Factors related to oral mucositis or dysgeusia in breast cancer patients undergoing fluorouracil, epirubicin, and cyclophosphamide therapy: A single-center, retrospective study

doi:10.21203/rs.3.rs-3962721/v1

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Factors related to oral mucositis or dysgeusia in breast cancer patients undergoing fluorouracil, epirubicin, and cyclophosphamide therapy: A single-center, retrospective study

https://doi.org/10.21203/rs.3.rs-3962721/v1

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Purpose: This retrospective study aimed to identify factors contributing to the development of oral mucositis (OM) or dysgeusia.

Methods: Between February 2016 and September 2020, 154 female breast cancer patients undergoing chemotherapy with fluorouracil, epirubicin, and cyclophosphamide were enrolled at our outpatient chemotherapy center. Variables related to the development of OM or dysgeusia were extracted from the patients’ medical records. The severity of OM or 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 OM 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 (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). 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 OM and renin-angiotensin system inhibitors for dysgeusia.

Conclusions: The identified factors for OM or dysgeusia may help develop strategies to improve the quality of life of patients receiving chemotherapy.

chemotherapy

oral mucositis

dysgeusia

Oral complications, such as oral mucositis (OM) or dysgeusia, are common adverse effects associated with chemotherapeutic agents [1, 2]. OM, an inflammation of the oral mucosa, affects 10–100% of patients undergoing conventional chemotherapy [3–6]. Though not life-threatening, OM or dysgeusia can have a significant impact on patients’ quality of life (QoL) and food intake. Moreover, the presence of OM or dysgeusia may require dose interruptions and reductions, potentially impacting both dose intensity and treatment outcomes.

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 OM or 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 OM or dysgeusia. Thus, this retrospective study aimed to identify factors for the development of OM or dysgeusia in breast cancer 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.

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 OM or 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 ≥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 OM or dysgeusia. The questionnaire was designed according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE; version 5). The questionnaire for OM 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 OM or 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 OM or dysgeusia was evaluated using a graded scale, since multiple factors could potentially contribute to the development of OM or 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 OM 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 OM, 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.

Table 1 presents the clinical characteristics of the 154 enrolled patients, potential variables related to the development of OM or 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 OM, 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 OM 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 OM, 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).

Table 1

Patients’ characteristics, extracted variables, and results of univariate analyses (n = 154)
Oral mucositis							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/m²), 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 (m²), 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, × 10³/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, × 10³/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
Variable	P value	Odds ratio	Lower 95%	Upper 95%
Oral mucositis
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

The receiver-operating characteristic (ROC) curve analysis for the group likely to develop OM 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).

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 OM, and albumin and palliative chemotherapy were factors for the development of dysgeusia. Although not significant, potential prophylactic factors were statins for OM and RAS inhibitors for dysgeusia.

The older the patient and the higher the number of administered doses, the more likely patients were to develop OM. These findings align with clinical observations. Clinicians should be aware of the incidence of OM with older age (> 72 years) and higher dosing frequency.

Patients receiving palliative chemotherapy tended to experience less OM. 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 OM pain, they also were risk factors for OM. 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 OM 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 OM treatment, the findings of the present study showed that OM developed irrespective of the specific mucoprotectant used [22, 23]. This aligns with the current absence of effective treatments for OM. Although not significant, the results suggested that statins might reduce the risk of developing OM. 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 OM, 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 OM 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 OM and dysgeusia development. OM-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 OM, 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 OM and dysgeusia may help in the development of strategies to improve the QoL of patients receiving chemotherapy.

Conflict of interest: None declared.

Acknowledgements

The authors would like to thank all of the patients and medical staff at University Hospital, Kyoto Prefectural University of Medicine, who participated in this study.

The authors also thank FORTE Science Communications (https://www.forte-science.co.jp/) for English language editing.

Author 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 Sources This article was not funded.

Data Availability Statement

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.

Code availability Not applicable

Statement of Ethics

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.

Consent to participate

Given the retrospective nature of this work, the need to obtain 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.

Consent for publication

All authors give their consent for this manuscript to be published in Supportive Care in Cancer.

Conflict of Interest Statement No author declares any conflict of interest.

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Factors related to oral mucositis or dysgeusia in breast cancer patients undergoing fluorouracil, epirubicin, and cyclophosphamide therapy: A single-center, retrospective study

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Abstract

Introduction

Patients and Methods

Study Period and Participants

Extraction of variables

Statistical analysis

Results

Discussion

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References

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