Risk Factors and Protective Measures for Stomatitis and Dysgeusia in Patients with Breast Cancer Undergoing FEC Therapy: An Exploratory Retrospective Study

Risk Factors and Protective Measures for Stomatitis and Dysgeusia in Patients with Breast Cancer Undergoing FEC Therapy: An Exploratory Retrospective Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Risk Factors and Protective Measures for Stomatitis and Dysgeusia in Patients with Breast Cancer Undergoing FEC Therapy: An Exploratory Retrospective Study Yuko Kanbayashi, Tetsuya Taguchi, Takeshi Ishikawa, Koichi Takayama This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6509469/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: To identify the risk factors associated with stomatitis and dysgeusia in women undergoing FEC therapy for breast cancer and evaluate potential protective measures. Methods: Between February 2016 and September 2020, 154 female breast cancer patients undergoing FEC therapy were enrolled at our outpatient chemotherapy center. Variables related to the development of stomatitis and dysgeusia were extracted from the patients’ medical records. The severity of stomatitis and dysgeusia was assessed at the end of chemotherapy using a questionnaire designed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5. Multivariate ordered logistic regression analysis was performed. Results: Factors significantly correlated with the development of stomatitis included age (odds ratio [OR] = 1.04, 95% confidence interval [CI] = 1.01-1.07; P = 0.025), number of cycles (OR = 1.60, 95% CI = 1.02-2.51; P = 0.042), non-steroidal anti-inflammatory drugs (OR = 4.52, 95% CI = 1.05-19.51; P = 0.043), mucoprotective agents (OR = 2.82, 95% CI = 1.24-6.45; P = 0.014), and palliative chemotherapy (OR = 0.09, 95% CI = 0.01-0.60; P = 0.013). Factors significantly correlated with the development of dysgeusia were albumin (OR = 0.46, 95% CI = 0.21- 0.998; P = 0.049) and palliative chemotherapy (OR = 0.14, 95% CI = 0.03- 0.68; P = 0.015). Although not significant, potential prophylactic factors were statins for stomatitis and renin-angiotensin system inhibitors for dysgeusia. Conclusion: The identified factors for stomatitis and dysgeusia may help develop strategies to improve the quality of life of patients receiving chemotherapy. Stomatitis Dysgeusia Breast Cancer FEC Therapy Risk Factors Protective Measures Introduction Oral complications, such as stomatitis and dysgeusia, are common adverse effects associated with chemotherapeutic agents [ 1 , 2 ]. Stomatitis, an inflammation of the oral mucosa, affects 10–100% of patients undergoing conventional chemotherapy [ 3 – 6 ]. Though not life-threatening, stomatitis and dysgeusia can have a significant impact on patients’ quality of life (QoL) and food intake. Moreover, these complications may necessitate dose interruptions or reductions, ultimately compromising dose intensity and treatment efficacy.stomatitis and dysgeusia Previous studies have explored preventive measures for these conditions, investigating the potential benefits of dexamethasone [ 7 , 8 ], statins [ 9 ], renin-angiotensin system (RAS) inhibitors [ 10 ], and others [ 11 – 15 ]. Factors related to stomatitis and dysgeusia have also been statistically analyzed in previous studies [ 1 , 6 , 7 , 16 ]. However, despite these efforts, there are currently no established preventive measures for stomatitis and dysgeusia. Thus, this retrospective study aimed to identify factors for the development of stomatitis and dysgeusia in patients treated with 5-fluorouracil 500 mg/m², epirubicin 100 mg/m², and cyclophosphamide 500 mg/m² (FEC) every 3 weeks for four cycles [ 17 – 19 ]. The ultimate goal was to facilitate the development of targeted strategies aimed at improving the QoL of patients undergoing chemotherapy. Patients and Methods Study Period and Participants This retrospective study included 154 female breast cancer patients who had undergone FEC therapy every 3 weeks at our outpatient chemotherapy center between February 2016 and September 2020. The Medical Ethics Review Committee of the Kyoto Prefectural University of Medicine approved this study (approval no. ERB-C-867-6). All procedures were performed in accordance with the ethical standards of the Kyoto Prefectural University of Medicine Institutional Medical Ethics Review Committee and the 1964 Declaration of Helsinki and its later amendments. Given the retrospective nature of this work, the need to obtain informed consent from the individual participants was waived by the Kyoto Prefectural University of Medicine Institutional Medical Ethics Review Committee. Extraction of variables Variables were extracted from clinical records and used in regression analysis. The variables potentially affecting stomatitis and dysgeusia were determined based on previous studies and clinical significance. These included demographics (age, body mass index, body surface area [BSA], etc.), laboratory tests, number of cycles, concomitant medications, and purpose of treatment. BSA was calculated using the Fujimoto formula [20]. Creatinine clearance (CCr) was estimated using the Cockcroft and Gault equation based on serum creatinine, sex, age, and weight. Clinical information was extracted prior to the first dose of FEC therapy. Concomitant medication was defined as the administration of another drug for ³2 weeks at the time of evaluation. A questionnaire, used since 2012 for all patients after each chemotherapy cycle at our outpatient oncology center, was used in this study to record all symptoms, including OM or dysgeusia. Each patient, assisted by qualified nurses in our center, reported severity information for stomatitis and dysgeusia. The questionnaire was designed according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE; version 5). The questionnaire for stomatitis included the following categories: 0 = none, 1 = symptomatic (few or no symptoms), 2 = symptomatic and painful (but not interfering with eating), and 3 = scarred and very painful (or strongly affecting eating). For dysgeusia, the categories were as follows: 0 = none, 1 = taste has changed but does not affect eating, and 2 = taste has changed and eating has decreased, so dietary supplements are used to supplement the diet. Severity information for stomatitis and dysgeusia was collected during the final administration of chemotherapy. Physicians, pharmacists, and nurses advised all patients to take preventive measures such as cryotherapy (including ice in the mouth) during 5-FU infusion [21] and to maintain good oral hygiene by brushing and gargling to keep the oral cavity clean. Statistical analysis Variables were examined for multicollinearity (correlation coefficient |r| ≥ 0.7), since correlations existing among variables can lead to the use of an inappropriate model. In the first step, univariate ordered logistic regression analysis between the outcomes and each potential independent variable was conducted. Subsequently, a multivariate ordered logistic regression model was constructed by including those candidate variables showing values of P < 0.2 on univariate regression analysis or selected based on previous studies [7-16]. The degree of stomatitis and dysgeusia was evaluated using a graded scale, since multiple factors could potentially contribute to the development of stomatitis and dysgeusia, thereby necessitating simultaneous evaluation of the factors. To overcome this issue, an ordered logistic regression analysis was performed. Furthermore, since Grade 3 or higher stomatitis or Grade 2 or higher dysgeusia significantly interfere with daily life, and these grades are used as criteria for the discontinuation of chemotherapy, binomial logistic regression analysis was also performed. This analysis categorized the variables into two groups each (≥ Grade 3 or not for stomatitis, and ≥ Grade 2 or not for dysgeusia). Threshold measurements were examined using a receiver-operating characteristic (ROC) curve analysis. All statistical analyses were conducted using JMP Pro ® version 16.2.0 (SAS Institute, Cary, NC, USA) with a two-sided significance level of 0.05. Results Table 1 presents the clinical characteristics of the 154 enrolled patients, potential variables related to the development of stomatitis and dysgeusia, and the results of univariate analyses. The selection of factors with P < 0.2 on univariate regression analysis or based on previous studies identified the following candidate variables: age, albumin, number of cycles, non-steroidal anti-inflammatory drugs (NSAIDs), mucoprotective agents, statins, and palliative chemotherapy for stomatitis, whereas height, albumin, number of cycles, RAS inhibitors, and palliative chemotherapy were identified for dysgeusia. These variables were then used in multivariate ordered logistic regression analysis. Factors identified as significantly correlated to the development of stomatitis included age (odds ratio [OR] = 1.04, 95% confidence interval [CI] = 1.01-1.07; P = 0.025), number of cycles (OR = 1.60, 95% CI = 1.02-2.51; P = 0.042), NSAIDs (OR = 4.52, 95% CI = 1.05-19.51; P = 0.043), mucoprotective agents (OR = 2.82, 95% CI = 1.24-6.45; P = 0.014), and palliative chemotherapy (OR = 0.09, 95% CI = 0.01-0.60; P = 0.013) (Table 2). The concomitant use of statins also appeared to be a protective factor for stomatitis, though it was not significant (Table 2). On the other hand, factors identified as significantly correlated with the development of dysgeusia were albumin (OR = 0.46, 95% CI = 0.21-0.998; P = 0.049) and palliative chemotherapy (OR = 0.14, 95% CI = 0.03-0.68; P = 0.015) (Table 2). The concomitant use of RAS inhibitors also appeared to be a protective factor for dysgeusia, though it was not significant (Table 2). The receiver-operating characteristic (ROC) curve analysis for the group likely to develop stomatitis of grade ≥ 3 showed an age threshold of greater than 72 years, with sensitivity of 42.9% and specificity of 95.2% (area under the curve [AUC] = 0.7099). The ROC curve analysis of the group likely to develop dysgeusia of grade ≥ 2 showed a threshold of albumin £ 4.4 g/dL, with sensitivity of 93.8% and specificity of 23.2% (AUC = 0.5718). Discussion The multivariate ordered logistic regression analysis conducted in this study showed that age, number of cycles, NSAIDs, mucoprotective agents, and palliative chemotherapy were significant factors for the development of stomatitis, and albumin and palliative chemotherapy were factors for the development of dysgeusia. Although not significant, potential prophylactic factors were statins for stomatitis and RAS inhibitors for dysgeusia. The older the patient and the higher the number of administered doses, the more likely patients were to develop stomatitis. These findings align with clinical observations. Clinicians should be aware of the incidence of stomatitis with older age (> 72 years) and higher dosing frequency. Patients receiving palliative chemotherapy tended to experience less stomatitis. This may be attributed to the treatment’s emphasis on symptom relief and QoL over therapeutic efficacy, aligning with routine clinical practices. Regarding concomitant medications, NSAIDs and mucoprotective agents were identified as significant factors. Whereas NSAIDs may have been administered in response to stomatitis pain, they also were risk factors for stomatitis. The pathogenic mechanism involves NSAIDs inhibiting cyclooxygenase (COX), subsequently reducing prostaglandin synthesis. Prostaglandins play a crucial role in mucosal protection, and by inhibiting COX activity, NSAIDs compromise this protective mechanism, making the oral mucosa more susceptible to injury and ulcer development. The pain caused by stomatitis is inflammatory in nature, and NSAIDs are effective; however, acetaminophen, which poses a lower risk of gastrointestinal mucosal damage, may be a preferable option for analgesia. Although mucoprotective agents are frequently used in stomatitis treatment, the findings of the present study showed that stomatitis developed irrespective of the specific mucoprotectant used [ 22 , 23 ]. This aligns with the current absence of effective treatments for stomatitis. Although not significant, the results suggested that statins might reduce the risk of developing stomatitis. The potential benefit of statins in oral ulcer treatment lies in their anti-inflammatory and tissue regenerative effects. The anti-inflammatory effects of statins may help alleviate inflammation associated with oral ulcers and inhibit the development and progression of ulcers caused by chemotherapy-induced inflammation[ 9 , 24 ]. Furthermore, statins may promote tissue regeneration and aid in repairing chemotherapy-damaged oral mucosa. The immunomodulatory and antioxidant effects of statins contribute to their potential therapeutic effects on oral ulcers [ 25 – 28 ]. Moving on to dysgeusia, albumin and palliative chemotherapy were significant factors. Palliative chemotherapy, akin to stomatitis, is thought to be a factor because its priority is symptom relief. On the other hand, low serum zinc levels are associated with dysgeusia [ 29 ], and albumin levels have been reported to correlate with serum zinc levels [ 30 ]. The results of the present study are consistent with this information. Previous studies have indicated that poor nutritional status hinders healing of inflammation [ 29 – 31 ], consistent with the present findings. Maintaining good nutritional status is crucial in chemotherapy administration. In the present study, though not significant, RAS inhibitor use appeared to be a prophylactic factor for dysgeusia. It is believed that the direct action of anticancer drugs generates reactive oxygen species in cells of the oral mucosa and salivary glands, leading to the development or exacerbation of stomatitis through cancer chemotherapy-induced weakening of systemic immunity, allowing infection with indigenous bacteria in the oral cavity. RAS inhibitors, including ACE inhibitors (ACE-Is) or type II ARBs, protect the vascular endothelium by reducing the angiotensin II concentration, which inhibits nitric oxide (NO) production and activity. RAS inhibitors prevent angiogenesis by increasing NO production [ 32 – 35 ], which may have contributed to dysgeusia prevention. Several limitations of this study need consideration. First, its retrospective nature may have compromised the reliability of collected data. Second, the relatively small cohort size, restricted to patients from a single center, makes identifying potential factors challenging. In fact, the sensitivity or specificity of the factor thresholds extracted by this model for ROC curve analysis is low. Larger multicenter studies are needed to confirm the present findings. Third, the possibility of confounding, selection, or information bias cannot be completely excluded. Comprehensive information about participants (e.g., general information about their behavior and living conditions) was not available for analysis. In summary, using a statistical approach, this study identified significant factors for stomatitis and dysgeusia development. stomatitis-related factors included age, number of cycles, NSAIDs, mucoprotective agents, and palliative chemotherapy; dysgeusia-related factors included albumin and palliative chemotherapy. Concomitant statin use appeared to be a protective factor for stomatitis, whereas RAS-inhibitor use appeared to be protective for dysgeusia, though neither one was significant. However, these preliminary findings require confirmation in further studies. Nevertheless, the identification of potential predictors of stomatitis and dysgeusia may help in the development of strategies to improve the QoL of patients receiving chemotherapy. Declarations Acknowledgements The authors would like to thank all the patients and medical staff at the University Hospital, Kyoto Prefectural University of Medicine who participated in this study. Authors contributions Y.K.: concept and design, data acquisition, data analysis, data interpretation, and manuscript writing; T.T. and T.I.: concept and design, data acquisition, and data interpretation; K.T.: concept and design, data interpretation, and supervision of the manuscript. All authors read and approved the final manuscript. Funding None. Data Availability The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request. Data on individual patients are not available due to ethical restrictions. Conflict of Interest No author declares any conflict of interest. Ethical approval The Medical Ethics Review Committee of the Kyoto Prefectural University of Medicine approved this study (approval no. ERB-C-867-6). All procedures were performed in accordance with the ethical standards of the Kyoto Prefectural University of Medicine Institutional Medical Ethics Review Committee and the 1964 Declaration of Helsinki and its later amendments. Consent to participate Given the retrospective nature of this work, informed consent was waived for the individual participants included in the study in accordance with the standards of the Kyoto Prefectural University of Medicine Institutional Medical Ethics Review Committee. References de Farias Gabriel A, Silveira FM, Curra M et al (2022) Risk factors associated with the development of oral mucositis in pediatric oncology patients: Systematic review and meta-analysis. Oral Dis 28:1068–1084 Worthington HV, Clarkson JE, Bryan G et al (2011) Interventions for preventing oral mucositis for patients with cancer receiving treatment. 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J Nutr Metab 2023:6711071 Tsutsumi R, Ohashi K, Tsutsumi YM et al (2014) Albumin-normalized serum zinc: a clinically useful parameter for detecting taste impairment in patients undergoing dialysis. Nutr Res 34:11–16 Russell L (2001) The importance of patients' nutritional status in wound healing. Br J Nurs 10:S42 Deshayes F, Nahmias C (2005) Angiotensin receptors: a new role in cancer? Trends Endocrinol Metab 16:293–299 Wu M, Lu Z, Wu K et al (2021) Recent advances in the development of nitric oxide-releasing biomaterials and their application potentials in chronic wound healing. J Mater Chem B 9:7063–7075 Kim MK, Kim KB, Kim HS et al (2019) Alternative skin sensitization prediction and risk assessment using proinflammatory biomarkers, interleukin-1 beta (IL-1beta) and inducible nitric oxide synthase (iNOS). J Toxicol Environ Health A 82:361–378 Medzhitov R (2008) Origin and physiological roles of inflammation. Nature 454:428–435 Tables Table 1. Patients’ characteristics, extracted variables, and results of univariate analyses (n = 154) Stomatitis Dysgeusia Grade 0 (n=81) Grade 1 (n=50) Grade 2 (n=16) Grade 3 (n=7) P value Odds ratio (95% CI) Grade 0 (n=55) Grade 1 (n=83) Grade 2 (n=16) P value Odds ratio (95% CI) Demographic data Age (y), median (range) 56 (34-71) 56.5 (34-78) 59.5 (46-76) 64 (46-76) 0.018* 1.03 (1.01-1.06) 60 (34-74) 56 (34-78) 58.5 (39-76) 0.976 1.00 (0.97- 1.03) BMI (kg/m 2 ), median (range) 21.3 (11.6-31.1) 21.4 (15.9- 34.6) 22.0 (17.4- 28.9) 21.8 (16.3-25.5) 0.770 1.01 (0.93- 1.10) 21.6 (15.8-31.1) 21.5 (11.6- 34.6) 19.3 (15.9- 25.4) 0.203 0.95 (0.87- 1.03) BSA (m 2 ), median (range) 1.48 (1.17- 1.89) 1.48 (1.25- 1.94) 1.47 (1.33-1.75) 1.44 (1.32- 1.63) 0.912 1.15 (0.10- 13.67) 1.46 (1.26- 1.75) 1.51 (1.17- 1.94) 1.40 (1.25- 1.56) 0.778 0.70 (0.06- 8.58) Body weight (kg), average (range) 53.8 (30-80) 54.6 (37.5- 92.0) 54.3 (42.2- 75.0) 52.3 (41.6- 64.6) 0.850 1.003 (0.97- 1.04) 53.6 (38-71) 55.5 (30- 92) 47.9 (37.5- 61) 0.503 0.99 (0.96- 1.02) Height (cm), Average (range) 157.4 (146- 173) 157.1 (147- 173) 156.9 (146- 163) 157.5 (154- 162) 0.729 0.99 (0.93- 1.05) 156.1 (146-168) 158.2 (148- 173) 156.5 (146- 163) 0.105 1.05 (0.99- 1.12) Laboratory test value Serum creatinine, mg/dL, median (range) 0.56 (0.38-0.96) 0.60 (0.45-097) 0.57 (0.40-0.79) 0.62 (0.46-0.78) 0.437 2.78 (0.21- 36.6) 0.6 (0.39-0.97) 0.56 (0.38-0.95) 0.6 (0.46-0.83) 0.556 0.45 (0.03- 6.27) Creatinine clearance, mL/min, median (range) 92.1 (53.4- 163.7) 82.9 (42.4- 171.3) 88.4 (59.1- 145.5) 75.0 (57.7- 97.2) 0.110 0.99 (0.98- 1.00) 85.6 (42.4- 163.7) 93.2 (52.9- 171.3) 79.4 (57.7- 94.4) 0.686 1.00 (0.99- 1.01) Albumin, g/dL, median (range) 4.1 (3.2-5.3) 4.1 (2.6-5.5) 4.1 (3.5-4.5) 3.9 (3.8-4.6) 0.197 0.62 (0.30- 1.29) 4.2 (3.4- 5.1) 4.1 (2.6- 5.3) 4.1 (3.2- 5.5) 0.283 0.67 (0.32- 1.39) WBC, × 10 3 /μL, median (range) 5.3 (2.7-16.7) 4.9 (2.9-9.8) 5.0 (2.9-7.7) 5.4 (3.6-7.3) 0.307 0.92 (0.77- 1.08) 5.3 (2.7-16.7) 5.0 (2.9- 11.8) 5.8 (3.6- 7.7) 0.499 0.95 (0.80- 1.11) Hb, g/dL, median (range) 12.5 (9.2-15.3) 12.2 (9.0- 14.3) 12.5 (10.6-14.0) 12.0 (11.0-12.9) 0.379 0.90 (0.70-1.14) 12.4 (9.7- 14.8) 12.4 (9- 15.3) 12.1 (9.8-14.3) 0.385 0.90 (0.70- 1.15) PLT, × 10 3 /μL, median (range) 251 (77-612) 263 (168-514) 264 (164- 434) 248 (169-375) 0.440 1.00 (1.00-1.01) 257 (158-452) 256 (77-612) 265 (169-514) 0.703 - Number of cycles, average (range) 4.0 (2-9) 4.1 (2-9) 4.3 (4-8) 4.0 (4-4) 0.551 1.10 (0.81- 1.49) 4.2 (2-9) 4.0 (2-8) 3.9 (2-4) 0.237 0.82 (0.60- 1.14) Concomitant medication NSAIDs, n (%) 3 (3.7) 2 (4.0) 2 (12.5) 1 (14.3) 0.154 2.59 (0.70- 9.59) 2 (3.6) 5 (6.0) 1 (6.3) 0.552 1.53 (0.38- 6.17) Mucoprotective agents, n (%) 10 (12.3) 10 (20.0) 2 (12.5) 4 (57.1) 0.060 2.13 (0.97- 4.69) 13 (23.6) 9 (10.8) 4 (25.0) 0.263 0.63 (0.28- 1.42) Anticholinergic drugs, n (%) 17 (21.0) 6 (12.0) 6 (37.5) 2 (28.6) 0.695 1.16 (0.55- 2.45) 9 (16.4) 19 (22.9) 3 (18.8) 0.514 1.29 (0.60- 2.79) RAS inhibitors, n (%) 7 (8.6) 8 (16.0) 1 (6.3) 0 0.845 1.10 (0.41- 2.94) 7 (12.7) 9 (10.8) 0 0.283 0.58 (0.21- 1.58) Statins, n (%) 16 (17.3) 6 (12.0) 4 (25.0) 1 (14.3) 0.899 0.95 (0.42- 2.95) 8 (14.5) 16 (19.3) 1 (6.25) 0.930 0.96 (0.42- 2.21) Purpose of treatment Neo-adjuvant, n (%) 24 (29.6) 13 (26.0) 5 (31.3) 3 (42.9) 0.887 1.05 (0.54-2.04) 11 (20.0) 29 (34.9) 5 (31.3) 0.110 1.75 (0.88- 3.47) Adjuvant, n (%) 48 (59.3) 33 (66.0) 11 (68.8) 4 (57.1) 0.452 1.27 (0.68- 2.39) 35 (63.6) 50 (60.2) 11 (68.8) 0.995 1.00 (0.53- 1.89) Palliative, n (%) 7 (8.6) 3 (6.0) 0 0 0.142 0.36 (0.09- 1.41) 7 (12.7) 3 (3.6) 0 0.014* 0.18 (0.04- 0.70) CI, confidence interval; BMI, body mass index; BSA, body surface area; WBC, white blood cell; Hb, hemoglobin; PLT, platelet, NSAIDs, non-steroidal anti-inflammatory drugs; RAS, renin-angiotensin system * P <0.05 Table 2. Results of multivariate logistic regression analysis (n = 154) Variable P value Odds ratio 95% CI Lower 95% Upper 95% Stomatitis Age 0.025* 1.04 1.01 1.07 Albumin 0.289 0.65 0.29 1.45 Number of cycles 0.042* 1.60 1.02 2.51 NSAIDs 0.043* 4.52 1.05 19.51 Mucoprotective agents 0.014* 2.82 1.24 6.45 Statins 0.627 0.80 0.32 2.00 Palliative chemotherapy 0.013* 0.09 0.01 0.60 Dysgeusia Height 0.053 1.06 0.999 1.13 Albumin 0.049* 0.46 0.21 0.998 Number of cycles 0.993 1.002 0.66 1.52 RAS inhibitors 0.291 0.57 0.20 1.61 Palliative chemotherapy 0.015* 0.14 0.03 0.68 CI, confidence interval; NSAIDs, non-steroidal anti-inflammatory drugs; RAS, renin-angiotensin system * P <0.05 Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6509469","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":449360929,"identity":"8057e5ec-c239-475b-b2b5-17820109cb1f","order_by":0,"name":"Yuko Kanbayashi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABFklEQVRIiWNgGAWjYFACNiA+wMBgAGIzNkjIwSUYG4jUYkyyFoZEnAphwOBGWuIDhjN20ebsZww//txhkd4vdvaYBEONHQPzbOy6gVoOGzDcSM7d2ZNjLM17RiJ35uy8NAmGY8kMjHMO4NCS3ibB8IE5d8OBHANpxjaJ3A23c8wkGNgOMDDOSMCnpT53w/k3xj9/tkmkG4C1/MOnJQ3o8huHczfcAKrkbZNIAGthbMOtRfLMs2SDhDPHc3fOeFZmDdRiCPRLskViXzIPLr/wHU8zfPDhWHXudv7kzTd/ttXJ80vnHrzx4ZudnCGOEFMAmQRxAIcBVIwHLMJjOAOrDgZ5hEnsDxBawFIS2LWMglEwCkbBiAMA1/plR8qrtsEAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-0095-2293","institution":"Osaka Yakka Daigaku: Osaka Ika Yakka Daigaku","correspondingAuthor":true,"prefix":"","firstName":"Yuko","middleName":"","lastName":"Kanbayashi","suffix":""},{"id":449360930,"identity":"2f125807-7cea-4a56-bc26-4a292c7a3c6e","order_by":1,"name":"Tetsuya Taguchi","email":"","orcid":"","institution":"Kyoto Prefectural University of Medicine: Kyoto Furitsu Ika Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Tetsuya","middleName":"","lastName":"Taguchi","suffix":""},{"id":449360931,"identity":"77b62485-42d9-4c91-a385-0d43e7b72113","order_by":2,"name":"Takeshi Ishikawa","email":"","orcid":"","institution":"Kyoto Prefectural University of Medicine: Kyoto Furitsu Ika Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Takeshi","middleName":"","lastName":"Ishikawa","suffix":""},{"id":449360932,"identity":"bab30cf9-73e7-45b1-991f-16389d5a109f","order_by":3,"name":"Koichi Takayama","email":"","orcid":"","institution":"Kyoto Prefectural University of Medicine: Kyoto Furitsu Ika Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Koichi","middleName":"","lastName":"Takayama","suffix":""}],"badges":[],"createdAt":"2025-04-23 06:27:32","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6509469/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6509469/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":82110752,"identity":"2dfc291d-86a0-4929-977b-6331d779fe3e","added_by":"auto","created_at":"2025-05-07 00:42:02","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":711750,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6509469/v1/c884601b-1c88-4e1e-baaa-e066df0c2e74.pdf"}],"financialInterests":"","formattedTitle":"Risk Factors and Protective Measures for Stomatitis and Dysgeusia in Patients with Breast Cancer Undergoing FEC Therapy: An Exploratory Retrospective Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eOral complications, such as stomatitis and dysgeusia, are common adverse effects associated with chemotherapeutic agents [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Stomatitis, an inflammation of the oral mucosa, affects 10\u0026ndash;100% of patients undergoing conventional chemotherapy [\u003cspan additionalcitationids=\"CR4 CR5\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Though not life-threatening, stomatitis and dysgeusia can have a significant impact on patients\u0026rsquo; quality of life (QoL) and food intake. Moreover, these complications may necessitate dose interruptions or reductions, ultimately compromising dose intensity and treatment efficacy.stomatitis and dysgeusia\u003c/p\u003e \u003cp\u003ePrevious studies have explored preventive measures for these conditions, investigating the potential benefits of dexamethasone [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], statins [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], renin-angiotensin system (RAS) inhibitors [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], and others [\u003cspan additionalcitationids=\"CR12 CR13 CR14\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Factors related to stomatitis and dysgeusia have also been statistically analyzed in previous studies [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. However, despite these efforts, there are currently no established preventive measures for stomatitis and dysgeusia. Thus, this retrospective study aimed to identify factors for the development of stomatitis and dysgeusia in patients treated with 5-fluorouracil 500 mg/m\u0026sup2;, epirubicin 100 mg/m\u0026sup2;, and cyclophosphamide 500 mg/m\u0026sup2; (FEC) every 3 weeks for four cycles [\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The ultimate goal was to facilitate the development of targeted strategies aimed at improving the QoL of patients undergoing chemotherapy.\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cp\u003e\u003cem\u003eStudy Period and Participants\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis retrospective study included 154 female breast cancer patients who had undergone FEC therapy every 3 weeks at our outpatient chemotherapy center between February 2016 and September 2020. The Medical Ethics Review Committee of the Kyoto Prefectural University of Medicine approved this study (approval no. ERB-C-867-6). All procedures were performed in accordance with the ethical standards of the Kyoto Prefectural University of Medicine Institutional Medical Ethics Review Committee and the 1964 Declaration of Helsinki and its later amendments. Given the retrospective nature of this work, the need to obtain informed consent from the individual participants was waived by the Kyoto Prefectural University of Medicine Institutional Medical Ethics Review Committee.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eExtraction of variables\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eVariables were extracted from clinical records and used in regression analysis. The variables potentially affecting stomatitis and dysgeusia were determined based on previous studies and clinical significance. These included demographics (age, body mass index, body surface area [BSA], etc.), laboratory tests, number of cycles, concomitant medications, and purpose of treatment. BSA was calculated using the Fujimoto formula [20]. Creatinine clearance (CCr) was estimated using the Cockcroft and Gault equation based on serum creatinine, sex, age, and weight. Clinical information was extracted prior to the first dose of FEC therapy. Concomitant medication was defined as the administration of another drug for \u0026sup3;2 weeks at the time of evaluation. A questionnaire, used since 2012 for all patients after each chemotherapy cycle at our outpatient oncology center, was used in this study to record all symptoms, including OM or dysgeusia. Each patient, assisted by qualified nurses in our center, reported severity information for stomatitis and dysgeusia. The questionnaire was designed according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE; version 5). The questionnaire for stomatitis included the following categories: 0 = none, 1 = symptomatic (few or no symptoms), 2 = symptomatic and painful (but not interfering with eating), and 3 = scarred and very painful (or strongly affecting eating). For dysgeusia, the categories were as follows: 0 = none, 1 = taste has changed but does not affect eating, and 2 = taste has changed and eating has decreased, so dietary supplements are used to supplement the diet. Severity information for stomatitis and dysgeusia was collected during the final administration of chemotherapy. Physicians, pharmacists, and nurses advised all patients to take preventive measures such as cryotherapy (including ice in the mouth) during 5-FU infusion [21] and to maintain good oral hygiene by brushing and gargling to keep the oral cavity clean.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStatistical analysis\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eVariables were examined for multicollinearity (correlation coefficient |r| \u0026ge; 0.7), since correlations existing among variables can lead to the use of an inappropriate model. In the first step, univariate ordered logistic regression analysis between the outcomes and each potential independent variable was conducted. Subsequently, a multivariate ordered logistic regression model was constructed by including those candidate variables showing values of \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.2 on univariate regression analysis or selected based on previous studies [7-16]. The degree of stomatitis and dysgeusia was evaluated using a graded scale, since multiple factors could potentially contribute to the development of stomatitis and dysgeusia, thereby necessitating simultaneous evaluation of the factors. To overcome this issue, an ordered logistic regression analysis was performed. Furthermore, since Grade 3 or higher stomatitis or Grade 2 or higher dysgeusia significantly interfere with daily life, and these grades are used as criteria for the discontinuation of chemotherapy, binomial logistic regression analysis was also performed. This analysis categorized the variables into two groups each (\u0026ge; Grade 3 or not for stomatitis, and \u0026ge; Grade 2 or not for dysgeusia). Threshold measurements were examined using a receiver-operating characteristic (ROC) curve analysis. All statistical analyses were conducted using JMP Pro\u003csup\u003e\u0026reg;\u003c/sup\u003e version 16.2.0 (SAS Institute, Cary, NC, USA) with a two-sided significance level of 0.05.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eTable 1 presents the clinical characteristics of the 154 enrolled patients, potential variables related to the development of stomatitis and dysgeusia, and the results of univariate analyses. The selection of factors with \u003cem\u003eP\u0026nbsp;\u003c/em\u003e\u0026lt; 0.2 on univariate regression analysis or based on previous studies identified the following candidate variables: age, albumin, number of cycles, non-steroidal anti-inflammatory drugs (NSAIDs),\u0026nbsp;mucoprotective agents, statins, and palliative chemotherapy for stomatitis, whereas height, albumin, number of cycles, RAS inhibitors,\u0026nbsp;and\u0026nbsp;palliative chemotherapy\u0026nbsp;were identified for dysgeusia. These variables were then used in multivariate ordered logistic regression analysis. Factors identified as significantly correlated to the development of stomatitis included age (odds ratio [OR] = 1.04, 95% confidence interval [CI] = 1.01-1.07; \u003cem\u003eP\u0026nbsp;\u003c/em\u003e= 0.025), number of cycles (OR = 1.60, 95% CI = 1.02-2.51; \u003cem\u003eP\u003c/em\u003e = 0.042), NSAIDs (OR = 4.52, 95% CI = 1.05-19.51; \u003cem\u003eP\u003c/em\u003e = 0.043), mucoprotective agents (OR = 2.82, 95% CI = 1.24-6.45; \u003cem\u003eP\u0026nbsp;\u003c/em\u003e= 0.014), and palliative chemotherapy (OR = 0.09, 95% CI = 0.01-0.60; \u003cem\u003eP\u0026nbsp;\u003c/em\u003e= 0.013)\u0026nbsp;(Table 2).\u0026nbsp;The concomitant use of statins also appeared to be a protective factor for stomatitis, though it was not significant (Table 2). On the other hand, factors identified as significantly correlated with the development of dysgeusia were\u0026nbsp;albumin (OR = 0.46, 95% CI = 0.21-0.998;\u003cem\u003e\u0026nbsp;P\u003c/em\u003e = 0.049) and palliative chemotherapy (OR = 0.14, 95% CI = 0.03-0.68; \u003cem\u003eP\u003c/em\u003e = 0.015)\u0026nbsp;(Table 2). The concomitant use of RAS inhibitors also appeared to be a protective factor for dysgeusia, though it was not significant (Table 2).\u003c/p\u003e\n\u003cp\u003eThe receiver-operating characteristic (ROC) curve analysis for the group likely to develop stomatitis of grade \u0026ge; 3 showed an age threshold of greater than 72 years, with sensitivity of 42.9% and specificity of 95.2% (area under the curve [AUC] = 0.7099). The ROC curve analysis of the group likely to develop dysgeusia of grade \u0026ge; 2 showed a threshold of albumin \u0026pound; 4.4 g/dL, with sensitivity of 93.8% and specificity of 23.2% (AUC = 0.5718).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe multivariate ordered logistic regression analysis conducted in this study showed that age, number of cycles, NSAIDs, mucoprotective agents, and palliative chemotherapy were significant factors for the development of stomatitis, and albumin and palliative chemotherapy were factors for the development of dysgeusia. Although not significant, potential prophylactic factors were statins for stomatitis and RAS inhibitors for dysgeusia.\u003c/p\u003e \u003cp\u003eThe older the patient and the higher the number of administered doses, the more likely patients were to develop stomatitis. These findings align with clinical observations. Clinicians should be aware of the incidence of stomatitis with older age (\u0026gt;\u0026thinsp;72 years) and higher dosing frequency.\u003c/p\u003e \u003cp\u003ePatients receiving palliative chemotherapy tended to experience less stomatitis. This may be attributed to the treatment\u0026rsquo;s emphasis on symptom relief and QoL over therapeutic efficacy, aligning with routine clinical practices.\u003c/p\u003e \u003cp\u003eRegarding concomitant medications, NSAIDs and mucoprotective agents were identified as significant factors. Whereas NSAIDs may have been administered in response to stomatitis pain, they also were risk factors for stomatitis. The pathogenic mechanism involves NSAIDs inhibiting cyclooxygenase (COX), subsequently reducing prostaglandin synthesis. Prostaglandins play a crucial role in mucosal protection, and by inhibiting COX activity, NSAIDs compromise this protective mechanism, making the oral mucosa more susceptible to injury and ulcer development. The pain caused by stomatitis is inflammatory in nature, and NSAIDs are effective; however, acetaminophen, which poses a lower risk of gastrointestinal mucosal damage, may be a preferable option for analgesia.\u003c/p\u003e \u003cp\u003eAlthough mucoprotective agents are frequently used in stomatitis treatment, the findings of the present study showed that stomatitis developed irrespective of the specific mucoprotectant used [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. This aligns with the current absence of effective treatments for stomatitis. Although not significant, the results suggested that statins might reduce the risk of developing stomatitis. The potential benefit of statins in oral ulcer treatment lies in their anti-inflammatory and tissue regenerative effects. The anti-inflammatory effects of statins may help alleviate inflammation associated with oral ulcers and inhibit the development and progression of ulcers caused by chemotherapy-induced inflammation[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Furthermore, statins may promote tissue regeneration and aid in repairing chemotherapy-damaged oral mucosa. The immunomodulatory and antioxidant effects of statins contribute to their potential therapeutic effects on oral ulcers [\u003cspan additionalcitationids=\"CR26 CR27\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMoving on to dysgeusia, albumin and palliative chemotherapy were significant factors. Palliative chemotherapy, akin to stomatitis, is thought to be a factor because its priority is symptom relief.\u003c/p\u003e \u003cp\u003eOn the other hand, low serum zinc levels are associated with dysgeusia [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], and albumin levels have been reported to correlate with serum zinc levels [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. The results of the present study are consistent with this information. Previous studies have indicated that poor nutritional status hinders healing of inflammation [\u003cspan additionalcitationids=\"CR30\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e], consistent with the present findings. Maintaining good nutritional status is crucial in chemotherapy administration.\u003c/p\u003e \u003cp\u003eIn the present study, though not significant, RAS inhibitor use appeared to be a prophylactic factor for dysgeusia. It is believed that the direct action of anticancer drugs generates reactive oxygen species in cells of the oral mucosa and salivary glands, leading to the development or exacerbation of stomatitis through cancer chemotherapy-induced weakening of systemic immunity, allowing infection with indigenous bacteria in the oral cavity. RAS inhibitors, including ACE inhibitors (ACE-Is) or type II ARBs, protect the vascular endothelium by reducing the angiotensin II concentration, which inhibits nitric oxide (NO) production and activity. RAS inhibitors prevent angiogenesis by increasing NO production [\u003cspan additionalcitationids=\"CR33 CR34\" citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e], which may have contributed to dysgeusia prevention.\u003c/p\u003e \u003cp\u003eSeveral limitations of this study need consideration. First, its retrospective nature may have compromised the reliability of collected data. Second, the relatively small cohort size, restricted to patients from a single center, makes identifying potential factors challenging. In fact, the sensitivity or specificity of the factor thresholds extracted by this model for ROC curve analysis is low. Larger multicenter studies are needed to confirm the present findings. Third, the possibility of confounding, selection, or information bias cannot be completely excluded. Comprehensive information about participants (e.g., general information about their behavior and living conditions) was not available for analysis.\u003c/p\u003e \u003cp\u003eIn summary, using a statistical approach, this study identified significant factors for stomatitis and dysgeusia development. stomatitis-related factors included age, number of cycles, NSAIDs, mucoprotective agents, and palliative chemotherapy; dysgeusia-related factors included albumin and palliative chemotherapy. Concomitant statin use appeared to be a protective factor for stomatitis, whereas RAS-inhibitor use appeared to be protective for dysgeusia, though neither one was significant. However, these preliminary findings require confirmation in further studies. Nevertheless, the identification of potential predictors of stomatitis and dysgeusia may help in the development of strategies to improve the QoL of patients receiving chemotherapy.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank all the patients and medical staff at the University Hospital, Kyoto Prefectural University of Medicine who participated in this study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eY.K.: concept and design, data acquisition, data analysis, data interpretation, and manuscript writing; T.T. and T.I.: concept and design, data acquisition, and data interpretation; K.T.: concept and design, data interpretation, and supervision of the manuscript. All authors read and approved the final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and analyzed during the current study are available from the corresponding author on reasonable request. Data on individual patients are not available due to ethical restrictions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo author declares any conflict of interest. \u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Medical Ethics Review Committee of the Kyoto Prefectural University of Medicine approved this study (approval no. ERB-C-867-6). All procedures were performed in accordance with the ethical standards of the Kyoto Prefectural University of Medicine Institutional Medical Ethics Review Committee and the 1964 Declaration of Helsinki and its later amendments.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGiven the retrospective nature of this work, informed consent was waived for the individual participants included in the study in accordance with the standards of the Kyoto Prefectural University of Medicine Institutional Medical Ethics Review Committee.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003ede Farias Gabriel A, Silveira FM, Curra M et al (2022) Risk factors associated with the development of oral mucositis in pediatric oncology patients: Systematic review and meta-analysis. Oral Dis 28:1068\u0026ndash;1084\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWorthington HV, Clarkson JE, Bryan G et al (2011) Interventions for preventing oral mucositis for patients with cancer receiving treatment. Cochrane Database Syst Rev 2011:CD000978\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLalla RV, Brennan MT, Gordon SM et al (2019) Oral Mucositis Due to High-Dose Chemotherapy and/or Head and Neck Radiation Therapy. J Natl Cancer Inst Monogr 2019\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDelbaldo C, Serin D, Mousseau M et al (2014) A phase III adjuvant randomised trial of 6 cycles of 5-fluorouracil-epirubicine-cyclophosphamide (FEC100) versus 4 FEC 100 followed by 4 Taxol (FEC-T) in node positive breast cancer patients (Trial B2000). 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Sci Rep 13:10169\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMedeiros CA, Leitao RF, Macedo RN et al (2011) Effect of atorvastatin on 5-fluorouracil-induced experimental oral mucositis. Cancer Chemother Pharmacol 67:1085\u0026ndash;1100\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAraujo AA, Araujo LS, Medeiros C et al (2018) Protective effect of angiotensin II receptor blocker against oxidative stress and inflammation in an oral mucositis experimental model. J Oral Pathol Med 47:972\u0026ndash;984\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCzyzewski K, Debski R, Krenska A et al (2014) Palifermin in children undergoing autologous stem cell transplantation: a matched-pair analysis. 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Clin Nutr ESPEN 43:31\u0026ndash;38\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eColella G, Boschetti CE, Vitagliano R et al (2023) Interventions for the Prevention of Oral Mucositis in Patients Receiving Cancer Treatment: Evidence from Randomised Controlled Trials. Curr Oncol 30:967\u0026ndash;980\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWuketich S, Hienz SA, Marosi C (2012) Prevalence of clinically relevant oral mucositis in outpatients receiving myelosuppressive chemotherapy for solid tumors. Support Care Cancer 20:175\u0026ndash;183\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHeibloem RE, Komen MMC, Ilozumba OUC et al (2023) Minimal added value of wetting hair before scalp cooling to prevent chemotherapy-induced alopecia in cancer patients - results from the Dutch Scalp Cooling Registry. Support Care Cancer 31:273\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHwang I, Kim JE, Jeong JH et al (2023) Randomized phase III trial of a neoadjuvant regimen of four cycles of adriamycin plus cyclophosphamide followed by four cycles of docetaxel (AC4-D4) versus a shorter treatment of three cycles of FEC followed by three cycles of docetaxel (FEC3-D3) in node-positive breast cancer (Neo-shorter; NCT02001506). Breast Cancer Res Treat 201:193\u0026ndash;204\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDel Mastro L, Poggio F, Blondeaux E et al (2022) Fluorouracil and dose-dense adjuvant chemotherapy in patients with early-stage breast cancer (GIM2): end-of-study results from a randomised, phase 3 trial. Lancet Oncol 23:1571\u0026ndash;1582\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKouno T, Katsumata N, Mukai H et al (2003) Standardization of the body surface area (BSA) formula to calculate the dose of anticancer agents in Japan. Jpn J Clin Oncol 33:309\u0026ndash;313\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePapadeas E, Naxakis S, Riga M et al (2007) Prevention of 5-fluorouracil-related stomatitis by oral cryotherapy: a randomized controlled study. Eur J Oncol Nurs 11:60\u0026ndash;65\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBlakaj A, Bonomi M, Gamez ME et al (2019) Oral mucositis in head and neck cancer: Evidence-based management and review of clinical trial data. Oral Oncol 95:29\u0026ndash;34\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eElad S, Yarom N, Zadik Y et al (2022) The broadening scope of oral mucositis and oral ulcerative mucosal toxicities of anticancer therapies. CA Cancer J Clin 72:57\u0026ndash;77\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMolania T, Akbari J, Babaei A et al (2023) Atorvastatin mucoadhesive tablets in the management of recurrent aphthous stomatitis: a randomized clinical study. BMC Oral Health 23:285\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDaliri M, Simental-Mendia LE, Jamialahmadi T et al (2023) Effect of Statins on Superoxide Dismutase Level: A Systematic Review. Curr Med Chem. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2174/0929867331666230831145809\u003c/span\u003e\u003cspan address=\"10.2174/0929867331666230831145809\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVital KD, Cardoso BG, Lima IP et al (2023) Therapeutic effects and the impact of statins in the prevention of ulcerative colitis in preclinical models: A systematic review. Fundam Clin Pharmacol 37:493\u0026ndash;507\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDaliri M, Johnston TP, Sahebkar A (2023) Statins and peripheral neuropathy in diabetic and non-diabetic cases: a systematic review. J Pharm Pharmacol 75:593\u0026ndash;611\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZinellu A, Mangoni AA (2021) A Systematic Review and Meta-Analysis of the Effect of Statins on Glutathione Peroxidase, Superoxide Dismutase, and Catalase. Antioxidants (Basel, p 10\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMozaffar B, Ardavani A, Muzafar H et al (2023) The Effectiveness of Zinc Supplementation in Taste Disorder Treatment: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. J Nutr Metab 2023:6711071\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTsutsumi R, Ohashi K, Tsutsumi YM et al (2014) Albumin-normalized serum zinc: a clinically useful parameter for detecting taste impairment in patients undergoing dialysis. Nutr Res 34:11\u0026ndash;16\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRussell L (2001) The importance of patients' nutritional status in wound healing. Br J Nurs 10:S42\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDeshayes F, Nahmias C (2005) Angiotensin receptors: a new role in cancer? Trends Endocrinol Metab 16:293\u0026ndash;299\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu M, Lu Z, Wu K et al (2021) Recent advances in the development of nitric oxide-releasing biomaterials and their application potentials in chronic wound healing. J Mater Chem B 9:7063\u0026ndash;7075\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKim MK, Kim KB, Kim HS et al (2019) Alternative skin sensitization prediction and risk assessment using proinflammatory biomarkers, interleukin-1 beta (IL-1beta) and inducible nitric oxide synthase (iNOS). J Toxicol Environ Health A 82:361\u0026ndash;378\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMedzhitov R (2008) Origin and physiological roles of inflammation. Nature 454:428\u0026ndash;435\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1. Patients\u0026rsquo; characteristics, extracted variables, and results of univariate analyses (n = 154) \u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"left\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" style=\"width: 63px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStomatitis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"5\" valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDysgeusia\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eGrade 0\u003c/p\u003e\n \u003cp\u003e(n=81)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eGrade 1\u003c/p\u003e\n \u003cp\u003e(n=50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eGrade 2\u003c/p\u003e\n \u003cp\u003e(n=16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eGrade 3\u003c/p\u003e\n \u003cp\u003e(n=7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eOdds ratio\u003c/p\u003e\n \u003cp\u003e(95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003eGrade 0\u003c/p\u003e\n \u003cp\u003e(n=55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eGrade 1\u003c/p\u003e\n \u003cp\u003e(n=83)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eGrade 2\u003c/p\u003e\n \u003cp\u003e(n=16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eOdds ratio\u003c/p\u003e\n \u003cp\u003e(95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"12\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDemographic data\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eAge (y), median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e56\u003c/p\u003e\n \u003cp\u003e(34-71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e56.5\u003c/p\u003e\n \u003cp\u003e(34-78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e59.5\u003c/p\u003e\n \u003cp\u003e(46-76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e64\u003c/p\u003e\n \u003cp\u003e(46-76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.018*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e1.03\u003c/p\u003e\n \u003cp\u003e(1.01-1.06)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003cp\u003e(34-74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e56\u003c/p\u003e\n \u003cp\u003e(34-78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e58.5\u003c/p\u003e\n \u003cp\u003e(39-76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.976\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003cp\u003e(0.97- 1.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e),\u0026nbsp;median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e21.3\u003c/p\u003e\n \u003cp\u003e(11.6-31.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e21.4\u003c/p\u003e\n \u003cp\u003e(15.9- 34.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e22.0\u003c/p\u003e\n \u003cp\u003e(17.4- 28.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e21.8\u003c/p\u003e\n \u003cp\u003e(16.3-25.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.770\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e1.01\u003c/p\u003e\n \u003cp\u003e(0.93- 1.10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e21.6\u003c/p\u003e\n \u003cp\u003e(15.8-31.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e21.5\u003c/p\u003e\n \u003cp\u003e(11.6- 34.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e19.3\u003c/p\u003e\n \u003cp\u003e(15.9- 25.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.203\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.95\u003c/p\u003e\n \u003cp\u003e(0.87- 1.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eBSA (m\u003csup\u003e2\u003c/sup\u003e),\u0026nbsp;median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e1.48\u003c/p\u003e\n \u003cp\u003e(1.17- 1.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e1.48\u003c/p\u003e\n \u003cp\u003e(1.25- 1.94)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e1.47\u003c/p\u003e\n \u003cp\u003e(1.33-1.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e1.44\u003c/p\u003e\n \u003cp\u003e(1.32- 1.63)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.912\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e1.15\u003c/p\u003e\n \u003cp\u003e(0.10- 13.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e1.46\u003c/p\u003e\n \u003cp\u003e(1.26- 1.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e1.51\u003c/p\u003e\n \u003cp\u003e(1.17- 1.94)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e1.40\u003c/p\u003e\n \u003cp\u003e(1.25- 1.56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.778\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.70\u003c/p\u003e\n \u003cp\u003e(0.06- 8.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eBody weight (kg), average (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e53.8\u003c/p\u003e\n \u003cp\u003e(30-80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e54.6\u003c/p\u003e\n \u003cp\u003e(37.5- 92.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e54.3\u003c/p\u003e\n \u003cp\u003e(42.2- 75.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e52.3\u003c/p\u003e\n \u003cp\u003e(41.6- 64.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.850\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e1.003\u003c/p\u003e\n \u003cp\u003e(0.97- 1.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e53.6\u003c/p\u003e\n \u003cp\u003e(38-71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e55.5\u003c/p\u003e\n \u003cp\u003e(30- 92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e47.9\u003c/p\u003e\n \u003cp\u003e(37.5- 61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.503\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.99\u003c/p\u003e\n \u003cp\u003e(0.96- 1.02)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eHeight (cm),\u003c/p\u003e\n \u003cp\u003eAverage (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e157.4\u003c/p\u003e\n \u003cp\u003e(146- 173)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e157.1\u003c/p\u003e\n \u003cp\u003e(147- 173)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e156.9\u003c/p\u003e\n \u003cp\u003e(146- 163)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e157.5\u003c/p\u003e\n \u003cp\u003e(154- 162)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.729\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.99\u003c/p\u003e\n \u003cp\u003e(0.93- 1.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e156.1\u003c/p\u003e\n \u003cp\u003e(146-168)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e158.2\u003c/p\u003e\n \u003cp\u003e(148- 173)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e156.5\u003c/p\u003e\n \u003cp\u003e(146- 163)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.105\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e1.05\u003c/p\u003e\n \u003cp\u003e(0.99- 1.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"12\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLaboratory test value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eSerum creatinine, mg/dL,\u0026nbsp;median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.56\u003c/p\u003e\n \u003cp\u003e(0.38-0.96)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.60\u003c/p\u003e\n \u003cp\u003e(0.45-097)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.57\u003c/p\u003e\n \u003cp\u003e(0.40-0.79)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.62\u003c/p\u003e\n \u003cp\u003e(0.46-0.78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.437\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e2.78\u003c/p\u003e\n \u003cp\u003e(0.21- 36.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.6\u003c/p\u003e\n \u003cp\u003e(0.39-0.97)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.56\u003c/p\u003e\n \u003cp\u003e(0.38-0.95)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.6\u003c/p\u003e\n \u003cp\u003e(0.46-0.83)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.556\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.45\u003c/p\u003e\n \u003cp\u003e(0.03- 6.27)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eCreatinine clearance, mL/min, median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e92.1\u003c/p\u003e\n \u003cp\u003e(53.4- 163.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e82.9\u003c/p\u003e\n \u003cp\u003e(42.4- 171.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e88.4\u003c/p\u003e\n \u003cp\u003e(59.1- 145.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e75.0\u003c/p\u003e\n \u003cp\u003e(57.7- 97.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.110\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.99\u003c/p\u003e\n \u003cp\u003e(0.98- 1.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e85.6\u003c/p\u003e\n \u003cp\u003e(42.4- 163.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e93.2\u003c/p\u003e\n \u003cp\u003e(52.9- 171.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e79.4\u003c/p\u003e\n \u003cp\u003e(57.7- 94.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.686\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003cp\u003e(0.99- 1.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eAlbumin, g/dL,\u0026nbsp;\u003c/p\u003e\n \u003cp\u003emedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e4.1\u003c/p\u003e\n \u003cp\u003e(3.2-5.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e4.1\u003c/p\u003e\n \u003cp\u003e(2.6-5.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e4.1\u003c/p\u003e\n \u003cp\u003e(3.5-4.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e3.9\u003c/p\u003e\n \u003cp\u003e(3.8-4.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.197\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.62\u003c/p\u003e\n \u003cp\u003e(0.30- 1.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e4.2\u003c/p\u003e\n \u003cp\u003e(3.4- 5.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e4.1\u003c/p\u003e\n \u003cp\u003e(2.6- 5.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e4.1\u003c/p\u003e\n \u003cp\u003e(3.2- 5.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.283\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.67\u003c/p\u003e\n \u003cp\u003e(0.32- 1.39)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eWBC,\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e3\u003c/sup\u003e/\u0026mu;L,\u0026nbsp;\u003c/p\u003e\n \u003cp\u003emedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e5.3\u003c/p\u003e\n \u003cp\u003e(2.7-16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e4.9\u003c/p\u003e\n \u003cp\u003e(2.9-9.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e5.0\u003c/p\u003e\n \u003cp\u003e(2.9-7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e5.4\u003c/p\u003e\n \u003cp\u003e(3.6-7.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.307\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.92\u003c/p\u003e\n \u003cp\u003e(0.77- 1.08)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e5.3\u003c/p\u003e\n \u003cp\u003e(2.7-16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e5.0\u003c/p\u003e\n \u003cp\u003e(2.9- 11.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e5.8\u003c/p\u003e\n \u003cp\u003e(3.6- 7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.499\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.95\u003c/p\u003e\n \u003cp\u003e(0.80- 1.11)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eHb, g/dL,\u0026nbsp;\u003c/p\u003e\n \u003cp\u003emedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e12.5\u003c/p\u003e\n \u003cp\u003e(9.2-15.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e12.2\u003c/p\u003e\n \u003cp\u003e(9.0- 14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e12.5\u003c/p\u003e\n \u003cp\u003e(10.6-14.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e12.0\u003c/p\u003e\n \u003cp\u003e(11.0-12.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.379\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.90\u003c/p\u003e\n \u003cp\u003e(0.70-1.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e12.4\u003c/p\u003e\n \u003cp\u003e(9.7- 14.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e12.4\u003c/p\u003e\n \u003cp\u003e(9- 15.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e12.1\u003c/p\u003e\n \u003cp\u003e(9.8-14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.385\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.90\u003c/p\u003e\n \u003cp\u003e(0.70- 1.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003ePLT,\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e3\u003c/sup\u003e/\u0026mu;L,\u0026nbsp;\u003c/p\u003e\n \u003cp\u003emedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e251\u003c/p\u003e\n \u003cp\u003e(77-612)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e263\u003c/p\u003e\n \u003cp\u003e(168-514)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e264\u003c/p\u003e\n \u003cp\u003e(164- 434)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e248\u003c/p\u003e\n \u003cp\u003e(169-375)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.440\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003cp\u003e(1.00-1.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e257\u003c/p\u003e\n \u003cp\u003e(158-452)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e256\u003c/p\u003e\n \u003cp\u003e(77-612)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e265\u003c/p\u003e\n \u003cp\u003e(169-514)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.703\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber of cycles, average (range)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e4.0\u003c/p\u003e\n \u003cp\u003e(2-9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e4.1\u003c/p\u003e\n \u003cp\u003e(2-9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e4.3\u003c/p\u003e\n \u003cp\u003e(4-8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e4.0\u003c/p\u003e\n \u003cp\u003e(4-4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.551\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e1.10\u003c/p\u003e\n \u003cp\u003e(0.81- 1.49)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e4.2\u003c/p\u003e\n \u003cp\u003e(2-9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e4.0\u003c/p\u003e\n \u003cp\u003e(2-8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e3.9\u003c/p\u003e\n \u003cp\u003e(2-4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.237\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.82\u003c/p\u003e\n \u003cp\u003e(0.60- 1.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"12\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eConcomitant medication\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eNSAIDs, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e(3.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e(4.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e(12.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e(14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.154\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e2.59\u003c/p\u003e\n \u003cp\u003e(0.70- 9.59)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e(3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003cp\u003e(6.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e(6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.552\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e1.53\u003c/p\u003e\n \u003cp\u003e(0.38- 6.17)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eMucoprotective agents, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003cp\u003e(12.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003cp\u003e(20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e(12.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003cp\u003e(57.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.060\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e2.13\u003c/p\u003e\n \u003cp\u003e(0.97- 4.69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003cp\u003e(23.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003cp\u003e(10.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003cp\u003e(25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.263\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.63\u003c/p\u003e\n \u003cp\u003e(0.28- 1.42)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eAnticholinergic drugs, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003cp\u003e(21.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003cp\u003e(12.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003cp\u003e(37.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e(28.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.695\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e1.16\u003c/p\u003e\n \u003cp\u003e(0.55- 2.45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003cp\u003e(16.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003cp\u003e(22.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e(18.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.514\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e1.29\u003c/p\u003e\n \u003cp\u003e(0.60- 2.79)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eRAS inhibitors, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003cp\u003e(8.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003cp\u003e(16.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e(6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.845\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e1.10\u003c/p\u003e\n \u003cp\u003e(0.41- 2.94)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003cp\u003e(12.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003cp\u003e(10.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.283\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.58\u003c/p\u003e\n \u003cp\u003e(0.21- 1.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eStatins, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003cp\u003e(17.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003cp\u003e(12.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003cp\u003e(25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e(14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.899\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.95\u003c/p\u003e\n \u003cp\u003e(0.42- 2.95)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003cp\u003e(14.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003cp\u003e(19.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e(6.25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.930\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.96\u003c/p\u003e\n \u003cp\u003e(0.42- 2.21)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"12\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePurpose of treatment\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eNeo-adjuvant, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003cp\u003e(29.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003cp\u003e(26.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003cp\u003e(31.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e(42.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.887\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e1.05\u003c/p\u003e\n \u003cp\u003e(0.54-2.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003cp\u003e(20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003cp\u003e(34.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003cp\u003e(31.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.110\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e1.75\u003c/p\u003e\n \u003cp\u003e(0.88- 3.47)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eAdjuvant, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e48\u003c/p\u003e\n \u003cp\u003e(59.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003cp\u003e(66.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003cp\u003e(68.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003cp\u003e(57.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.452\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e1.27\u003c/p\u003e\n \u003cp\u003e(0.68- 2.39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e35\u003c/p\u003e\n \u003cp\u003e(63.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003cp\u003e(60.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003cp\u003e(68.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.995\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003cp\u003e(0.53- 1.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003ePalliative, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003cp\u003e(8.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e(6.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.142\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.36\u003c/p\u003e\n \u003cp\u003e(0.09- 1.41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003cp\u003e(12.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e(3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.014*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.18\u003c/p\u003e\n \u003cp\u003e(0.04- 0.70)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCI, confidence interval; BMI, body mass index; BSA, body surface area; WBC, white blood cell; Hb, hemoglobin; PLT, platelet, NSAIDs, non-steroidal anti-inflammatory drugs; RAS, renin-angiotensin system\u003c/p\u003e\n\u003cp\u003e*\u003cem\u003eP\u003c/em\u003e\u0026lt;0.05\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 2. Results of multivariate logistic regression analysis (n = 154)\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 15px;\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u0026nbsp;\u003c/em\u003evalue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 18px;\"\u003e\n \u003cp\u003eOdds ratio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 49px;\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 24px;\"\u003e\n \u003cp\u003eLower 95%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24px;\"\u003e\n \u003cp\u003eUpper 95%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStomatitis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0.025*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e1.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e1.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e1.07\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eAlbumin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0.289\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e0.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e0.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e1.45\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eNumber of cycles\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0.042*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e1.60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e1.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e2.51\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eNSAIDs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0.043*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e4.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e1.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e19.51\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eMucoprotective agents\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0.014*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e2.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e1.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e6.45\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eStatins\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0.627\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e0.80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e0.32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e2.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003ePalliative chemotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0.013*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e0.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e0.60\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDysgeusia\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eHeight\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0.053\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e1.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e0.999\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e1.13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eAlbumin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0.049*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e0.46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e0.21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e0.998\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003eNumber of cycles\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0.993\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e1.002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e0.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e1.52\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003eRAS inhibitors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0.291\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e0.57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e0.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e1.61\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003ePalliative chemotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0.015*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e0.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e0.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e0.68\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eCI, confidence interval; NSAIDs, non-steroidal anti-inflammatory drugs; RAS, renin-angiotensin system\u003c/p\u003e\n\u003cp\u003e*\u003cem\u003eP\u003c/em\u003e\u0026lt;0.05\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Stomatitis, Dysgeusia, Breast Cancer, FEC Therapy, Risk Factors, Protective Measures","lastPublishedDoi":"10.21203/rs.3.rs-6509469/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6509469/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003e\u0026nbsp;To identify the risk factors associated with stomatitis and dysgeusia in women undergoing FEC therapy for breast cancer and evaluate potential protective measures.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eBetween February 2016 and September 2020, 154 female breast cancer patients undergoing FEC therapy were enrolled at our outpatient chemotherapy center. Variables related to the development of stomatitis and dysgeusia were extracted from the patients’ medical records. The severity of stomatitis and dysgeusia was assessed at the end of chemotherapy using a questionnaire designed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5. Multivariate ordered logistic regression analysis was performed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003e\u0026nbsp;Factors significantly correlated with the development of stomatitis included age (odds ratio [OR] = 1.04, 95% confidence interval [CI] = 1.01-1.07; \u003cem\u003eP\u003c/em\u003e = 0.025), number of cycles (OR = 1.60, 95% CI = 1.02-2.51; \u003cem\u003eP \u003c/em\u003e= 0.042), non-steroidal anti-inflammatory drugs (OR = 4.52, 95% CI = 1.05-19.51;\u003cem\u003eP\u003c/em\u003e = 0.043), mucoprotective agents (OR = 2.82, 95% CI = 1.24-6.45; \u003cem\u003eP\u003c/em\u003e= 0.014), and palliative chemotherapy (OR = 0.09, 95% CI = 0.01-0.60; \u003cem\u003eP\u003c/em\u003e= 0.013). Factors significantly correlated with the development of dysgeusia were albumin (OR = 0.46, 95% CI = 0.21- 0.998;\u003cem\u003e P\u003c/em\u003e = 0.049) and palliative chemotherapy (OR = 0.14, 95% CI = 0.03- 0.68; \u003cem\u003eP\u003c/em\u003e = 0.015). Although not significant, potential prophylactic factors were statins for stomatitis and renin-angiotensin system inhibitors for dysgeusia.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e The identified factors for stomatitis and dysgeusia may help develop strategies to improve the quality of life of patients receiving chemotherapy.\u003c/p\u003e","manuscriptTitle":"Risk Factors and Protective Measures for Stomatitis and Dysgeusia in Patients with Breast Cancer Undergoing FEC Therapy: An Exploratory Retrospective Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-05 10:57:47","doi":"10.21203/rs.3.rs-6509469/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2cf8baea-ad8d-4801-9beb-41066f006f84","owner":[],"postedDate":"May 5th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-05-07T00:33:55+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-05 10:57:47","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6509469","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6509469","identity":"rs-6509469","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}