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Body Surface Area Capping May Not Improve Cytotoxic Drugs Tolerance

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Body Surface Area Capping May Not Improve Cytotoxic Drugs Tolerance www.nature.com/scientificreports OPEN Body surface area capping may not improve cytotoxic drugs tolerance Wafa Bouleftour1*, Agathe Viard2, Benoite Mery1, Robin Chaux3, Nicolas Magne4, Xavier Simoens2, Romain Rivoirard1 & Fabien Forges2 Capping body surface area (BSA) at 2 m2 is a routine clinical practice. It aims at reducing toxicities in over 2 m2 BSA patients. 455,502 computerized chemotherapy prescriptions made between 2011 and 2017 were taken from BPC software. Chemotherapy computerized order entry is created by a senior physician prescribers before patient consultation. Only prescriptions with dose calculation involving BSA were selected. 51,179 chemotherapy prescriptions were analyzed; corresponding to 7206 patients who received intravenous chemotherapy. The number of chemotherapy prescriptions in over 2 m2 BSA patients was nearly the same in the hematology as in the oncology departments. But, 79.1% of prescriptions were capped at 2 m2 in the oncology department contrary to 21.9% in the hematology department. Practices analysis showed more dose limitation in palliative situations in both departments. Unexpectedly, 6.53% of capped prescriptions were performed in patients with normal BMI. The patients who received capped doses of chemotherapy had neither fewer dose reductions due to toxicity nor deterioration of their general condition. Capping did not induce fewer dose reductions in patients with BSA greater than 2 m2. Prospective studies in this population are needed to standardize chemotherapy administration in population with BSA > 2 m2. What characterizes injectable anticancer drugs is their narrow therapeutic index, posology liked with dose intensity and signifcant variable non-specifc toxic efects. In an attempt to maximize anti-tumor efects associ- ated with a good tolerance of treatment and acceptable levels of toxicity, drugs prescriptions were based on body surface area (BSA). Historically, BSA has been the dose calculation indicator that best limits inter-individual variations1. Indeed, BSA allows to normalize some physiological parameters infuencing pharmacokinetic (car- diac output, lef ventricular mass, renal clearance) and to determine the dose of drug to be administered in patients with diferent body sizes 2,3. Tese parameters have been shown to be better correlated with BSA than other weight descriptors4–6. BSA formula was originally developed by Du bois and Du bois7. Tis formula dates back to 1916, it was validated on nine patients whose weight ranged from 25 to 90 kg. It was not designed for obese or underweight population. Many other formulae have been developed to sharpen BSA estimation but unfortunately they have resulted in a too high variability between formulae8. None of the formulae gives accept- able estimation for unstandardized populations regarding fat and lean body mass, especially in cancer patients who are ofen over or underweight, or presenting edema. Given pharmacokinetic parameters uncertainty such as volume of distribution or clearances, overweight patients were usually considered at risk of overdosing. In order to limit toxic efects, other more suitable BSA estimators were tested 9,10 such as the use of ideal body weight 11, limitation of BSA to 2 m2, reduction of doses. Tese dose reductions may partially explain poor clinical outcomes in the obese population12. Capping BSA at 2 m 2 is a priori a common clinical practice used by physicians to reduce toxicities in over 2 m2 BSA patients. Te traditional use of this empiric practice could be explained by the fear of overdosing and misestimating BSA in patients with extreme height and weight. Yet, this practice seems to be mainly related to obesity as extreme BSA is largely linked with overweight. Nevertheless, such medical practice is supported by neither scientifc rational nor clinical studies. It is an arbitrary practice, which does not take into account body mass index (BMI): tall patients with normal BMI are usually capped and certainly underdosed. Moreover, short obese patients with BSA less than 2 m2 are not 1Medical Oncology Department, Lucien Neuwirth Cancer Center, 42270 Saint Priest en Jarez, France. 2Pharmacy Department, Lucien Neuwirth Cancer Center, 42270 Saint-Priest en Jarez, France. 3Clinical Research, Innovation and Pharmacology Unit, University Hospital of Saint-Etienne, 42000 Saint Etienne, France. 4Radiotherapy Department, Lucien Neuwirth Cancer Center, 42270 Saint Priest en Jarez, France. *email: wafa.bouleftour@ icloire.fr Scientifc Reports | (2021) 11:2431 | https://doi.org/10.1038/s41598-021-81792-6 1 Vol.:(0123456789) www.nature.com/scientificreports/ Variable Patients receiving intravenous chemotherapy (n = 7206) Age (years) Median [Q1–Q3] 64 [54–72] Gender Men (%) 3113 (43.2%) Women (%) 4093 (56.8%) BMI (kg/m2) Underweight (< 18.5) 763 (10.5%) Normal weight (18.5–24.9) 3859 (53.5%) Overweight (25–29.9) 1762 (24.5%) Obesity (30–34.9) 822 (11.5%) BSA (m2) > 2 m2 595 (8.3%) ≤ 2 m2 6611 (91.7%) Table 1. Patients characteristics (n = 7206). considered as at risk of overdosing. BSA estimation could lead to substantial underestimations and thus, to weak antitumor activity8. Indeed, the formula Du bois and Du bois mostly used would already underestimate BSA13. Moreover, capping BSA arbitrarily is not pharmacologically satisfying given the heterogeneity of pharmacokinetic parameters for each drug. In addition, there is no pharmacokinetic arguments to support this practice. Even if few clinical trials decree capping, there is no oncological guideline. All clinical trials focused on capping BSA practice in obese populations. ASCO guidelines recommend against chemotherapy dose reduction in obese patients, in order to avoid compromising clinical outcomes12. Moreover, ASCO reported that more than 40% of obese patients received adjusted chemotherapy doses without any justifcation 12. Terefore, given to the scarcity of data, more studies are needed to defne a consensus of capping practice use. Te aim of this study was to describe practices regarding chemotherapy doses capping within a French anticancer hospital. Tereby, risk factors infuencing capping practices and the correlation between capping and toxicities were analyzed. Results Characteristics of patients receiving intravenous chemotherapy prescription. Between January 1st, 2011 and the May 31st, 2017, 7206 patients received intravenous chemotherapy prescription. Te sex ratio (M/W) in this population was 0.8 (56.8% of women). 64% of this population had a BMI below 25 kg/m2 while 24.5% and 11.5% of patients were respectively overweight (BMI 25–29.9) and obese (BMI ≥ 30). 8.3% of patients had a BSA greater than 2 m2. All patient characteristics are summarized in Table 1. Global analysis of chemotherapy prescriptions. 7206 patients received 51,179 chemotherapy pre- scription. 41,773 (81.6%) were prescribed within the medical oncology department and 9406 (18.4%) within the hematology department. For solid cancer treatments, 25.1%, 22.5%, 8.8% and 7.3% of chemotherapy prescriptions were for digestive, breast, gynecological and lung cancer, respectively. Lymphoma, acute leukemia and myeloma received 9.8%, 2.5% and 2.3% of all prescriptions. (Table 2). Distribution of chemotherapy prescriptions according to medical indication and body surface area. Out of 51,179 chemotherapy prescriptions, the percentage of chemotherapy prescriptions for patients with BSA over 2 m2 was nearly the same in the oncology department as in the hematology department. Indeed, these prescriptions accounted for respectively 10% and 15% of the total number of prescriptions in both depart- ments (Table 3). Interestingly in the population with BSA > 2 m2, the sex ratio (M/W) is 4.46 (18.3% of women with BSA > 2 m2. Data not shown). 5735 chemotherapy prescriptions were administered in patients with BSA > 2 m2. Respectively, 79.1% and 21.9% of chemotherapy prescription were capped to 2 m2 in oncology and hematology departments. (Table 3). Interestingly, capping approach depended on the practice of each physician. It could be divided into 3 groups: rare capping (less than 30%), variable capping (30–70%) and systematic capping (more than 70%) (data not shown). Distribution of chemotherapy prescriptions according to BMI and body surface area. Out of the 51,179 chemotherapy prescriptions, 11.21% were for patients with BSA > 2 m2. More precisely, 1.18% (n = 606), 4.48% (n = 2292), 5.54% (n = 2836) of these prescriptions were dispensed respectively in patients with normal, overweight and obese BMI. (Table 4). Interestingly, 0.73% (n = 375) of the patients who received capped chemotherapy doses, had normal BMI. It corresponded to 6.53% of capped prescriptions. Intent of treatment and capping. In the medical oncology department, the therapeutic objective was curative for 35.8% of capped prescriptions, and for 47.3% of uncapped doses, whereas in the hematology depart- Scientifc Reports | (2021) 11:2431 | https://doi.org/10.1038/s41598-021-81792-6 2 Vol:.(1234567890) www.nature.com/scientificreports/ Department Localization N % Digestive 12,862 25.1 Breast 11,513 22.5 Gynecological 4526 8.8 Lung 3717 7.3 Prostate 2023 4 Medical oncology UADC 2883 2.6 Urological 1343 2.6 CNS 1228 2.4 Sarcoma 1103 2.2 Other 486 0.9 Dermatological 80 0.2 Lymphoma 5022 9.8 Acute Leukemia 1279 2.5 Myeloma 1197 2.3 Hematology CLL 852 1.7 Myelodysplasic syndrome 532 1 Graf 503 1 Other 21 0.1 Total 51,179 100 Table 2. Distribution of prescriptions by cancer location. UADC upper aero digestive cancer, CNS central nervous system, CLL
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