Stomatitis is a common adverse effect of chemotherapy consisting on ulcerative and painful lesions at the oral cavity that can prevent oral intake and may be also a source of secondary infections1 causing low adherence and quality of life, leading to dose reduction or treatment discontinuation, potentially affecting survival2.

The prophylactic use of an alcohol-free dexamethasone mouthwash reduced the incidence and severity of stomatitis in patients with breast cancer receiving everolimus3. Patients swished four times daily a US commercially available alcohol-free dexamethasone 0.1 mg/mL solution. The incidence of G2 or higher of stomatitis at 8 weeks compared to BOLERO-2 study was 2.4% vs. 33% and the incidence of all grades was 21.2% vs. 67%3. Adverse events associated with the dexamethasone mouthwash were minimal with only two patients presenting oral candidiasis3.

The hypothesis that everolimus associated stomatitis may arise from an inflammatory process4,5 suggests that the use of steroid-based mouthwashes might be effective6,7.

However, the main drawback of this strategy is the lack of either commercially available dexamethasone mouthwash or standard compounded-formulation in Europe. In addition, there is no further evidence of the use of dexamethasone in other everolimus indications or stomatitis induced agents.

Our objective was to describe a novel dexamethasone mouthwash formulation (DMF) and to assess its effectiveness and safety preventing stomatitis among patients on everolimus. DMF was also evaluated as stomatitis treatment due to high probability of producing stomatitis chemotherapy therapies (HPSCT).

Prospective observational study conducted in a university hospital between March 2017 and November 2019. Consecutive patients starting everolimus regardless their indications were enrolled. A second patient cohort on HPSCT (afatinib and fluorouracil) with grade 2 or 3 of stomatitis was also recruited at the discretion of the investigator to assess treatment effectiveness. The study protocol was approved by the ethics committee of our institution.

Patients under the age of 18, with allergy to dexamethasone or excipients were excluded.

Data collected from the patients’ electronic medical record included demographical, clinical and regarding efficacy/safety of DMF. Also, data concerning cancer treatment, diagnosis, DMF onset and treatment duration were recorded.

The proposed formula composition is shown in table 1. In preventive cohort, DMF was initiated early in antineoplastic treatment. Unlike SWISH trial3 and to improve adherence in a real-world situation, patients were instructed to rinse DMF only twice daily that lasted during antineoplastic treatment. The treatment cohort initiated DMF at the discretion of the investigator. In this case, it was allowed to use twice or 4-times daily at the discretion of the investigator.

In preventive cohort, primary endpoint was the stomatitis incidence evaluated by the oncologist after DMF beginning. The incidences of all-grade and specific grade of stomatitis were summarised by counts and percentages, for the entire treatment duration.

Secondary endpoints included duration of DMF, antineoplastic treatment discontinuation or dose reduction because of stomatitis and other AE. Assessment of DMF compliance was based on medication records and interviews at pharmacy pick-up visits and was assessed by the Morisky Medication Adherence Scale8,9.

Adverse events (AE) were graded according the Common Terminology Criteria for Adverse Events (CTCAE) version 5.08. The efficacy and safety values were compared with those described in the pivotal everolimus (Afinitor®) clinical trials.

For descriptive analysis, quantitative variables were described through median and interquartile range (IQR) and qualitative variables were described through frequencies table (number and percentage). STATA version 15.1 (StataCorp, College Station, TX, USA) was used for statistical analysis.

A total of fourteen patients were included in the study (Table 2).

To our knowledge, this is the first study describing an alternative DMF for patients receiving HPSCT. This study also shows long-term DMF effectiveness and safety.

Our protocol differs from SWISH trial recommending DMF twice daily in the preventive cohort to improve adherence10, rising to a 100%, since the 95% compliance rate reported by SWISH may not reflect real true-to-life proportions3. Additionally, DMF was administered throughout antineoplastic treatment in the preventive cohort to avoid stomatitis recurrence.

In the preventive cohort, the incidence of grade 2 or worse stomatitis was lower than in the BOLERO-2 pivotal trial despite the reduced number of patients included (one (11%) of nine patients compared with 159 (33%) of 482 patients in BOLERO-2 study). DMF reduced the proportion of all-grade stomatitis by 27% and grade 2 or worse stomatitis by 59% compared with BOLERO-2 by 8 weeks.

Therefore, as in the SWISH study (the incidence of G2 or higher of stomatitis at 8 weeks was 2.4% and the incidence of all grades was 21.2%), a reduction in the occurrence of stomatitis was observed.

The most frequently AE leading to dose reductions/disruptions were consistent with those reported previously: pneumonitis, dyspnoea and fatigue2. Moreover, the major reason for discontinuation was PD.

Although not all patients improved on DMF treatment, no dose reduction/discontinuation was required because of stomatitis. Significantly, there were no adverse effects related to DMF, since no patient developed oral candidiasis, despite longer duration of DMF (median of duration 76.6 [98.3] days).

Finally, it was shown that DMF might be applicable to other indications with same effectiveness and safety results and with a longer duration of use than previously reported.

The most frequent AE of afatinib are rash, diarrhoea, stomatitis, nausea and anorexia11. Notably, despite no previous literature about DMF effectiveness in afatinib-induced stomatitis, this was resolved allowing full dose treatment resulting in another partial response after a PD during afatinib discontinuation. Despite our limited experience, DMF could be considered for patients on afatinib presenting stomatitis.

Drugs that affect DNA synthesis, such as 5-fluorouracil, are associated with incidences of oral mucositis close to 40-60%12. Several studies have shown that application of cryotherapy before, during, and up to 30 minutes after 5-fluorouracil bolus administration significantly reduces stomatitis12. DMF was employed on patients with severe 5-fluororuracil induced stomatitis refractory to other treatments. Unfortunately, results on these patients were not optimal. One possible explanation is that fluorouracil interferes in DNA synthesis, causing cell death, while everolimus and afatinib inhibit different cellular growth mechanism.

Study limitations include the low number of patients and the lack of randomization and controlled arm. However, is the first real-life study assessing efficacy and toxicity of DMF in different indications of everolimus and other HPSCT.

On the whole, DMF may be a suitable alternative to commercial product for stomatitis. Further research with more patients is needed to provide unequivocally evidence about efficacy of preventing and treating stomatitis with this DMF.

No funding.

No conflict of interests.