I believe this mouthwash to be a new standard of care for postmenopausal women receiving everolimus/exemestane for treatment of hormone receptor–positive HER2-advanced or metastatic breast cancer.— Hope S. Rugo, MD
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Prophylactic use of dexamethasone mouthwash significantly minimized the incidence of all grades of stomatitis in postmenopausal women receiving everolimus (Afinitor, Zortress) and exemestane for the treatment of hormone receptor–positive metastatic breast cancer, according to data presented by Hope S. Rugo, MD, at the 2016 Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) International Symposium on Supportive Care in Cancer in Adelaide, Australia.1 Stomatitis is a dose-limiting toxicity commonly associated with mTOR (mammalian target of rapamycin) inhibition.
“I believe this mouthwash to be a new standard of care for postmenopausal women receiving everolimus/exemestane for treatment of hormone receptor–positive HER2-advanced or metastatic breast cancer,” said Dr. Rugo, Director of Breast Oncology and Clinical Trials Education at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center. “If we can control stomatitis in all of these patients, it would really improve their quality of life and, potentially, their chance to benefit from this drug.”
The SWISH trial sought to evaluate an alcohol-free, steroid mouthwash to prevent stomatitis (grade ≥ 2) in patients with advanced HER2-positive breast cancer receiving everolimus/exemestane, when compared with historical data from the BOLERO-2 trial.2,3 The BOLERO-2 trial led to the approval of everolimus as the first targeted agent for HER2-negative hormone receptor–positive disease in combination with hormone therapy, but many patients in the trial experienced a rapid onset of stomatitis.4,5
“We classified stomatitis as grade 2 or greater in the SWISH trial, because that’s where patients have symptoms,” explained Dr. Rugo. “And we didn’t want to do a big randomized trial because it was difficult for us to think about randomizing patients not to use the steroid mouthwash since our anecdotal experience was so strong. We decided to use BOLERO-2 as a historical control, since the patients would be similar, and we used the same eligibility criteria.”
A total of 92 postmenopausal patients with metastatic hormone receptor–positive, HER2-positive breast cancer prescribed everolimus at 10 mg and exemestane at 25 mg were evaluated in the trial. “Although many of us will treat sicker patients with lower doses to start, in this trial you had to start at 10 mg,” Dr. Rugo revealed.
SWISH was a U.S.-based, multicenter, single-arm, phase II prevention trial conducted at 23 investigational sites. More than 35% of patients received everolimus and exemestane treatment in the second- or greater-line setting, and most patients had at least three metastatic sites, including visceral involvement of the lungs (51%) or liver (36%).
At baseline, oral pain, normalcy of diet scale (NDS), and visual analog scale (VAS) were assessed, and patients were instructed on routine good oral care.
The study objective was comparing the incidence of grade 2 or greater stomatitis at 8 weeks, where 90% of first events tend to occur, with BOLERO-2 historical controls. This information was confirmed by a physical exam and at least one of the following measures: NDS ≤ 50 and a patient-reported VAS of 7 on 2 consecutive days or 8–10 on any 1 day. “We wanted to have a strict definition of what stomatitis was,” added Dr. Rugo.
Patients received 10 mL of alcohol-free dexamethasone 0.5 mg/5 mL oral solution, in addition to the standard approved dosing for everolimus and exemestane. They started the mouthwash on the first day of their treatment (1 cycle = 28 days); they were told to swish for 2 minutes and spit 4 times per day for 8 weeks and not to eat for 1 hour after using the mouthwash. Physicians could reduce or interrupt the dose of everolimus to manage adverse events.
Reduced Stomatotoxic Effect
At week 8, compared to our historical cohort, it was astounding to see the reduction in the stomatotoxic effect in the SWISH trial.— Mark S. Chambers, DMD, MS
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“At week 8, compared to our historical cohort, it was astonishing to see the reduction in stomatotoxic effect in the SWISH trial,” said Mark S. Chambers, DMD, MS, a coauthor of the study and Professor and Chief of Oral Oncology in the Department of Head and Neck Surgery at The University of Texas MD Anderson Cancer Center in Houston.
For patients in the trial, the incidence of grade 2 or higher stomatitis at 8 weeks was 2.4% compared with 33% in BOLERO-2 (P < .001). “This is highly statistically significant and a marked difference, even more than we had expected,” Dr. Rugo reported. The incidence of all-grade stomatitis at 8 weeks was 21.2%, compared with 67% in BOLERO-2.
“The majority of patients had minimal discomfort due to what we believe was the dexamethasone rinse,” added Dr. Chambers.
Normal diet was reported in 88% of patients at 8 weeks, and 90% experienced no or few dietary restrictions throughout the study. “So this is really different from what we saw in an untreated population,” Dr. Rugo added.
Most patients (95%) used the mouthwash 3 to 4 times a day. Additionally, more than 70% remained on the mouthwash as well as the two treatment drugs for more than 8 weeks.
“The toxicity was quite modest and related to the everolimus,” Dr. Rugo reported. “Hyperglycemia was the most common grade 3 toxicity, but it wasn’t really increased compared to what we saw in BOLERO-2, which is encouraging given the fact that we were using steroids.”
According to Dr. Chambers, “less is more, and supportive care medicine can be used comfortably with greater efficacy if it’s easy to use; cost-efficient; and morbidity education is customized to patient ability, particularly when treating stomatitis.”
Dr. Rugo added that the approach also seems warranted for patients with other malignancies who receive everolimus. ■
Disclosure: Drs. Rugo and Chambers reported no potential conflicts of interest.
1. Rugo H, Seneviratne L, Beck J, et al: Prevention of everolimus/exemestane stomatitis in postmenopausal women with hormone receptor–positive metastatic breast cancer using a dexamethasone-based mouthwash: Results of the SWISH trial. MASCC/ISOO International Symposium on Supportive Care in Cancer. Abstract MASCC-0638. Presented June 23, 2016.
2. Yardley DA, Noguchi S, Pritchard KI, et al: Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis. Adv Ther 30:870-884, 2013.
5. 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 25:808-815, 2014.