Real-world management of oral mucositis/stomatitis among patients with advanced non-small cell lung cancer (NSCLC) or breast cancer (BC).

1.
Introduction
Advances in cancer treatment and management over the past several decades have reduced cytotoxic side effects for patients, including the development of effective new therapies with lower rates of alopecia (e.g., targeted therapy) and administration of growth factors to reduce severity and duration of cytopenia [1,2]. Despite these advances, oral mucositis/stomatitis (OM/S), a side effect characterized by inflammation and ulceration in the mucosal lining, remains a common complication for patients receiving cancer treatment. OM/S has long been associated with classical chemotherapy regimens but is also a side effect for targeted therapies (e.g., tyrosine kinase inhibitors) and immune-oncologic agents (e.g., PD-L1 inhibitors) [3]. OM/S symptoms can significantly impact treatment outcomes by disrupting adherence, necessitating dose modifications, and potentially leading to discontinuation [3,4]. For patients with advanced or metastatic disease, OM/S-related disruptions in first-line (1 L) treatment are of particular concern, as treatment adherence during 1 L therapy is known to impact long-term survival and selection of future treatments [5]. Mismanagement of OM/S may also lead to downstream patient quality of life impairments (e.g., difficulty eating, drinking and speaking) [6–8].
Guidelines on OM/S prophylaxis and management secondary to cancer therapy have been published by the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) [9]. These guidelines focus heavily on recommendations specific to head and neck cancer therapy and hematopoietic stem cell transplant (HSCT)-related treatment; guidelines for solid tumor chemotherapy-related OM/S outside of those scenarios are limited (e.g., multiagent combination oral care and cryotherapy) [9]. While offering physicians some support in preventing and managing chemotherapy-induced OM/S, the MASCC/ISOO guidelines have not been expanded to address OM/S arising from non-chemotherapy treatments (e.g., targeted therapy; immunotherapy) and non-conventional chemotherapy treatments (e.g., antibody drug conjugates) used for treating solid tumors. Current National Comprehensive Cancer Network (NCCN) supportive care guidelines include some management recommendations for OM/S but are limited to OM/S caused by immune checkpoint inhibitors [10].
For patients diagnosed with non-small cell lung cancer (NSCLC) and breast cancer (BC), which account for approximately 25–30% of new cancer diagnoses each year in the United States (US), OM/S prevention and management is an ongoing concern [11–14]. Prior studies estimate OM/S occurs in approximately 50% of patients with solid tumors undergoing chemotherapy [7,15]. In addition to well-studied associations with conventional chemotherapy, several non-chemotherapy and non-conventional chemotherapy treatments used for advanced NSCLC and/or BC are known to cause OM/S at high frequency (e.g., everolimus: 67% of patients with BC; datopotamab deruxtecan: 59% of patients with BC, 66% of patients with NSCLC; afatinib: 71% of patients with NSCLC), while other treatments are associated with OM/S at lower frequencies (e.g., palbociclib: 25% of patients with BC; osimertinib: 14–18% of patients with NSCLC) [13,16–22]. For everolimus and datopotamab deruxtecan, OM/S prophylaxis and management recommendations are included in the published drug labels (e.g., dexamethasone mouthwash for prophylaxis with everolimus; steroid-containing mouthwash for prophylaxis with datopotamab deruxtecan) [23,24]. Although OM/S is known to occur with other non-chemotherapy regimens with moderate to high frequency, established guidelines are limited and no recommendations are made in their labels.
Current real-world evidence on OM/S among patients with NSCLC and BC has predominantly focused on describing incidence rates and identifying risk factors for developing OM/S, but data on real-world OM/S management is limited, particularly for patients receiving 1 L treatment and during treatment with targeted therapy or immunotherapy [3,8,25]. Physician perspectives on OM/S prevention and management among patients with NSCLC or BC are also unknown. The goal of this study was to describe real-world OM/S management for patients with advanced NSCLC or BC treated in US real-world community practices and to document oncologist awareness of OM/S guidelines, perceived risk factors for OM/S development, and barriers to OM/S care.

2.
Methods
To describe current OM/S management in US real-world settings, this study included a cross-sectional physician survey and a retrospective, double-blinded, multi-site, physician-abstracted medical chart review of patients with locally advanced or metastatic NSCLC or BC who experienced at least one OM/S event during cancer treatment. Participating physicians were recruited from the Cardinal Health Oncology Provider Extended Network (OPEN), a group of more than 350 active physicians from across the US [26]. Physicians completed data abstraction between 18 March 2024 and 16 April 2024. The study protocol and case report form (CRF) were reviewed and granted a waiver of informed consent by the WCG Institutional Review Board prior to data collection. Due to the proprietary nature, data used in this study is not publicly available but may be available upon reasonable request to the corresponding author.
2.1.
Patient eligibility and chart abstraction
Patients were eligible for the chart review portion of this study if they were diagnosed with either locally advanced (stage IIIA-IIIC) or metastatic NSCLC or BC, were at least 18 years of age at time of advanced diagnosis, had an occurrence of OM/S related to systemic treatment (chemotherapy or non-chemotherapy) for NSCLC or BC on or after 1 January 2021, and had data available for at least 3 months prior to and after the OM/S event. Patients were not eligible for the study if they had been diagnosed with any other malignancy (excluding non-melanoma skin cancer) or participated in an interventional clinical trial for advanced or metastatic NSCLC or BC between 1 January 2021 and 3 months prior to data collection. Follow-up was defined as the time from first OM/S event to the last recorded encounter with the provider prior to data collection. Data on patient demographics, clinical characteristics, OM/S event details, and treatment management were abstracted for each patient. Physicians were instructed to select and abstract patient data into an electronic case report form (eCRF) in chronological order based on the date of each patient’s first OM/S event. During abstraction, eCRF questions could not be skipped, and physicians indicated missing data through selection of “Unknown.” To minimize overrepresentation, each physician was allowed to contribute data for a maximum of 10 patients. This study had a target sample size of N = 300 charts (n = 150 patients with NSCLC, n = 150 patients with BC), which was driven by feasibility estimates from OPEN.

2.2.
Physician eligibility and survey
Participating physicians were required to have managed or treated at least 10 patients with advanced or metastatic NSCLC or BC in the year prior to data collection, to have at least 3 years of post-fellowship experience treating NSCLC or BC, and to spend at least 50% of their time on patient care (as opposed to research or other activities). Participating physicians completed a survey collecting information on their demographics and practice characteristics, awareness of OM/S management guidelines, and perceptions of OM/S risk factors and barriers to care.

2.3.
Statistical analysis
Descriptive statistics were used to summarize data collected in the physician survey and patient-level chart abstraction, including counts and frequencies for categorical variables and measures of center and spread for continuous variables. Patient results were summarized by cancer type (NSCLC, BC) as well as among patients whose OM/S event occurred during first-line (1 L) systemic treatment. All analyses were performed using SAS v9.4 (SAS Institute Inc, Cary, NC, USA).

3.
Results
Overall, 31 US-based providers participated in the physician survey and abstracted data for 272 patients who had developed OM/S, including 146 patients with NSCLC and 126 patients with BC.
3.1.
Patient baseline characteristics
Among patients with NSCLC, mean age at advanced/metastatic diagnosis was 65.9 years (standard deviation [SD]: 7.9), 34.9% were female, and all US regions were represented (Table 1). The majority of patients with NSCLC were White (66.4%), with 20.5% identifying as Black/African American, 7.5% as Asian, and 13.0% as Hispanic. Medicare was the most common primary insurance type (54.1%) followed by commercial insurance (31.5%). Most patients with NSCLC had an Eastern Cooperative Oncology Group (ECOG) performance status of 0/1 (82.2%) and at least one comorbidity at time of OM/S event (82.2%). Patient demographics among those who developed OM/S during 1 L treatment were consistent with the overall NSCLC cohort (Table S1).
Patients with BC who developed OM/S were a mean age of 60.2 years (SD: 10.8) at advanced/metastatic diagnosis, 99.2% female, and resided across the US (Table 1). As with patients with NSCLC, the majority of patients were White (62.7%), with smaller frequencies identifying as Black/African American (22.2%), Asian (9.5%), and Hispanic (11.9%). Half of patients with BC (50.0%) had commercial insurance followed by Medicare (32.5%). At time of OM/S event, most patients with BC had an ECOG performance status of 0/1 (84.1%) and the majority (67.5%) had at least one comorbidity. Demographics for patients with OM/S during 1 L treatment were consistent with the overall BC cohort (Table S1).

3.2.
Patient OM/S event
Median (interquartile range [IQR]) time from systemic therapy initiation to the first OM/S event was 1.2 months (0.5–2.2) and 1.4 months (0.7–2.3) for NSCLC and BC patients, respectively (Table 2). Most patients in this study experienced their first OM/S event during 1 L treatment (95.2% for NSCLC; 76.2% for BC). For patients with NSCLC who experienced an OM/S event, systemic treatment regimens most commonly contained chemotherapy (86.3%) and/or immunotherapy (56.8%), with 9.6% of regimens containing a targeted therapy. OM/S was reported on immunotherapy-only regimens for 7.5% of patients with NSCLC (n = 10 on pembrolizumab monotherapy; n = 1 on nivolumab + ipilimumab). Patients with BC reported OM/S most commonly with regimens containing chemotherapy (67.5%) and/or targeted therapy (46.8%), with 10.3% of regimens containing immunotherapy (no immunotherapy-only regimens reported). For regimens including targeted therapy, HER2 (21.4%), CDK4/6 (15.1%), and mTOR (10.3%) inhibitors were reported among patients with BC, and EGFR inhibitors (6.2%) were reported among patients with NSCLC. Details on the treatment class combinations can be found in Table S2 and on immunotherapy agents in Table S3.
Approximately half of patients received an OM/S-related prophylactic mouthwash or other external agent (e.g., cryotherapy) prior to the first OM/S event (NSCLC: 41.8%; BC: 54.8%; Table 2), with sodium bicarbonate mouthwash (NSCLC: 17.8%; BC: 25.4%) and Biotène™ mouthwash (NSCLC: 11.0%; BC: 8.7%) most commonly reported (prophylaxis treatment details in Table S4). For patients who did not receive OM/S-related prophylaxis, common reasons included provider’s perceived ineffectiveness (NSCLC: 56.1%; BC: 40.0%), patient choice (NSCLC: 35.4%; BC: 43.6%), and low perceived risk of OM/S (NSCLC: 8.5%; BC: 16.4%). Median (IQR) follow-up time after the OM/S event was 6.9 months (4.2–12.9) and 9.2 months (4.8–16.8) for patients with NSCLC and BC, respectively (Table 3).
Most OM/S events were either grade 2 (NSCLC: 74.0%; BC: 54.8%) or grade 3 (NSCLC: 15.8%: BC, 32.5%), with few grade 4 events reported (NSCLC: 2.1%; BC: 4.8%). OM/S management actions taken in response to the OM/S event, excluding cancer treatment modifications, included encouraging good oral hygiene (NSCLC: 94.5%; BC: 97.6%), prescribing “magic” mouthwash (NSCLC: 72.6%; BC: 83.3%), and dietary modifications (NSCLC: 71.2%; BC: 76.2%). OM/S management strategies were most commonly chosen based on physicians’ previous experience (NSCLC: 69.9%; BC: 77.8%) and guidelines (NSCLC: 30.8%; BC: 37.3%).
Systemic treatment modifications (interruption, reduction, or discontinuation) due to OM/S were reported for 20.5% of patients with NSCLC and 35.7% of patients with BC. Dose reductions (NSCLC: 15.8%; BC: 27.0%) occurred a median (IQR) of 14.0 days (9.0–20.0) after the OM/S event for patients with NSCLC and 14.0 days (7.0–18.0) after OM/S event for patients with BC. For patients with an OM/S-related treatment interruption (NSCLC: 10.3%; BC: 16.7%), median (IQR) time from OM/S event to first interruption was 0.0 days (0.0–13.0) for patients with NSCLC and 0.0 days (0.0–5.0) for patients with BC. Median duration of the interruption was approximately 2 weeks for both the NSCLC and BC cohorts. OM/S events led to treatment discontinuation among 1.4% and 4.8% of patients with NSCLC or BC, respectively. Among patients with OM/S-related changes in cancer treatment (n = 75 overall), all reported improvement in OM/S symptoms after cancer treatment modification. The frequency of OM/S-related cancer treatment changes among the 1 L subgroups was consistent with those described above.

3.3.
Provider survey results
Thirty-one physicians met the study eligibility criteria and completed the physician survey (Table 4). Most physicians practiced in community settings (74.2%) and within urban (54.8%) or suburban (35.5%) areas; all US regions were represented. Physicians had a mean 16.4 years (SD: 6.4) in practice and were primarily medical oncologists (90.3%) with 51.6% certified in hematology and 9.7% in radiation oncology. All physicians had a history of treating patients with advanced or metastatic NSCLC who experienced OM/S and estimated that a mean 35.2% (SD: 17.7%) of their patients with advanced or metastatic NSCLC treated with systemic therapy had experienced an OM/S event in the past year. Most physicians (93.5%) also had experience treating patients with advanced or metastatic BC who experienced treatment-related OM/S. Similar to NSCLC, physicians estimated a mean 34.9% (SD: 14.5%) of their patients with advanced or metastatic BC treated with systemic therapy had experienced an OM/S event in the past year.
Twelve (38.7%) participating physicians were aware of published OM/S management strategies or guidelines; of these physicians, the majority (58.3%) followed guidelines on drug labels and three (25.0%) followed MASCC/ISOO guidelines. Further, four physicians (12.9%) had practice-specific OM/S protocols at their practice. OM/S-dedicated training methods were most commonly self-directed training (74.2%), journal resources (22.6%), and in-house training (16.1%). Three providers (9.7%) reported having received no OM/S-dedicated training.
For treatment-related risk factors for OM/S, physicians identified treatment type (83.9%), treatment dose (74.2%) and dosing schedule (61.3%) as either high or very high risk factors (Figure 1). The top patient-level risk factors for OM/S according to physicians were poor oral hygiene (90.3% very high/high), smoking status (90.3% high/very high), and low pre-treatment neutrophil counts (77.4% very high/high; Figure 2). When asked about perceived barriers to OM/S management, poor adherence to basic oral care (80.6%), dental care access (74.2%), and limited knowledge (71.0%) and access (64.5%) to OM/S management guidelines were most frequently identified as being barriers (any level) to OM/S management (Figure 3).

4.
Discussion
In this US real-world study, OM/S was a complication for patients that crossed treatment classes and affected the execution of planned treatment for some patients. Provider doubt about the effectiveness of preventative measures and lack of knowledge on current OM/S guidelines highlights that further work is needed to address these issues.
OM/S-related cancer treatment changes including dose interruption, reduction, or discontinuation occurred for 20.5% and 35.7% of patients with advanced NSCLC or BC, respectively; similar rates of OM/S-related treatment modification were observed when limited to patients whose OM/S event occurred during 1 L treatment (NSCLC: 18.0%; BC: 36.5%). While most cases of OM/S were low grade, these results suggest that OM/S leads to cancer treatment interruptions, reductions, and/or discontinuation in some patients. While patients’ OM/S symptoms were reported to improve after cancer treatment modifications, treatment adherence, particularly during 1 L treatment for advanced or metastatic disease, is known to impact clinical outcomes and later treatment selection; improvements in OM/S management are needed to mitigate the impacts of OM/S on planned cancer treatment [5,27]. Outside of cancer treatment modification, the OM/S management actions taken in this study were variable. This study was purely descriptive and the high heterogeneity in cancer treatments, prophylaxis, and OM/S management precluded evaluating the effectiveness of management measures. Future studies focused on specific treatments, prophylactic measures, management interventions, and patient-reported outcomes are needed to support the development of effective OM/S prevention and management strategies.
For all cancer types (NSCLC or BC) and lines of therapy (1 L; second-line or later), OM/S events occurred across a variety of treatment classes and often included cross-class combinations (e.g., platinum-based chemotherapy plus targeted therapy). Overall, the results from this study align with the well-established risk of OM/S for certain chemotherapy drugs (e.g., taxanes, anthracyclines) as well as emerging data on OM/S associated with immunotherapy (e.g., 7.5% of patients with NSCLC on immunotherapy without chemotherapy) and targeted therapies (e.g., 46.8% of patients with BC on a regimen containing a targeted therapy) [3,28]. For patients with BC who developed OM/S, targeted therapy regimens included treatments known to be associated with OM/S (e.g., 10.3% on everolimus, an mTOR inhibitor; 15.1% on regimens including CDK4/6 inhibitors) [13,20]. For patients with NSCLC, 6.2% developed OM/S on a regimen containing EGFR inhibitors, which prior studies have linked to higher OM/S risk [29]. These results support the need for additional guidance on how to prevent and manage OM/S for patients receiving targeted therapy or immunotherapy, particularly now that many patients with BC or NSCLC may receive multiple therapies with OM/S risk in combination.
For the approximately half of the patients who did not receive prophylaxis (mouthwash or other external agent) for OM/S, physicians indicated they did not recommend or prescribe any because they viewed the prophylactic options as ineffective. This highlights a need for both new research on effective prophylaxis methods as well as improved dissemination of clinical work. Prior research on best prophylactic practices does exist for some therapies, such as in the SWISH trial for everolimus wherein use of dexamethasone mouthwash was evaluated and identified as effective prophylaxis for OM/S; more evidence is also available for chemotherapy-associated OM/S (e.g., cryotherapy prophylaxis; steroid mouthwash for prophylaxis and management) [30–32]. Nevertheless, few drug labels (everolimus, datopotamab deruxtecan) include recommendations for OM/S prophylaxis and management despite known OM/S risk (e.g., for EGFR inhibitors in NSCLC) [14]. Lack of OM/S prophylaxis and management guidelines within drug labels may be due to the relative low frequency of OM/S-related treatment discontinuation (e.g., 1.4% and 4.8% of NSCLC and BC patients with OM/S, respectively, in the current study). Nevertheless, even if OM/S does not frequently result in treatment discontinuation, it is known to impair patients’ quality of life and can lead to treatment reductions and interruptions [8]. In this study, some physicians indicated already using drug labels for OM/S management information, and 61.3% identified lack of OM/S direction from manufacturers as a barrier. Drug labels may represent one avenue where research-supported OM/S recommendations could be added more broadly to increase physician knowledge, but additional generalized education on OM/S prevention and management may also be needed, particularly as OM/S can occur on combination treatments.
Despite relatively low awareness of published OM/S guidelines, physicians were able to identify treatment- and patient-level risk factors OM/S. Top treatment-level factors that physicians viewed as high or very high risk for OM/S included treatment type, dose, and dosing schedule, which have been identified in prior work [25,33]. Poor oral hygiene was the patient-level risk factor most frequently identified as a very high-risk factor for OM/S in this study (54.8% of physicians), a result which has been identified in prior studies on OM/S risk factors and aligns with MASCC/ISOO guidelines recommending that people with cancer follow standard oral care [9,34,35]. These results suggest that oncologists were broadly informed on the important risk factors that play a role in OM/S and that future educational resources for physicians should consider focusing on other areas of greater need (e.g., specific prophylaxis and management recommendations by drug or treatment type).
While several physician-level barriers were identified in this study, patient adherence to basic oral care was the factor identified by the greatest number of physicians as a barrier to optimal OM/S management. Additionally, among patients who experienced OM/S and did not receive prophylaxis, prophylaxis was not administered for approximately a third due to patient choice. These results indicate that a multi-pronged approach may be required to reduce OM/S incidence and burden during cancer treatment, including improvements in patient education on OM/S risk and management as well as research-supported recommendations for physicians on OM/S prophylaxis and management.
4.1.
Strengths and limitations
This real-world study provides insights into current OM/S management in US community settings by leveraging both physician-abstracted chart review data as well as physician survey data. Patient-level data was highly complete and included typically hard-to-obtain information (e.g., reasons for OM/S management; reasons why prophylaxis was not administered). Nevertheless, these findings represent only patient and physician results for US-based oncologists who elected to participate in the study and therefore may not be representative of all oncologists who treat patients with advanced NSCLC or BC who develop OM/S. Additionally, this study was purely descriptive (i.e., no adjusted analyses were conducted) and any comparisons with other studies or between subgroups should be made with caution; outcomes analyses were not conducted because of the high level of heterogeneity in disease, patient characteristics, cancer treatments, and OM/S management actions. Because this study was conducted to describe real-world OM/S management, all patients experienced at least one OM/S event and these data therefore cannot be used to estimate prevalence or incidence of OM/S or the effectiveness of prophylaxis at preventing OM/S. Patients were required to have data available for at least 3 months prior to and following their first OM/S event, which could introduce selection bias if patients missing this data (e.g., due to changing providers) were systematically different from those with data. As a physician-abstracted study, selection bias may also exist if physicians selected patients based on recall of OM/S events (e.g., patients with most severe OM/S events); however, participating physicians were instructed to abstract patient charts starting with the first eligible based on OM/S event.

5.
Conclusions
In this US real-world study on patients with advanced NSCLC or BC who developed treatment-related OM/S, OM/S occurred across a wide range of treatment regimens and impacted the delivery of cancer treatment for some patients. An unmet need remains for improved OM/S prevention and management strategies; inclusion of OM/S prophylaxis and management recommendations on drug labels, as has been done for few therapies to date, may provide an avenue for both expanding provider knowledge on appropriate OM/S actions and patient awareness of the most relevant OM/S recommendations for their treatment.

Supplementary Material

Nguyen_et_al_2025_Supplementary_Tables.docx

Nguyen et al 2025 Supplementary Tables revised tracked changes.docx