Patient-Reported Oral Adverse Events During Cancer Chemotherapy: Longitudinal Evaluation Using Patient- Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) and Concordance with Clinician Assessments

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Methods Conducted at the Outpatient Cancer Chemotherapy Center, Niigata University Medical and Dental Hospital (June–December 2023), oral adverse events were assessed using PRO-CTCAE and CTCAE at baseline and every 3 weeks up to 24 weeks. Concordance for dry mouth and oral mucositis was evaluated using paired same-day scores. Results Among patients receiving multidisciplinary oral care, 85.2% experienced at least one oral adverse event, most commonly dry mouth. Based on PRO-CTCAE, symptoms rated as moderate or higher were reported in fewer than 10% of cases for most items. Notably, over half of patients reported persistent dry mouth of at least mild severity, and 20–30% of other symptoms also remained. These findings suggest that even lower-grade symptoms may persist and affect quality of life. Concordance between PRO-CTCAE and CTCAE was limited, with 31.1% of patients reporting greater dry mouth severity than clinicians documented. Conclusions Patient-reported oral adverse events, as assessed by PRO-CTCAE, were frequently mild but persistent throughout outpatient chemotherapy, suggesting a cumulative impact on quality of life. Concordance between PRO-CTCAE and clinician-reported CTCAE was limited, indicating that clinician assessments may underestimate symptoms such as dry mouth. These findings underscore the need to integrate patient-reported outcomes into routine oral care. Oral adverse events Chemotherapy Patient-Reported Outcomes Multidisciplinary oral care Outpatient cancer treatment Concordance Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 INTRODUCTION Oral adverse events (AEs), such as mucositis, dry mouth, hoarseness, and taste changes, are common complications during cancer chemotherapy that can significantly impair quality of life (QOL) by affecting eating, speaking, and daily functioning [ 1 ]. Although clinician-reported assessments using the Common Terminology Criteria for Adverse Events (CTCAE) are standard for grading toxicity, evidence suggests they often underestimate the frequency and severity of subjective symptoms experienced by patients [ 2 , 3 ]. To address this gap, the Patient-Reported Outcomes version of CTCAE (PRO-CTCAE) was developed [ 4 – 6 ], enabling more accurate capture of patient symptoms. The National Cancer Institute (NCI) indicated that using both CTCAE and PRO-CTCAE may improve recognition of mild AEs [ 7 ]. Although PRO-CTCAE has been increasingly utilized in oncology, longitudinal data specifically focusing on oral AEs during outpatient chemotherapy remain limited. Our previous study demonstrated that patients receiving 5-fluorouracil (5FU)-, taxane-, and anthracycline-based regimens are particularly susceptible to oral complications and may benefit from specialized oral management [ 8 ]. Multidisciplinary oral care is widely recommended to prevent and manage these toxicities and thereby improve patient outcomes[ 9 , 10 ]. Building on these findings, we identified the need for a tailored multidisciplinary oral care intervention for patients undergoing these regimens and subsequently developed a structured oral care tool. Moreover, direct comparisons between PRO-CTCAE and clinician-reported CTCAE for oral AEs remain limited, and the concordance between these assessment methods is not well understood [ 11 , 12 ]. Given these considerations, a focused investigation was deemed necessary. In this study, we aimed to characterize the frequency, severity, and longitudinal changes of patient-reported oral AEs using PRO-CTCAE among outpatients receiving multidisciplinary oral care. We also evaluated the concordance between PRO-CTCAE and clinician-reported CTCAE scores. METHODS Study Design This was a retrospective observational study designed to evaluate longitudinal oral adverse events and symptom concordance among chemotherapy outpatients. Patients This study was conducted at the Outpatient Cancer Chemotherapy Center of Niigata University Medical and Dental Hospital between June 1 and December 31, 2023. Patients were eligible for inclusion if they 1) had cancer, 2) were undergoing taxane-based and/or 5FU-based chemotherapy at the center, and 3) were between 18 and 100 years of age. Patients were excluded if they 1) never responded to the PRO-CTCAE, 2) were receiving or had previously received radiation therapy, or 3) were already receiving oral care from dental professionals, including dentists or dental hygienists. Data on patient characteristics, including age, sex, smoking and alcohol history, activities of daily living (ADL), communication ability, medication management, and drug therapies, were extracted from electronic medical records. Ethical Considerations This study was conducted in accordance with the ‘Ethical Guidelines for Medical and Health Research Involving Human Subjects’ and approved by the Ethics Committee of the Niigata University School of Medicine (approval number: 2023 − 0315). Oral AEs Assessment To assess oral AEs, the Japanese version 1.0 of PRO-CTCAE [ 13 ] and CTCAE version 5.0 were used. Patients reported seven oral AE symptom terms in the PRO-CTCAE: 1) dry mouth, 2) difficulty swallowing, 3) mouth/throat sores, 4) cracking at the corners of the mouth (cheilosis/cheilitis), 5) voice quality changes, 6) hoarseness, and 7) taste changes. Dry mouth and oral mucositis were selected for clinician assessment using the CTCAE, as these AEs are well-defined and supported by established clinical criteria, ensuring greater inter-rater reliability and reproducibility. Although taste changes were frequently reported, their evaluation is highly subjective and relies on patient-reported outcomes rather than objective clinical assessment. Similarly, symptoms like hoarseness or voice quality changes are difficult to assess consistently in clinical practice. Therefore, we focused on the two most objectively evaluable and clinically relevant symptoms within CTCAE. In this study, PRO-CTCAE 'Mouth/throat sores' was evaluated as equivalent to CTCAE 'Oral mucositis,' as both terms reflect mucosal inflammation and associated symptoms [ 7 , 14 ]. Patient- and clinician-reported scores were assessed at each visit. Statistical analysis To evaluate concordance in the grading of dry mouth and oral mucositis between patients and clinicians, paired scores from the same day were analyzed. Concordance was defined as the same severity of adverse events reported by patients using the PRO-CTCAE (none, mild, moderate, severe, very severe) and by clinicians using the CTCAE (grades 0, 1, 2, 3, or 4) at a given time point [ 11 ], for a given time point. Weighted kappa value (k w ) and its associated 95% confidence interval were calculated as a measure of concordance between assessment by patients and clinicians. This concordance is considered; poor: k w 0.80. All statistical analyses were performed using EZR ver.1.66 (Saitama Medical Center, Jichi Medical University, Saitama, Japan) [ 15 ], which is for R (The R Foundation for Statistical Computing, Vienna, Austria). It is a modified version of R commander designed to add statistical functions that are frequently used in biostatistics. RESULTS Patient characteristics A total of 243 patients received oral care following the protocol shown in Fig. 1 at the Outpatient Cancer Chemotherapy Center of Niigata University Medical and Dental Hospital between June 1 and December 31, 2023. Of these, five patients did not receive taxane-based and/or 5FU-based chemotherapy, and one patient did not complete any PRO-CTCAE assessments.. Therefore, 237 patients were included in the analysis. The mean age was 64 years (range: 23–84), and 112(47.3%) were male. Most patients had normal physical and cognitive functions. Among the patients, 65.0% received taxane-based therapies, while 41.4% received 5-FU-based therapies. Detailed demographic and clinical characteristics are summarized in Table 1 . Table 1 patient characteristics N = 237 N (%) Age(years) Range 23–84 Average 64 Sex Male 112(47.3%) Female 125(52.7%) Smoking History No-smoking 100(42.2%) Smoking 128(54.0%) quit smoking 109 1 or 10 cigarettes a day 9 more than 10 cigarettes a day 10 Unknown 9(3.8%) Drinking history Drink socially 153(64.6%) Habitual drinking 74(31.2%) once a week 11 three or four times a week 14 every day 49 Unknown 10(4.2%) ADL Independence 223(94.1%) Assistance 10(4.2%) Unknown 4(1.7%) Communication No problem 223(94.1%) Hearing loss 6(2.5%) Unknown 8(3.4%) Manage medicine Self-management 193(81.4%) Family-management 6(2.5%) Unknown 38(16.0%) Chemotherapy Fluorinated pyrimidines 98(41.4%) Taxans 154(65.0%) Oral care intervention Figure 1 illustrates the multidisciplinary oral care protocol for patients receiving outpatient chemotherapy. Based on our previous results, we targeted patients receiving 5FU- and taxane-based therapies [ 8 ]. First step: Patients completed the seven PRO-CTCAE items related to oral symptoms. Second step: The nurse reviewed PRO-CTCAE responses, assessed oral adverse events using the CTCAE, and provided patient education on oral care. If the CTCAE grade was 2 or higher, the nurse consulted a pharmacist Third step: The pharmacist evaluated oral symptoms and recommended appropriate interventions, such as coating agents for grade 2 oral mucositis and moisturizers for grade 2 dry mouth. If a dental consultation was deemed necessary, the pharmacist requested an appointment with a dentist. Frequency and Severity of Oral AEs Assessed by PRO-CTCAE The frequency and severity of oral AEs assessed by PRO-CTCAE are shown in Figs. 2 and 3 . 85.2% (202/237) of the patients experienced at least one symptom. Among these, dry mouth was the most frequently reported symptom (68.8%) (Fig. 2 ). Based on the highest PRO-CTCAE scores recorded during the study period, the proportion of patients reporting moderate or greater symptoms were: dry mouth (21.9%), taste changes (18.2%), and mouth/throat sores (16.5%). In contrast, no patients reported changes in voice quality (0.0%) (Fig. 3 ). Longitudinal changes in PRO-CTCAE Figure 4 displays the distribution of oral symptom severity based on PRO-CTCAE grades at the initiation of multidisciplinary oral care and at subsequent 3-week intervals. The proportion of patients with moderate or greater AEs remained below 10% at nearly all time points, indicating that the severity of all symptoms was generally mild. However, the proportion of patients reporting any symptoms (as mild or greater) ranged from 30–50% for dry mouth, 20–35% for taste change, and 10–30% for mouth/throat sores, dysphagia, and hoarseness. For all symptoms, the proportion of patients reporting symptoms declined until approximately week 15, followed by a trend toward symptom exacerbation. Concordance between PRO-CTCAE and CTCAE To assess alignment between patient and clinician evaluations, we evaluated the agreement between PRO-CTCAE and CTCAE for dry mouth and oral mucositis. A total of 1,066 assessment pairs for dry mouth and 1,058 assessment pairs for oral mucositis were obtained. The agreement between patients and clinicians was fair for both dry mouth and oral mucositis (kw = 0.39, 95%CI = 0.34–0.45: kw = 0.4, 95%CI = 0.32–0.48). The distribution of PRO-CTCAE and CTCAE assessment pairs is shown in Fig. 5 . The percentages of perfect agreement between patients and clinicians were 65.8% for dry mouth (agreement ± 1: 96.3%) and 81.9% for oral mucositis (agreement ± 1: 97.2%). Compared to clinicians, 31.1% (332/1066) of patients reported more severe dry mouth, while 14.0% (148/1058) reported more severe oral mucositis. Conversely, clinicians rated symptoms as more severe than patients in 3.1% of dry mouth cases and 4.1% of oral mucositis cases. DISCUSSION In this study, we implemented multidisciplinary oral care and evaluated oral adverse events using PRO-CTCAE. Three key findings emerged. First, 85.2% of patients experienced at least one oral adverse event, with dry mouth being the most frequently reported symptom; notably, 21.9% (52/237) reported dry mouth of moderate or greater severity. Second, although the severity of oral symptoms remained generally mild (≥ moderate < 10% throughout), a substantial proportion of patients reported persistent symptoms (≥ mild), such as dry mouth (30–50%), taste changes (20–35%), and oral mucositis, dysphagia, or hoarseness (10–30%) over the 24-week period, suggesting a prolonged impact on QOL. Third, the concordance between PRO-CTCAE and CTCAE for dry mouth and oral mucositis was limited, with 31.1% of patients reporting greater severity of dry mouth than assessed by clinicians. The high incidence of oral adverse events (85.2%) among patients receiving 5-FU- and taxane-based regimens supports the validity of our screening approach and aligns with previous studies reporting strong associations between these agents and oral toxicities [ 1 , 16 , 17 ]. Targeting this population was therefore appropriate for establishing an effective referral system. Dry mouth was the most frequently reported adverse event (68.8%), consistent with prior findings showing rates of 56–69% in patients treated with 5-FU and 56% in those receiving taxanes [ 16 ]. These agents are known to reduce salivary secretion [ 18 – 20 ], likely contributing to the high frequency of reported dry mouth. In this observational study using PRO-CTCAE, longitudinal monitoring of chemotherapy outpatients receiving multidisciplinary oral care showed that symptoms of ≥ moderate severity remained relatively infrequent, with most AEs persisting in the mild range. These findings suggest that ongoing multidisciplinary interventions may help prevent symptom escalation. However, the continued presence of ≥ mild symptoms—particularly dry mouth and taste changes—underscores the limitations of current care in fully alleviating these issues during treatment. Notably, after an initial decline in symptom prevalence, a rebound was observed beyond week 15, highlighting the need for sustained and extended intervention. Nonetheless, in the absence of a control group, we cannot definitively attribute these trends to the intervention rather than natural symptom fluctuations [ 21 , 22 ]. The agreement between PRO-CTCAE and CTCAE was moderate (κ = 0.39–0.4), with 31.1% of patients reporting more severe dry mouth than clinicians, reflecting CTCAE's limitations in capturing subjective symptoms [ 4 , 23 , 24 ]. Although perfect agreement was achieved in 65.8% of cases for dry mouth and 81.9% for oral mucositis, agreement within ± 1 grade was high (96.3% and 97.2%, respectively), suggesting that major discrepancies were infrequent. These findings highlight the structural differences between PRO-CTCAE and CTCAE: the former captures patients ' experiences, whereas the latter often relies on observable or functional changes, which may underestimate symptom burden [ 4 , 25 – 31 ]. The relatively lower concordance for dry mouth likely stems from its subjective nature, lacking objective signs, unlike oral mucositis, which can be visually confirmed. The tendency for patients to report greater symptom severity than clinicians further supports the integration of PROs into routine care to improve symptom recognition [ 32 ]. PRO-CTCAE and CTCAE provide complementary perspectives, and their combined use may enhance the sensitivity and accuracy of AE monitoring in clinical oncology [ 32 ]. This study has some limitations that should be considered when interpreting the findings. First, the study population was limited to patients receiving 5FU- and taxane-based chemotherapy, restricting the generalizability of findings to those undergoing different regimens. Second, dental examinations or microbiological tests were not performed, as dental evaluations were only conducted when CTCAE grades 2–4 were identified. Third, there may be variability in the frequency of oral care interventions, underscoring the need for a more standardized intervention protocol. Fourth, the follow-up period was limited to a maximum of 24 weeks, preventing assessment of long-term effects. Longer follow-up would be necessary to assess whether symptoms improve or worsen over time. Fifth, as this study lacks a control group, the effects of the multidisciplinary intervention cannot be conclusively determined. Further studies with a controlled design are needed to establish causality. Finally, as the study was conducted at a single institution, potential biases related to patient characteristics should be considered. Our findings highlight the importance of regular monitoring by a multidisciplinary team for effective management of oral symptoms in cancer outpatients. Incorporating PRO-CTCAE into routine assessments may improve the detection of symptoms that are under-recognized by clinician-reported CTCAE alone. Given the limitations of recommending moisturizers and protective agents without prescriptions, future studies should evaluate the clinical impact of prescribing such interventions. Further research is also needed to assess the generalizability and long-term effectiveness of multidisciplinary oral care through multicenter studies, standardized intervention protocols, and extended follow-up durations. CONCLUSIONS This study demonstrated that patient-reported oral AEs were frequently observed during outpatient chemotherapy, with dry mouth as the most common symptom. Longitudinal assessment using PRO-CTCAE showed that while the proportion of patients reporting symptoms fluctuated over time, oral AEs of at least mild severity persisted in 10–50% of patients throughout the 24-week observation period. The limited concordance between PRO-CTCAE and clinician-reported CTCAE—particularly for dry mouth—suggests that certain symptoms may be underrecognized in routine oncology practice. These findings support the integration of patient-reported outcome into multidisciplinary oral care to enhance symptom detection and management. Future studies should aim to standardize intervention protocols, evaluates the impact of prescription-based supportive care, and validate these findings in multi-center settings with longer follow-up. Declarations Funding Not applicable Competing interests The authors declare that they have no competing interests Authors’ contributions Conceptualization: YS, KK. Data collection: YS, MK. Formal analysis and investigation: YS. Writing—original draft preparation: YS, YK, AT. All authors critically revised the article and approved the final version for publication. Ethics approval and consent to participate This study was approved by the Ethics Committee of the Niigata University School of Medicine (approval number: 2023-0315). As this was a retrospective observational study using existing medical records, we employed an opt-out method for obtaining consent in accordance with the Ethical Guidelines for Medical and Health Research Involving Human Subjects in Japan. Information about the study was publicly disclosed on the Niigata University School of Medicine website, providing participants with the opportunity to refuse participation. The study was conducted in accordance with the Declaration of Helsinki. The authors declare no conflicts of interest. Consent of publish Not applicable. Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author upon reasonable request . References Japanese Association of Supportive Care in Cancer (2020) Japanese Association of Oral Supportive Care in Cancer: Clinical Guidance of Management for Mucositis. Kanehara Co., Tokyo Trotti A, Colevas AD, Setser A, Basch E (2007) Patient-reported outcomes and the evolution of adverse event reporting in oncology. In: J Clin Oncol 25:5121–5127. https://doi.org/10.1200/JCO.2007.12.4784 Bruner DW (2007) Should patient-reported outcomes be mandatory for toxicity reporting in cancer clinical trials? J Clin Oncol 25:5345–5347. https://doi.org/10.1200/JCO.2007.13.3330 Dueck AC, Mendoza TR, Mitchell SA, et al (2015) Validity and reliability of the us National Cancer Institute’s patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE). JAMA Oncol 1:1051–1059. https://doi.org/10.1001/jamaoncol.2015.2639 Kawaguchi T, Azuma K, Sano M, et al (2017) The Japanese version of the National Cancer Institute’s patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE): Psychometric validation and discordance between clinician and patient assessments of adverse events. J Patient Rep Outcomes, Japanese version 2:. https::2. https://doi.org/10.1186/s41687-017-0022-5 Miyaji T, Iioka Y, Kuroda Y, et al (2017) Japanese translation and linguistic validation of the us National Cancer Institute’s patient-reported outcomes version of the common terminology criteria for adverse events (Pro-ctcae). J Patient Rep Outcomes 1:8. https://doi.org/10.1186/s41687-017-0012-7 Minasian LM, O’Mara A, Mitchell SA (2022) Clinician and patient reporting of symptomatic adverse events in cancer clinical trials: Using CTCAE and PRO-CTCAE® to provide two distinct and complementary perspectives. Patient Relat Outcome Meas 13:249–258. https://doi.org/10.2147/PROM.S256567 Sakai Y, Katsura K, Kotake M, Toyama A (2025) A cross-sectional survey of oral adverse events and oral management needs in outpatients receiving cancer drug therapy. Cancers (Basel) 17:. https::641. https://doi.org/10.3390/cancers17040641 Elad S, Cheng KKF, Lalla RV, et al (2020) MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer 126:4423–4431. https://doi.org/10.1002/cncr.33100 Mercadante V, Jensen SB, Smith DK, et al (2021) Salivary Gland Hypofunction and/or xerostomia Induced by Nonsurgical Cancer Therapies: ISOO/MASCC/ASCO Guideline. J Clin Oncol 39:2825–2843. https://doi.org/10.1200/JCO.21.01208 Falchook AD, Green R, Knowles ME, et al (2016) Comparison of patient- and practitioner-reported toxic effects associated with chemoradiotherapy for head and neck cancer. JAMA Otolaryngol Head Neck Surg 142:517–523. https://doi.org/10.1001/jamaoto.2016.0656 Arahori H, Kondo K, Imai Y, et al (2024) Symptomatic adverse events of chemotherapy in breast cancer patients: Using CTCAE, PRO-CTCAE, and EORTC QLQ-C30. J Med Invest 71:82–91. https://doi.org/10.2152/jmi.71.82 NCI. PRO-CTCAE® ITEMS-JAPANESE Item Library, version 1.0. Accessed 1 Mar 2024 Correspondence between PRO-CTCAE and CTCAE terminologies. Accessed 1 Mar 2024 Kanda Y (2013) Investigation of the freely available easy-to-use software “EZR” for medical statistics. Bone Marrow Transplant 48:452–458. https://doi.org/10.1038/bmt.2012.244 Wilberg P, Hjermstad MJ, Ottesen S, Herlofson BB (2014) Chemotherapy-associated oral sequelae in patients with cancers outside the head and neck region. J Pain Symptom Manag 48:1060–1069. https://doi.org/10.1016/j.jpainsymman.2014.02.009 Speck RM, Demichele A, Farrar JT, et al (2013) Taste alteration in breast cancer patients treated with taxane chemotherapy: Experience, effect, and coping strategies. Support Care Cancer 21:549–555. https://doi.org/10.1007/s00520-012-1551-3 Jensen SB, Pedersen AML, Vissink A, et al (2010) A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: Prevalence, severity and impact on quality of life. Support Care Cancer 18:1039–1060. https://doi.org/10.1007/s00520-010-0827-8 Paz C, Glassey A, Frick A, et al (2024) Cancer therapy–related salivary dysfunction. J Clin Invest 134:e182661. https://doi.org/10.1172/JCI182661 Jensen SB, Mouridsen HT, Reibel J, Brünner N, Nauntofte B (2008) Adjuvant chemotherapy in breast cancer patients induces temporary salivary gland hypofunction. Oral Oncol 44:162–173. https://doi.org/10.1016/j.oraloncology.2007.01.015 Boltong A, Keast R, Aranda S (2012) Experiences and consequences of altered taste, flavour and food hedonics during chemotherapy treatment. Support Care Cancer 20:2765–2774. https://doi.org/10.1007/s00520-012-1398-7 Boltong A, Aranda S, Keast R, et al (2014) A prospective cohort study of the effects of adjuvant breast cancer chemotherapy on taste function, food liking, appetite and associated nutritional outcomes. PLOS One 9:. https::e103512. https://doi.org/10.1371/journal.pone.0103512 Basch E, Iasonos A, Mcdonough TA, et al (2006) Articles Patient versus clinician symptom reporting using the National Cancer Institute Common Terminology Criteria for Adverse Events: Results of a questionnaire-based study. https://doi.org/10.1016/S1470 Huynh-Dagher S, Duong T-A, Tournigand C, Kempf E, Lamé G (2025) Concordance between patient-reported outcomes and CTCAE clinician-reported toxicities during outpatient chemotherapy courses: A retrospective cohort study in routine care. ESMO Real World Data Digital Oncology 8:100127. https://doi.org/10.1016/j.esmorw.2025.100127 Basch E, Becker C, Rogak LJ, et al (2021) Composite grading algorithm for the National Cancer Institute’s Patient-Reported outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Clin Trials 18:104–114. https://doi.org/10.1177/1740774520975120 Gounder MM, Mahoney MR, Van Tine BA, et al (2018) Sorafenib for advanced and refractory desmoid tumors. N Engl J Med 379:2417–2428. https://doi.org/10.1056/NEJMoa1805052 Basch EM, Scholz M, de Bono JS, et al (2019) Cabozantinib versus mitoxantrone-prednisone in symptomatic metastatic castration-resistant prostate cancer: A randomized Phase 3 trial with a primary pain endpoint. Eur Urol 75:929–937. https://doi.org/10.1016/j.eururo.2018.11.033 Takenaga T, Kuji S, Tanabe KI, et al (2024) Prospective analysis of patient-reported outcomes and physician-reported outcomes with gynecologic cancer chemotherapy. J Obstet Gynaecol Res 50:75–85. https://doi.org/10.1111/jog.15811 Gu S, Menzer C, Hay JL, et al (2023) PRO-CTCAE reveals under-recognition of dermatologic symptom burden in hospitalized cancer patients. Support Care Cancer 31:337. https://doi.org/10.1007/s00520-023-07793-5 Tan AC, McCrary JM, Park SB, Trinh T, Goldstein D (2019) Chemotherapy-induced peripheral neuropathy-Patient-reported outcomes compared with NCI-CTCAE grade. Support Care Cancer 27:4771–4777. https://doi.org/10.1007/s00520-019-04781-6 Dueck AC, Scher HI, Bennett AV, et al (2020) Assessment of adverse events from the patient perspective in a Phase 3 metastatic castration-resistant prostate cancer clinical trial. JAMA Oncol 6:. https::e193332. https://doi.org/10.1001/jamaoncol.2019.3332 Basch E, Spertus J, Dudley RA, et al (2015) Methods for developing patient-reported outcome-based performance measures (PRO-PMs). Value Health 18:493–504. https://doi.org/10.1016/j.jval.2015.02.018 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 13 Nov, 2025 Read the published version in Supportive Care in Cancer → Version 1 posted Editorial decision: Revision requested 01 Oct, 2025 Reviews received at journal 10 Sep, 2025 Reviews received at journal 09 Sep, 2025 Reviews received at journal 02 Sep, 2025 Reviews received at journal 31 Aug, 2025 Reviewers agreed at journal 26 Aug, 2025 Reviewers agreed at journal 22 Aug, 2025 Reviewers agreed at journal 22 Aug, 2025 Reviewers agreed at journal 21 Aug, 2025 Reviewers agreed at journal 20 Aug, 2025 Reviewers invited by journal 20 Aug, 2025 Editor assigned by journal 06 Aug, 2025 Submission checks completed at journal 28 Jun, 2025 First submitted to journal 25 Jun, 2025 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-6970435","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":505983257,"identity":"317c229f-daa2-4a21-ba40-4e03a9c78e34","order_by":0,"name":"Yuki Sakai","email":"data:image/png;base64,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","orcid":"","institution":"Niigata University Medical and Dental Hospital","correspondingAuthor":true,"prefix":"","firstName":"Yuki","middleName":"","lastName":"Sakai","suffix":""},{"id":505983258,"identity":"fb5629fa-05f3-4515-8ab3-dd6ae155dc41","order_by":1,"name":"Kouji Katsura","email":"","orcid":"","institution":"Niigata University Medical and Dental Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kouji","middleName":"","lastName":"Katsura","suffix":""},{"id":505983259,"identity":"e4d2aad8-d4e8-4eab-b24a-3ebb97c7fd3a","order_by":2,"name":"Yoshitomi Kanemitsu","email":"","orcid":"","institution":"Niigata University Medical and Dental Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yoshitomi","middleName":"","lastName":"Kanemitsu","suffix":""},{"id":505983260,"identity":"e4d20f04-fff3-4f84-a459-606b61a00e97","order_by":3,"name":"Masaaki Kotake","email":"","orcid":"","institution":"Niigata University Medical and Dental Hospital","correspondingAuthor":false,"prefix":"","firstName":"Masaaki","middleName":"","lastName":"Kotake","suffix":""},{"id":505983261,"identity":"e13f3983-89be-4b22-b3d9-f39c4279f8e9","order_by":4,"name":"Akira Toyama","email":"","orcid":"","institution":"Niigata University Medical and Dental Hospital","correspondingAuthor":false,"prefix":"","firstName":"Akira","middleName":"","lastName":"Toyama","suffix":""}],"badges":[],"createdAt":"2025-06-25 04:23:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6970435/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6970435/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00520-025-10126-3","type":"published","date":"2025-11-13T15:57:37+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":90305882,"identity":"ed24b056-3831-4013-be47-702b4df8cbc5","added_by":"auto","created_at":"2025-09-01 09:25:11","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":39046,"visible":true,"origin":"","legend":"\u003cp\u003eMultidisciplinary approach to oral care at the Outpatient Cancer Chemotherapy Center of Niigata University Medical and Dental Hospital\u003c/p\u003e\n\u003cp\u003eFOLFOX: Oxaliplatin, 5FU FOLFIRI: Irinotecan,5FU XELOX: Oxaliplatin Capecitabine IRIS: Irinotecan, Tegafur/Gimeracil/Oteracil Potassium FOLFIRINOX: Irinotcan, Oxaliplatin,5FU PTX: Paclitaxel DTX: Docetaxel\u003c/p\u003e","description":"","filename":"Fig11.png","url":"https://assets-eu.researchsquare.com/files/rs-6970435/v1/e118c9684a333e05daa1562b.png"},{"id":90305883,"identity":"d0e31577-58ee-45c4-a5e2-4045573b4dc4","added_by":"auto","created_at":"2025-09-01 09:25:11","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":28464,"visible":true,"origin":"","legend":"\u003cp\u003eProportion of patients who reported each symptom at least once during the 24-week PRO-CTCAE assessment period\u003c/p\u003e","description":"","filename":"Fig21.png","url":"https://assets-eu.researchsquare.com/files/rs-6970435/v1/506f6254d866a38790f5fc44.png"},{"id":90309939,"identity":"7e664d21-106b-42fd-81df-f7fdcf0bf162","added_by":"auto","created_at":"2025-09-01 09:41:11","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":14124,"visible":true,"origin":"","legend":"\u003cp\u003eProportion of patients by maximum PRO-CTCAE severity over 24 weeks. Percentages represent symptoms rated as moderate or higher\u003c/p\u003e","description":"","filename":"Fig31.png","url":"https://assets-eu.researchsquare.com/files/rs-6970435/v1/98d0bf8fe9a56fc8517885ba.png"},{"id":90307578,"identity":"90b5abf2-fccc-44f3-9afb-bb29801234be","added_by":"auto","created_at":"2025-09-01 09:33:12","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":72557,"visible":true,"origin":"","legend":"\u003cp\u003eLongitudinal changes in PRO-CTCAE \u0026nbsp;oral symptoms after initiation of multidisciplinary oral care\u003c/p\u003e\n\u003cp\u003eStacked bar charts present the number of patients with each PRO-CTCAE (none to very severe) for each symptom over time\u003c/p\u003e","description":"","filename":"Fig41.png","url":"https://assets-eu.researchsquare.com/files/rs-6970435/v1/46eed625496b7254f3435d80.png"},{"id":90307576,"identity":"a17a5349-49fe-4f8a-a391-978ebdded0f2","added_by":"auto","created_at":"2025-09-01 09:33:12","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":30248,"visible":true,"origin":"","legend":"\u003cp\u003eAgreement between patient and clinician reporting dry mouth(A) and oral mucositis(B). The number of agreements between patients and clinicians is illustrated by the size of the bubbles\u003c/p\u003e","description":"","filename":"Fig51.png","url":"https://assets-eu.researchsquare.com/files/rs-6970435/v1/4f470e3771704983aa4aab0d.png"},{"id":96105185,"identity":"c7300fed-6b8a-4207-82fe-8037e0027cd5","added_by":"auto","created_at":"2025-11-17 16:09:49","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":908956,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6970435/v1/a8edd448-13a0-4cee-93a3-12c0f0694714.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Patient-Reported Oral Adverse Events During Cancer Chemotherapy: Longitudinal Evaluation Using Patient- Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) and Concordance with Clinician Assessments","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eOral adverse events (AEs), such as mucositis, dry mouth, hoarseness, and taste changes, are common complications during cancer chemotherapy that can significantly impair quality of life (QOL) by affecting eating, speaking, and daily functioning [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Although clinician-reported assessments using the Common Terminology Criteria for Adverse Events (CTCAE) are standard for grading toxicity, evidence suggests they often underestimate the frequency and severity of subjective symptoms experienced by patients [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. To address this gap, the Patient-Reported Outcomes version of CTCAE (PRO-CTCAE) was developed [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], enabling more accurate capture of patient symptoms. The National Cancer Institute (NCI) indicated that using both CTCAE and PRO-CTCAE may improve recognition of mild AEs [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Although PRO-CTCAE has been increasingly utilized in oncology, longitudinal data specifically focusing on oral AEs during outpatient chemotherapy remain limited.\u003c/p\u003e\u003cp\u003eOur previous study demonstrated that patients receiving 5-fluorouracil (5FU)-, taxane-, and anthracycline-based regimens are particularly susceptible to oral complications and may benefit from specialized oral management [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Multidisciplinary oral care is widely recommended to prevent and manage these toxicities and thereby improve patient outcomes[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Building on these findings, we identified the need for a tailored multidisciplinary oral care intervention for patients undergoing these regimens and subsequently developed a structured oral care tool.\u003c/p\u003e\u003cp\u003eMoreover, direct comparisons between PRO-CTCAE and clinician-reported CTCAE for oral AEs remain limited, and the concordance between these assessment methods is not well understood [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Given these considerations, a focused investigation was deemed necessary.\u003c/p\u003e\u003cp\u003e In this study, we aimed to characterize the frequency, severity, and longitudinal changes of patient-reported oral AEs using PRO-CTCAE among outpatients receiving multidisciplinary oral care. We also evaluated the concordance between PRO-CTCAE and clinician-reported CTCAE scores.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy Design\u003c/h2\u003e\u003cp\u003eThis was a retrospective observational study designed to evaluate longitudinal oral adverse events and symptom concordance among chemotherapy outpatients.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003ePatients\u003c/h3\u003e\n\u003cp\u003eThis study was conducted at the Outpatient Cancer Chemotherapy Center of Niigata University Medical and Dental Hospital between June 1 and December 31, 2023. Patients were eligible for inclusion if they 1) had cancer, 2) were undergoing taxane-based and/or 5FU-based chemotherapy at the center, and 3) were between 18 and 100 years of age. Patients were excluded if they 1) never responded to the PRO-CTCAE, 2) were receiving or had previously received radiation therapy, or 3) were already receiving oral care from dental professionals, including dentists or dental hygienists.\u003c/p\u003e\u003cp\u003eData on patient characteristics, including age, sex, smoking and alcohol history, activities of daily living (ADL), communication ability, medication management, and drug therapies, were extracted from electronic medical records.\u003c/p\u003e\n\u003ch3\u003eEthical Considerations\u003c/h3\u003e\n\u003cp\u003e This study was conducted in accordance with the \u0026lsquo;Ethical Guidelines for Medical and Health Research Involving Human Subjects\u0026rsquo; and approved by the Ethics Committee of the Niigata University School of Medicine (approval number: 2023\u0026thinsp;\u0026minus;\u0026thinsp;0315).\u003c/p\u003e\n\u003ch3\u003eOral AEs Assessment\u003c/h3\u003e\n\u003cp\u003eTo assess oral AEs, the Japanese version 1.0 of PRO-CTCAE [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] and CTCAE version 5.0 were used. Patients reported seven oral AE symptom terms in the PRO-CTCAE: 1) dry mouth, 2) difficulty swallowing, 3) mouth/throat sores, 4) cracking at the corners of the mouth (cheilosis/cheilitis), 5) voice quality changes, 6) hoarseness, and 7) taste changes.\u003c/p\u003e\u003cp\u003e Dry mouth and oral mucositis were selected for clinician assessment using the CTCAE, as these AEs are well-defined and supported by established clinical criteria, ensuring greater inter-rater reliability and reproducibility. Although taste changes were frequently reported, their evaluation is highly subjective and relies on patient-reported outcomes rather than objective clinical assessment. Similarly, symptoms like hoarseness or voice quality changes are difficult to assess consistently in clinical practice. Therefore, we focused on the two most objectively evaluable and clinically relevant symptoms within CTCAE. In this study, PRO-CTCAE 'Mouth/throat sores' was evaluated as equivalent to CTCAE 'Oral mucositis,' as both terms reflect mucosal inflammation and associated symptoms [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Patient- and clinician-reported scores were assessed at each visit.\u003c/p\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003e To evaluate concordance in the grading of dry mouth and oral mucositis between patients and clinicians, paired scores from the same day were analyzed. Concordance was defined as the same severity of adverse events reported by patients using the PRO-CTCAE (none, mild, moderate, severe, very severe) and by clinicians using the CTCAE (grades 0, 1, 2, 3, or 4) at a given time point [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], for a given time point. Weighted kappa value (k\u003csub\u003ew\u003c/sub\u003e) and its associated 95% confidence interval were calculated as a measure of concordance between assessment by patients and clinicians. This concordance is considered; poor: k\u003csub\u003ew\u003c/sub\u003e\u0026lt;0.2, fair:0.21\u0026ndash;0.40, moderate:0.41\u0026ndash;0.60, substantial:0.61\u0026ndash;0.80, almost perfect:\u0026gt;0.80.\u003c/p\u003e\u003cp\u003eAll statistical analyses were performed using EZR ver.1.66 (Saitama Medical Center, Jichi Medical University, Saitama, Japan) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], which is for R (The R Foundation for Statistical Computing, Vienna, Austria). It is a modified version of R commander designed to add statistical functions that are frequently used in biostatistics.\u003c/p\u003e\u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003ePatient characteristics\u003c/h2\u003e\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eA total of 243 patients received oral care following the protocol shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e at the Outpatient Cancer Chemotherapy Center of Niigata University Medical and Dental Hospital between June 1 and December 31, 2023. Of these, five patients did not receive taxane-based and/or 5FU-based chemotherapy, and one patient did not complete any PRO-CTCAE assessments.. Therefore, 237 patients were included in the analysis. The mean age was 64 years (range: 23\u0026ndash;84), and 112(47.3%) were male. Most patients had normal physical and cognitive functions. Among the patients, 65.0% received taxane-based therapies, while 41.4% received 5-FU-based therapies. Detailed demographic and clinical characteristics are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003epatient characteristics\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;237\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eN\u003c/em\u003e(%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAge(years)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRange\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e23\u0026ndash;84\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAverage\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e64\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSex\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e112(47.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e125(52.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSmoking History\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNo-smoking\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e100(42.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSmoking\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e128(54.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003equit smoking\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e109\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1 or 10 cigarettes a day\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003emore than 10 cigarettes a day\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUnknown\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9(3.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eDrinking history\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDrink socially\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e153(64.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHabitual drinking\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e74(31.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eonce a week\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ethree or four times a week\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eevery day\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUnknown\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10(4.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eADL\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIndependence\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e223(94.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAssistance\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10(4.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUnknown\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4(1.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCommunication\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNo problem\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e223(94.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHearing loss\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6(2.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUnknown\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8(3.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eManage medicine\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSelf-management\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e193(81.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFamily-management\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6(2.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUnknown\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e38(16.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eChemotherapy\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFluorinated pyrimidines\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e98(41.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTaxans\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e154(65.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eOral care intervention\u003c/h3\u003e\n\u003cp\u003eFigure \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e illustrates the multidisciplinary oral care protocol for patients receiving outpatient chemotherapy. Based on our previous results, we targeted patients receiving 5FU- and taxane-based therapies [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eFirst step: Patients completed the seven PRO-CTCAE items related to oral symptoms.\u003c/p\u003e\u003cp\u003eSecond step: The nurse reviewed PRO-CTCAE responses, assessed oral adverse events using the CTCAE, and provided patient education on oral care. If the CTCAE grade was 2 or higher, the nurse consulted a pharmacist\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eThird step: The pharmacist evaluated oral symptoms and recommended appropriate interventions, such as coating agents for grade 2 oral mucositis and moisturizers for grade 2 dry mouth. If a dental consultation was deemed necessary, the pharmacist requested an appointment with a dentist.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eFrequency and Severity of Oral AEs Assessed by PRO-CTCAE\u003c/h2\u003e\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eThe frequency and severity of oral AEs assessed by PRO-CTCAE are shown in Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. 85.2% (202/237) of the patients experienced at least one symptom. Among these, dry mouth was the most frequently reported symptom (68.8%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Based on the highest PRO-CTCAE scores recorded during the study period, the proportion of patients reporting moderate or greater symptoms were: dry mouth (21.9%), taste changes (18.2%), and mouth/throat sores (16.5%). In contrast, no patients reported changes in voice quality (0.0%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eLongitudinal changes in PRO-CTCAE\u003c/h2\u003e\u003cp\u003eFigure \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e displays the distribution of oral symptom severity based on PRO-CTCAE grades at the initiation of multidisciplinary oral care and at subsequent 3-week intervals. The proportion of patients with moderate or greater AEs remained below 10% at nearly all time points, indicating that the severity of all symptoms was generally mild. However, the proportion of patients reporting any symptoms (as mild or greater) ranged from 30\u0026ndash;50% for dry mouth, 20\u0026ndash;35% for taste change, and 10\u0026ndash;30% for mouth/throat sores, dysphagia, and hoarseness. For all symptoms, the proportion of patients reporting symptoms declined until approximately week 15, followed by a trend toward symptom exacerbation.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eConcordance between PRO-CTCAE and CTCAE\u003c/h2\u003e\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003e To assess alignment between patient and clinician evaluations, we evaluated the agreement between PRO-CTCAE and CTCAE for dry mouth and oral mucositis. A total of 1,066 assessment pairs for dry mouth and 1,058 assessment pairs for oral mucositis were obtained. The agreement between patients and clinicians was fair for both dry mouth and oral mucositis (kw\u0026thinsp;=\u0026thinsp;0.39, 95%CI\u0026thinsp;=\u0026thinsp;0.34\u0026ndash;0.45: kw\u0026thinsp;=\u0026thinsp;0.4, 95%CI\u0026thinsp;=\u0026thinsp;0.32\u0026ndash;0.48). The distribution of PRO-CTCAE and CTCAE assessment pairs is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e. The percentages of perfect agreement between patients and clinicians were 65.8% for dry mouth (agreement\u0026thinsp;\u0026plusmn;\u0026thinsp;1: 96.3%) and 81.9% for oral mucositis (agreement\u0026thinsp;\u0026plusmn;\u0026thinsp;1: 97.2%). Compared to clinicians, 31.1% (332/1066) of patients reported more severe dry mouth, while 14.0% (148/1058) reported more severe oral mucositis. Conversely, clinicians rated symptoms as more severe than patients in 3.1% of dry mouth cases and 4.1% of oral mucositis cases.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn this study, we implemented multidisciplinary oral care and evaluated oral adverse events using PRO-CTCAE.\u003c/p\u003e\u003cp\u003eThree key findings emerged. First, 85.2% of patients experienced at least one oral adverse event, with dry mouth being the most frequently reported symptom; notably, 21.9% (52/237) reported dry mouth of moderate or greater severity. Second, although the severity of oral symptoms remained generally mild (\u0026ge;\u0026thinsp;moderate\u0026thinsp;\u0026lt;\u0026thinsp;10% throughout), a substantial proportion of patients reported persistent symptoms (\u0026ge;\u0026thinsp;mild), such as dry mouth (30\u0026ndash;50%), taste changes (20\u0026ndash;35%), and oral mucositis, dysphagia, or hoarseness (10\u0026ndash;30%) over the 24-week period, suggesting a prolonged impact on QOL. Third, the concordance between PRO-CTCAE and CTCAE for dry mouth and oral mucositis was limited, with 31.1% of patients reporting greater severity of dry mouth than assessed by clinicians.\u003c/p\u003e\u003cp\u003eThe high incidence of oral adverse events (85.2%) among patients receiving 5-FU- and taxane-based regimens supports the validity of our screening approach and aligns with previous studies reporting strong associations between these agents and oral toxicities [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Targeting this population was therefore appropriate for establishing an effective referral system. Dry mouth was the most frequently reported adverse event (68.8%), consistent with prior findings showing rates of 56\u0026ndash;69% in patients treated with 5-FU and 56% in those receiving taxanes [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. These agents are known to reduce salivary secretion [\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], likely contributing to the high frequency of reported dry mouth.\u003c/p\u003e\u003cp\u003eIn this observational study using PRO-CTCAE, longitudinal monitoring of chemotherapy outpatients receiving multidisciplinary oral care showed that symptoms of \u0026ge;\u0026thinsp;moderate severity remained relatively infrequent, with most AEs persisting in the mild range. These findings suggest that ongoing multidisciplinary interventions may help prevent symptom escalation. However, the continued presence of \u0026ge;\u0026thinsp;mild symptoms\u0026mdash;particularly dry mouth and taste changes\u0026mdash;underscores the limitations of current care in fully alleviating these issues during treatment. Notably, after an initial decline in symptom prevalence, a rebound was observed beyond week 15, highlighting the need for sustained and extended intervention. Nonetheless, in the absence of a control group, we cannot definitively attribute these trends to the intervention rather than natural symptom fluctuations [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe agreement between PRO-CTCAE and CTCAE was moderate (κ\u0026thinsp;=\u0026thinsp;0.39\u0026ndash;0.4), with 31.1% of patients reporting more severe dry mouth than clinicians, reflecting CTCAE's limitations in capturing subjective symptoms [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Although perfect agreement was achieved in 65.8% of cases for dry mouth and 81.9% for oral mucositis, agreement within \u0026plusmn;\u0026thinsp;1 grade was high (96.3% and 97.2%, respectively), suggesting that major discrepancies were infrequent. These findings highlight the structural differences between PRO-CTCAE and CTCAE: the former captures patients ' experiences, whereas the latter often relies on observable or functional changes, which may underestimate symptom burden [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan additionalcitationids=\"CR26 CR27 CR28 CR29 CR30\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. The relatively lower concordance for dry mouth likely stems from its subjective nature, lacking objective signs, unlike oral mucositis, which can be visually confirmed.\u003c/p\u003e\u003cp\u003eThe tendency for patients to report greater symptom severity than clinicians further supports the integration of PROs into routine care to improve symptom recognition [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. PRO-CTCAE and CTCAE provide complementary perspectives, and their combined use may enhance the sensitivity and accuracy of AE monitoring in clinical oncology [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThis study has some limitations that should be considered when interpreting the findings. First, the study population was limited to patients receiving 5FU- and taxane-based chemotherapy, restricting the generalizability of findings to those undergoing different regimens. Second, dental examinations or microbiological tests were not performed, as dental evaluations were only conducted when CTCAE grades 2\u0026ndash;4 were identified. Third, there may be variability in the frequency of oral care interventions, underscoring the need for a more standardized intervention protocol. Fourth, the follow-up period was limited to a maximum of 24 weeks, preventing assessment of long-term effects. Longer follow-up would be necessary to assess whether symptoms improve or worsen over time. Fifth, as this study lacks a control group, the effects of the multidisciplinary intervention cannot be conclusively determined. Further studies with a controlled design are needed to establish causality. Finally, as the study was conducted at a single institution, potential biases related to patient characteristics should be considered.\u003c/p\u003e\u003cp\u003eOur findings highlight the importance of regular monitoring by a multidisciplinary team for effective management of oral symptoms in cancer outpatients. Incorporating PRO-CTCAE into routine assessments may improve the detection of symptoms that are under-recognized by clinician-reported CTCAE alone. Given the limitations of recommending moisturizers and protective agents without prescriptions, future studies should evaluate the clinical impact of prescribing such interventions. Further research is also needed to assess the generalizability and long-term effectiveness of multidisciplinary oral care through multicenter studies, standardized intervention protocols, and extended follow-up durations.\u003c/p\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003e This study demonstrated that patient-reported oral AEs were frequently observed during outpatient chemotherapy, with dry mouth as the most common symptom. Longitudinal assessment using PRO-CTCAE showed that while the proportion of patients reporting symptoms fluctuated over time, oral AEs of at least mild severity persisted in 10\u0026ndash;50% of patients throughout the 24-week observation period. The limited concordance between PRO-CTCAE and clinician-reported CTCAE\u0026mdash;particularly for dry mouth\u0026mdash;suggests that certain symptoms may be underrecognized in routine oncology practice. These findings support the integration of patient-reported outcome into multidisciplinary oral care to enhance symptom detection and management. Future studies should aim to standardize intervention protocols, evaluates the impact of prescription-based supportive care, and validate these findings in multi-center settings with longer follow-up.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Conceptualization: YS, KK. Data collection: YS, MK. Formal analysis and investigation: YS. Writing\u0026mdash;original draft preparation: YS, YK, AT. All authors critically revised the article and approved the final version for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Ethics Committee of the Niigata University School of Medicine (approval number: 2023-0315). As this was a retrospective observational study using existing medical records, we employed an opt-out method for obtaining consent in accordance with the Ethical Guidelines for Medical and Health Research Involving Human Subjects in Japan. Information about the study was publicly disclosed on the Niigata University School of Medicine website, providing participants with the opportunity to refuse participation. The study was conducted in accordance with the Declaration of Helsinki. The authors declare no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent of publish\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author upon reasonable request\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eJapanese Association of Supportive Care in Cancer (2020) Japanese Association of Oral Supportive Care in Cancer: Clinical Guidance of Management for Mucositis. Kanehara Co., Tokyo\u003c/li\u003e\n\u003cli\u003eTrotti A, Colevas AD, Setser A, Basch E (2007) Patient-reported outcomes and the evolution of adverse event reporting in oncology. In: J Clin Oncol 25:5121\u0026ndash;5127. https://doi.org/10.1200/JCO.2007.12.4784\u003c/li\u003e\n\u003cli\u003eBruner DW (2007) Should patient-reported outcomes be mandatory for toxicity reporting in cancer clinical trials? J Clin Oncol 25:5345\u0026ndash;5347. https://doi.org/10.1200/JCO.2007.13.3330\u003c/li\u003e\n\u003cli\u003eDueck AC, Mendoza TR, Mitchell SA, et al (2015) Validity and reliability of the us National Cancer Institute\u0026rsquo;s patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE). JAMA Oncol 1:1051\u0026ndash;1059. https://doi.org/10.1001/jamaoncol.2015.2639\u003c/li\u003e\n\u003cli\u003eKawaguchi T, Azuma K, Sano M, et al (2017) The Japanese version of the National Cancer Institute\u0026rsquo;s patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE): Psychometric validation and discordance between clinician and patient assessments of adverse events. J Patient Rep Outcomes, Japanese version 2:. https::2. https://doi.org/10.1186/s41687-017-0022-5\u003c/li\u003e\n\u003cli\u003eMiyaji T, Iioka Y, Kuroda Y, et al (2017) Japanese translation and linguistic validation of the us National Cancer Institute\u0026rsquo;s patient-reported outcomes version of the common terminology criteria for adverse events (Pro-ctcae). J Patient Rep Outcomes 1:8. https://doi.org/10.1186/s41687-017-0012-7\u003c/li\u003e\n\u003cli\u003eMinasian LM, O\u0026rsquo;Mara A, Mitchell SA (2022) Clinician and patient reporting of symptomatic adverse events in cancer clinical trials: Using CTCAE and PRO-CTCAE\u0026reg; to provide two distinct and complementary perspectives. Patient Relat Outcome Meas 13:249\u0026ndash;258. https://doi.org/10.2147/PROM.S256567\u003c/li\u003e\n\u003cli\u003eSakai Y, Katsura K, Kotake M, Toyama A (2025) A cross-sectional survey of oral adverse events and oral management needs in outpatients receiving cancer drug therapy. Cancers (Basel) 17:. https::641. https://doi.org/10.3390/cancers17040641\u003c/li\u003e\n\u003cli\u003eElad S, Cheng KKF, Lalla RV, et al (2020) MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer 126:4423\u0026ndash;4431. https://doi.org/10.1002/cncr.33100\u003c/li\u003e\n\u003cli\u003eMercadante V, Jensen SB, Smith DK, et al (2021) Salivary Gland Hypofunction and/or xerostomia Induced by Nonsurgical Cancer Therapies: ISOO/MASCC/ASCO Guideline. J Clin Oncol 39:2825\u0026ndash;2843. https://doi.org/10.1200/JCO.21.01208\u003c/li\u003e\n\u003cli\u003eFalchook AD, Green R, Knowles ME, et al (2016) Comparison of patient- and practitioner-reported toxic effects associated with chemoradiotherapy for head and neck cancer. JAMA Otolaryngol Head Neck Surg 142:517\u0026ndash;523. https://doi.org/10.1001/jamaoto.2016.0656\u003c/li\u003e\n\u003cli\u003eArahori H, Kondo K, Imai Y, et al (2024) Symptomatic adverse events of chemotherapy in breast cancer patients: Using CTCAE, PRO-CTCAE, and EORTC QLQ-C30. J Med Invest 71:82\u0026ndash;91. https://doi.org/10.2152/jmi.71.82\u003c/li\u003e\n\u003cli\u003eNCI. PRO-CTCAE\u0026reg; ITEMS-JAPANESE Item Library, version 1.0. Accessed 1 Mar 2024\u003c/li\u003e\n\u003cli\u003eCorrespondence between PRO-CTCAE and CTCAE terminologies. Accessed 1 Mar 2024\u003c/li\u003e\n\u003cli\u003eKanda Y (2013) Investigation of the freely available easy-to-use software \u0026ldquo;EZR\u0026rdquo; for medical statistics. Bone Marrow Transplant 48:452\u0026ndash;458. https://doi.org/10.1038/bmt.2012.244\u003c/li\u003e\n\u003cli\u003eWilberg P, Hjermstad MJ, Ottesen S, Herlofson BB (2014) Chemotherapy-associated oral sequelae in patients with cancers outside the head and neck region. J Pain Symptom Manag 48:1060\u0026ndash;1069. https://doi.org/10.1016/j.jpainsymman.2014.02.009\u003c/li\u003e\n\u003cli\u003eSpeck RM, Demichele A, Farrar JT, et al (2013) Taste alteration in breast cancer patients treated with taxane chemotherapy: Experience, effect, and coping strategies. Support Care Cancer 21:549\u0026ndash;555. https://doi.org/10.1007/s00520-012-1551-3\u003c/li\u003e\n\u003cli\u003eJensen SB, Pedersen AML, Vissink A, et al (2010) A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: Prevalence, severity and impact on quality of life. Support Care Cancer 18:1039\u0026ndash;1060. https://doi.org/10.1007/s00520-010-0827-8\u003c/li\u003e\n\u003cli\u003ePaz C, Glassey A, Frick A, et al (2024) Cancer therapy\u0026ndash;related salivary dysfunction. J Clin Invest 134:e182661. https://doi.org/10.1172/JCI182661\u003c/li\u003e\n\u003cli\u003eJensen SB, Mouridsen HT, Reibel J, Br\u0026uuml;nner N, Nauntofte B (2008) Adjuvant chemotherapy in breast cancer patients induces temporary salivary gland hypofunction. Oral Oncol 44:162\u0026ndash;173. https://doi.org/10.1016/j.oraloncology.2007.01.015\u003c/li\u003e\n\u003cli\u003eBoltong A, Keast R, Aranda S (2012) Experiences and consequences of altered taste, flavour and food hedonics during chemotherapy treatment. Support Care Cancer 20:2765\u0026ndash;2774. https://doi.org/10.1007/s00520-012-1398-7\u003c/li\u003e\n\u003cli\u003eBoltong A, Aranda S, Keast R, et al (2014) A prospective cohort study of the effects of adjuvant breast cancer chemotherapy on taste function, food liking, appetite and associated nutritional outcomes. PLOS One 9:. https::e103512. https://doi.org/10.1371/journal.pone.0103512\u003c/li\u003e\n\u003cli\u003eBasch E, Iasonos A, Mcdonough TA, et al (2006) Articles Patient versus clinician symptom reporting using the National Cancer Institute Common Terminology Criteria for Adverse Events: Results of a questionnaire-based study. https://doi.org/10.1016/S1470\u003c/li\u003e\n\u003cli\u003eHuynh-Dagher S, Duong T-A, Tournigand C, Kempf E, Lam\u0026eacute; G (2025) Concordance between patient-reported outcomes and CTCAE clinician-reported toxicities during outpatient chemotherapy courses: A retrospective cohort study in routine care. ESMO Real World Data Digital Oncology 8:100127. https://doi.org/10.1016/j.esmorw.2025.100127\u003c/li\u003e\n\u003cli\u003eBasch E, Becker C, Rogak LJ, et al (2021) Composite grading algorithm for the National Cancer Institute\u0026rsquo;s Patient-Reported outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Clin Trials 18:104\u0026ndash;114. https://doi.org/10.1177/1740774520975120\u003c/li\u003e\n\u003cli\u003eGounder MM, Mahoney MR, Van Tine BA, et al (2018) Sorafenib for advanced and refractory desmoid tumors. N Engl J Med 379:2417\u0026ndash;2428. https://doi.org/10.1056/NEJMoa1805052\u003c/li\u003e\n\u003cli\u003eBasch EM, Scholz M, de Bono JS, et al (2019) Cabozantinib versus mitoxantrone-prednisone in symptomatic metastatic castration-resistant prostate cancer: A randomized Phase 3 trial with a primary pain endpoint. Eur Urol 75:929\u0026ndash;937. https://doi.org/10.1016/j.eururo.2018.11.033\u003c/li\u003e\n\u003cli\u003eTakenaga T, Kuji S, Tanabe KI, et al (2024) Prospective analysis of patient-reported outcomes and physician-reported outcomes with gynecologic cancer chemotherapy. J Obstet Gynaecol Res 50:75\u0026ndash;85. https://doi.org/10.1111/jog.15811\u003c/li\u003e\n\u003cli\u003eGu S, Menzer C, Hay JL, et al (2023) PRO-CTCAE reveals under-recognition of dermatologic symptom burden in hospitalized cancer patients. Support Care Cancer 31:337. https://doi.org/10.1007/s00520-023-07793-5\u003c/li\u003e\n\u003cli\u003eTan AC, McCrary JM, Park SB, Trinh T, Goldstein D (2019) Chemotherapy-induced peripheral neuropathy-Patient-reported outcomes compared with NCI-CTCAE grade. Support Care Cancer 27:4771\u0026ndash;4777. https://doi.org/10.1007/s00520-019-04781-6\u003c/li\u003e\n\u003cli\u003eDueck AC, Scher HI, Bennett AV, et al (2020) Assessment of adverse events from the patient perspective in a Phase 3 metastatic castration-resistant prostate cancer clinical trial. JAMA Oncol 6:. https::e193332. https://doi.org/10.1001/jamaoncol.2019.3332\u003c/li\u003e\n\u003cli\u003eBasch E, Spertus J, Dudley RA, et al (2015) Methods for developing patient-reported outcome-based performance measures (PRO-PMs). Value Health 18:493\u0026ndash;504. https://doi.org/10.1016/j.jval.2015.02.018\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"supportive-care-in-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jscc","sideBox":"Learn more about [Supportive Care in Cancer](https://www.springer.com/journal/520)","snPcode":"520","submissionUrl":"https://submission.nature.com/new-submission/520/3","title":"Supportive Care in Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Oral adverse events, Chemotherapy, Patient-Reported Outcomes, Multidisciplinary oral care, Outpatient cancer treatment, Concordance","lastPublishedDoi":"10.21203/rs.3.rs-6970435/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6970435/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e\u003cp\u003eThis study aimed to (1) describe longitudinal trends in patient-reported oral adverse events using the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) in patients receiving multidisciplinary oral care during outpatient cancer drug therapy, and (2) evaluate concordance between PRO-CTCAE and clinician-reported CTCAE scores.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eConducted at the Outpatient Cancer Chemotherapy Center, Niigata University Medical and Dental Hospital (June\u0026ndash;December 2023), oral adverse events were assessed using PRO-CTCAE and CTCAE at baseline and every 3 weeks up to 24 weeks. Concordance for dry mouth and oral mucositis was evaluated using paired same-day scores.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003e Among patients receiving multidisciplinary oral care, 85.2% experienced at least one oral adverse event, most commonly dry mouth. Based on PRO-CTCAE, symptoms rated as moderate or higher were reported in fewer than 10% of cases for most items. Notably, over half of patients reported persistent dry mouth of at least mild severity, and 20\u0026ndash;30% of other symptoms also remained. These findings suggest that even lower-grade symptoms may persist and affect quality of life. Concordance between PRO-CTCAE and CTCAE was limited, with 31.1% of patients reporting greater dry mouth severity than clinicians documented.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003ePatient-reported oral adverse events, as assessed by PRO-CTCAE, were frequently mild but persistent throughout outpatient chemotherapy, suggesting a cumulative impact on quality of life. Concordance between PRO-CTCAE and clinician-reported CTCAE was limited, indicating that clinician assessments may underestimate symptoms such as dry mouth. These findings underscore the need to integrate patient-reported outcomes into routine oral care.\u003c/p\u003e","manuscriptTitle":"Patient-Reported Oral Adverse Events During Cancer Chemotherapy: Longitudinal Evaluation Using Patient- Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) and Concordance with Clinician Assessments","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-01 09:25:07","doi":"10.21203/rs.3.rs-6970435/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-10-01T15:48:03+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-10T15:18:59+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-09T21:00:40+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-02T20:46:23+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-31T09:39:45+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"23764967381541441997391827688543692596","date":"2025-08-26T17:31:42+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"87642636822244905698816221025445632063","date":"2025-08-22T21:41:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"274553800904122297278019863806279267620","date":"2025-08-22T09:58:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"165613692622619092886436366681700782638","date":"2025-08-21T12:14:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"58369080613697858205081076925279645170","date":"2025-08-20T18:25:00+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-20T04:15:13+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-06T19:57:02+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-06-28T12:52:50+00:00","index":"","fulltext":""},{"type":"submitted","content":"Supportive Care in Cancer","date":"2025-06-25T04:21:31+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"supportive-care-in-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jscc","sideBox":"Learn more about [Supportive Care in Cancer](https://www.springer.com/journal/520)","snPcode":"520","submissionUrl":"https://submission.nature.com/new-submission/520/3","title":"Supportive Care in Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"b63d8fc4-b060-4bb7-a481-6952c28f468e","owner":[],"postedDate":"September 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-11-17T16:04:57+00:00","versionOfRecord":{"articleIdentity":"rs-6970435","link":"https://doi.org/10.1007/s00520-025-10126-3","journal":{"identity":"supportive-care-in-cancer","isVorOnly":false,"title":"Supportive Care in Cancer"},"publishedOn":"2025-11-13 15:57:37","publishedOnDateReadable":"November 13th, 2025"},"versionCreatedAt":"2025-09-01 09:25:07","video":"","vorDoi":"10.1007/s00520-025-10126-3","vorDoiUrl":"https://doi.org/10.1007/s00520-025-10126-3","workflowStages":[]},"version":"v1","identity":"rs-6970435","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6970435","identity":"rs-6970435","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}