical parameters and drug dosing indexed to body surface area (BSA) have been widely used. For example, cardiologists use indexation to BSA for the cardiac linear measurements, aortic valve area (AVA), stroke volume, left ventricular mass, and so on; oncologists use BSA indexed dosing for chemotherapeutic agents; nephrologists use indexation of renal function parameters to BSA. BSA is calculated by the 2 most commonly used formulas, Du Bois or Mosteller. However, despite its wide use, little attention was paid to the accuracy and validation of the calculated BSA.
The classic Du Bois formula, BSA(m2) = Weight (kg)0.425 × height (cm)0.725 × 0.007184, was developed in 1916 and has been considered the gold standard.
1
The equation is derived from the direct tape measurements of only 9 patients. Its validation with the direct tape measurement of BSA was done in only 17 cadavers.2
Mosteller further developed a simplified formula in 1987,3
BSA (m²) = ([Height (cm) × Weight (kg)] / 3600)½, which is the most commonly used in the United States due to its simplicity. The Mosteller formula was only validated by the correlation with the Du Bois equation. Du Bois was found to overestimate the BSA by more than 15% when compared with the direct measurements of BSA of 401 individuals, especially in patients who are obese.4
Furthermore, Mosteller BSA is 5% higher in female and 3% higher in male patients than the BSA from the Du Bois formula.5
This implies that the BSA calculated from Mosteller formula could overestimate BSA by 20%. The clinical impact of BSA overestimation has not been directly studied. Here I have summarized some indirect evidence to illustrate the impact by using 2 BSA indexation approaches, aortic valve stenosis and anthracycline dosing, as I practice in both cardiac imaging and cardio-oncology.AVA Indexed to BSA
Severe aortic stenosis (AS) is defined by a fixed AVA ≤ 1.0 cm2 with a transaortic velocity ≥4 m/s (mean gradient ≥40 mm Hg).
6
However, it is believed that indexing AVA by BSA (AVAi) can increase diagnostic specificity in small-sized patients with absolute AVA < 1 cm2 who have less-than-severe AS and increase sensitivity in large-sized patients with absolute AVA > 1 cm2 who do have severe AS. Current US guidelines recommend a value of 0.6 cm2/m2 as a cutoff for defining severe AS,6
which is consistent with an absolute AVA of 1.0 cm2 by assuming an average BSA of 1.67 cm2. However, the guidelines did not specify when or how to use AVAi.A growing body of evidence challenges 0.6 cm2/m2 as a cutoff for severe AS. In the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) population, the prevalence of severe AS increased from 29% to 44% when AVAi 0.6 cm2/m2 was used, in which BSA was calculated by the Mosteller formula. Patients with severe AS categorized by AVAi had significantly fewer events than those fulfilling only the AVA criteria.
7
High risk of events were only observed with AVA/BSA < 0.4 cm2/m2 if AVAi was used.8
All this evidence suggests that a cutoff of 0.6 cm2/m2 overestimated the severity of AS. However, the underlying mechanism for the overestimation was not explored. The explanation is likely an oversized BSA calculated by the formula. The cutoff 0.6 cm2/m2 will become 0.72 cm2/m2 if a 20% overestimation of BSA is taken into consideration. It is why a smaller cutoff of AVAi could better identify patients at high risk. A value of 0.6 cm2/m2 likely categorizes many patients with insignificant AS into severe AS due to the overestimated BSA, directly leading to many unnecessary aortic replacements.Therefore, the recommended cutoff value of 0.6 cm2/m2 based on a calculated BSA for defining severe AS should be abandoned. Severe AS diagnosed with the cutoff AVA 0.6 cm2/m2 if used should oblige diligent workup including peak transaortic velocity and dimensionless index. An exact BSA can be easily acquired from a low-cost, portable 3D anthropometric scanner or more sophisticated laser body scan
9
and should be used for indexing AVA. Of course, this approach itself should be validated and tested.Anthracycline Dosing Indexed to BSA
Despite the advances in targeted therapies in cancer treatment, anthracycline is still a mainstay of chemotherapy for patients with many types of solid tumors, hematological malignancies, and childhood cancers. BSA dosing, in which dosing of anthracycline is indexed to BSA, has been used for many decades. The overestimated BSA from the Mosteller formula will directly lead to the patient's overexposure to anthracycline, particularly in obese patients. There has been no study investigating the impact of anthracycline overexposure from BSA dosing. However, there is some indirect evidence.
Obesity has been known as a major risk factor for many chronic diseases. Interestingly, though the results were not fully consistent, many studies have reported that patients who are obese and received anthracycline-based chemotherapy had longer progression-free survival, overall survival, or increased pathological complete response when comparing patients who were not obese with breast cancer, Hodgkin lymphoma and diffuse large B-cell lymphoma (see Supplementary References, available online). However, the mechanism for better efficacy is unclear and the reduced drug clearance in patients who were obese was proposed but not supported.
10
Anthracycline overexposure from a formula-generated BSA dosing in patients who are obese is likely the underlying mechanism.The impact of obesity on anthracycline toxicity has been evaluated in retrospective studies with conflicting results. However, a prospective trial in patients who are obese with breast cancer concluded that toxicities rate is significantly increased when comparing a full BSA dosing of anthracycline-based chemotherapy with either a capped BSA at 2.0 m2 or ideal weight adjusted dosing.
11
Cardiotoxicity, the most common toxicity that limits the use of anthracycline, was not studied in the trial. In retrospective studies, obesity is independently associated with anthracycline-induced cardiac toxicity.12
The mechanism was not fully understood. In our practice, we have often observed that patients who are obese develop cardiotoxicity with a relatively low dose of cumulative doxorubicin indexed by BSA(<240 mg/m2). However, the absolute dose is much higher due to a large BSA. Our recent study shows that the absolute cumulative dose of doxorubicin not the accumulative dose indexed by BSA is an independent predictor of cardiotoxicity.13
Higher absolute dose due to the overestimated BSA calculated from the Mosteller formula, thereby increasing doxorubicin exposure, is likely the explanation for our finding.Anthracycline dosing, one of the most commonly used cytotoxic drugs in cancer treatment, has been largely empirical. Therefore, it is imperative to develop a better dose approach based on the exact 3D measurement of BSA with consideration of individual drug handling.
In conclusion, it is time to abandon formula-generated BSA in clinical practice. Its clinical impact could be far larger than what we know. It sounds ironic that we make clinical decisions based on measurements and give cytotoxic drugs, which are indexed to BSA derived from poorly validated formula, and meanwhile we claim that we are in the era of precision medicine. An exact BSA measured by a low-cost 3D scanner should be adopted and validated in clinical practice.
Supplemental References
Farr A, Stolz M, Baumann L, et al. The effect of obesity on pathological complete response and survival in breast cancer patients receiving uncapped doses of neoadjuvant anthracycline-taxane-based chemotherapy. Breast. 2017;33:153-158.
Landgren O, Andren H, Nilsson B, Ekbom A, Bjorkholm M. Risk profile and outcome in Hodgkin's lymphoma: is obesity beneficial? Ann Oncol. 2005;16:838-840.
Jones JA, Fayad LE, Elting LS, Rodriguez MA. Body mass index and outcomes in patients receiving chemotherapy for intermediate-grade B-cell non-Hodgkin lymphoma. Leuk Lymphoma. 2010;51:1649-1657.
Carson KR, Bartlett NL, McDonald JR, et al. Increased body mass index is associated with improved survival in United States veterans with diffuse large B-cell lymphoma. J Clin Oncol. 2012;30:3217-3222.
Weiss L, Melchardt T, Habringer S, et al. Increased body mass index is associated with improved overall survival in diffuse large B-cell lymphoma. Ann Oncol. 2014;25:171-176.
References
- Clinical calorimetry: tenth paper a formula to estimate the approximate surface area if height and weight be known.Arch Int Med. 1916; XVII: 863-871
- Human body surface area: validation of formulae based on a cadaver study.Hum Biol. 1984; 56: 475-488
- Simplified calculation of body-surface area.N Engl J Med. 1987; 317: 1098
- Body surface area formulae: an alarming ambiguity.Sci Rep. 2016; 6: 27966
- Body surface area in normal-weight, overweight, and obese adults. A comparison study.Metabolism. 2006; 55: 515-524
- 2020 ACC/AHA guideline for the management of patients with valvular heart disease: executive summary: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.Circulation. 2021; 143: e35-e71
- Indexing aortic valve area by body surface area increases the prevalence of severe aortic stenosis.Heart. 2014; 100: 28-33
- Outcome implication of aortic valve area normalized to body size in asymptomatic aortic stenosis.Circ Cardiovasc Imaging. 2016; 9e005121
- Total body and regional surface area: Quantification with low-cost three-dimensional optical imaging systems.Am J Phys Anthropol. 2021; 175: 865-875
- Chemotherapy dosing part I: scientific basis for current practice and use of body surface area.Clin Oncol. 2007; 19: 23-37
- Higher rate of severe toxicities in obese patients receiving dose-dense (dd) chemotherapy according to unadjusted body surface area: results of the prospectively randomized GAIN study.Ann Oncol. 2016; 27: 2053-2059
- Obesity as a risk factor for anthracyclines and trastuzumab cardiotoxicity in breast cancer: a systematic review and meta-analysis.J Clin Oncol. 2016; 34: 3157-3165
- Absolute cumulative dose not cumulative dose indexed by BSA predicts doxorubicin-induced subclinical cardiotoxicity.J Am College Cardiol. 2021; 77: 3307
Article Info
Publication History
Published online: April 22, 2022
Footnotes
Funding: None.
Conflicts of Interest: None.
Authorship: The author is solely responsible for all content.
Identification
Copyright
© 2022 Elsevier Inc. All rights reserved.
