Relief for Everolimus-Associated Stomatitis

The endocrine therapy landscape has evolved from tamoxifen and aromatase inhibitors to CDK4/6 inhibitors and mTOR inhibitors. Along with the newer treatments come different toxicity profiles. Oral stomatitis, an adverse event seen frequently with mTOR-inhibitor therapy, can affect quality of life for patients, as well as their adherence to treatment.

In the BOLERO-2 trial, patients with hormone receptor–positive advanced breast cancer who had disease recurrence or progression with aromatase inhibitor therapy in the adjuvant setting were randomized to receive everolimus plus exemestane versus placebo plus exemestane.^1,2 Although the addition of the mTOR inhibitor everolimus more than doubled median progression-free survival, the incidence of all-grade stomatitis was 67%, with 24% of patients developing grade 2 and 8% developing grade 3 stomatitis.¹ Twenty-four percent of patients treated with everolimus required dose reduction for stomatitis.²

At the American Society of Clinical Oncology 2016 Annual Meeting, Hope S. Rugo, MD, and colleagues presented the results of a trial that addressed this adverse effect.³ The SWISH trial enrolled 86 women with hormone receptor–positive metastatic breast cancer who were treated with everolimus plus exemestane. These patients received a 10-mL oral solution containing dexamethasone 0.5 mg/5 mL to be swished for 2 minutes and then expectorated, 4 times daily for 8 weeks. The results of the SWISH trial were compared with the BOLERO-2 results; the incidence of grade 2 stomatitis was 2.4% and grade 1 was 17.4% after 8 weeks of the SWISH trial. No patients experienced grade 3 events.

A trial for everolimus-associated stomatitis evaluated the prophylactic use of 2 different steroid-based mouth rinses, a “miracle mouthwash” hydrocortisone rinse versus a prednisolone mouth rinse.⁴ The results of this trial were presented at the recent San Antonio Breast Cancer Symposium.

The “miracle mouthwash” was comprised of 320 mL of oral Benadryl, 2 g of tetracycline, 80 mg of hydrocortisone, and 40 mL of nystatin suspension. The alternate mouth rinse consisted of an oral solution of prednisolone 15 mg/5 mL.

Patients within the US Oncology Network with hormone receptor–positive metastatic breast cancer treated with everolimus were randomized 1:1 for 12 weeks of treatment (49 patients received the “miracle mouthwash” and 51 received the prednisolone rinse), with the primary objective being to determine the incidence of grade ≥2 stomatitis or related oral adverse events during the study period. Patients were instructed to swish for 2 minutes and expectorate 10 mL of the assigned mouth rinse 4 times daily, starting on day 1 of treatment. The incidence of any-grade stomatitis within the first 12 weeks was 29% for the “miracle mouthwash” group and 27.5% for the prednisolone rinse group. The incidence of grade 2 stomatitis was 12% for the “miracle mouthwash” group and 8% for the prednisolone rinse group. There was 1 case of grade 3 stomatitis with the “miracle mouthwash,” and no grade 4 for either mouth therapy. No patients stopped either steroid mouth rinse therapy because of rinse-related toxicity.

The prophylactic use of a steroid mouth rinse can decrease the incidence of overall stomatitis, especially grade 2, thus helping to avoid everolimus dose interruption and reduction during therapy with mTOR inhibitors.

References
1. Perez AT, Rugo HS, Baselga J, et al. Clinical management and resolution of stomatitis in BOLERO-2. Presented at American Society of Clinical Oncology annual meeting; May 31-June 4, 2013; Chicago, IL.
2. Rugo HS, Pritchard KI, Gnant M, et al. Incidence and time course of everolimus-related adverse events in postmenopausal women with hormone receptor-positive advanced breast cancer: insights from BOLERO-2. Ann Oncol. 2014;25:808-815.
3. Rugo HS, Seneviratne L, Beck JT, et al. Prevention of everolimus/exemestane (EVE/EXE) stomatitis in postmenopausal (PM) women with hormone receptor-positive (HR+) metastatic breast cancer (MBC) using a dexamethasone-based mouthwash (MW): results of the SWISH trial. Presented at American Society of Clinical Oncology annual meeting; June 3-7, 2016; Chicago, IL.
4. Jones VE, McIntyre KJ, Paul D, et al. Evaluation of miracle mouthwash (MMW) plus hydrocortisone or prednisolone mouth rinses as prophylaxis for everoli­mus-associated stomatitis: results of a randomized phase II study. Presented at San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX.