TREATMENT RELATED MUCOSITIS

A swish-and-spit steroid mouthwash regimen that dramatically reduces the symptoms of treatment-induced oral mucositis and improves the quality of life for women with advanced breast cancer should become a new standard of care, say researchers.

The new findings come from the single-arm phase 2 SWISH trial, which tested the mouthwash in a cohort of 85 postmenopausal women with metastatic hormone receptor–positive, human epidermal hormone receptor 2 (HER2)–negative breast cancer who were receiving treatment with the mammalian target of rapamycin inhibitor everolimus (Afinitor, Novartis) and the aromatase inhibitor exemestane (Aromasin, Pfizer).

Results show that during a period of 8 weeks, the dexamethasone mouthwash reduced the proportion of all-grade stomatitis by 61% and reduced grade 2 or worse stomatitis by 91% when compared with historical controls from the BOLERO-2 trial receiving the same drugs but no mouthwash, reports a research team led by Hope S. Rugo, MD, professor of medicine at the University of California at San Francisco.

Use of the mouthwash in theSWISH study resulted in fewer dose reductions, drug interruptions, and drug discontinuations than in BOLERO-2, and the patients in the SWISH trial reported less oral pain and said they could eat normally, the researchers report.

The results were published online March 14 in The Lancet Oncology.

"Our results show that a commercially available, inexpensive, and well tolerated dexamethasone mouthwash resulted in a more than ten-times reduction in the incidence of grade 2 or higher stomatitis by 8 weeks compared with BOLERO-2 historical controls," the researchers write.

"Steroid mouthwash as prophylaxis for everolimus-related stomatitis should be considered as a new standard of oral care for patients who are postmenopausal and receiving everolimus and exemestane for treatment of hormone receptor-positive, HER2-negative metastatic or advanced breast cancer, especially in the first 8 weeks of treatment and as needed thereafter," they add.

Dr Rugo and colleagues also suggest that steroid prophylaxis "might be considered as a treatment option" for everolimus-induced oral mucositis in other diseases with a high incidence of stomatitis, such as renal cell carcinoma and advanced neuroendocrine tumors.

"The reduction in stomatotoxic effect in the SWISH trial compared with BOLERO-2 is certainly impressive," say Laura M. Spring, MD, and Aditya Bardia, MD, MPH, from the

Massachusetts General Hospital Cancer Center and Harvard Medical School in Boston, in an accompanying comment.

In an era of precision medicine, "studies such as the SWISH trial, dedicated to the mitigation of adverse effects from targeted therapies to improve quality of life and tolerability, are particularly refreshing," the editorialists say. They note that life expectancy for many patients with advanced breast cancer can now be measured in years. "The authors of the SWISH trial should be commended for a well-conducted study of a cost-effective measure to prevent a potentially debilitating side-effect."

However, Dr Spring and Dr Bardia also point out that SWISH wasn't randomized and didn't report any efficacy findings. They also note that that neither SWISH nor BOLERO-2 had study populations pretreated with a CDK 4/6 inhibitor as would be the case for most patients today. "The effect of previous CDK 4/6 inhibitor treatment as a risk factor for developing everolimus-induced oral mucositis is unclear," they saY.

In answering the question of whether the prophylactic use of dexamethasone mouthwash four times daily should be a new standard of care for everolimus-induced oral mucositis, Dr Spring and Dr Bardia caution that getting patients to adhere to the intensive regimen "might be difficult" and that the 95% compliance rate reported by SWISH may not reflect "real-world proportions."

Some patients "do not want to use a mouthwash for 2 full minutes, four times a day," Dr Bardia told Medscape Medical News, pointing out that not all patients taking everolimus develop mucositis. "However, for a compliant patient, in general the preferred approach would be to recommend the mouthwash," he added, noting that SWISH participants had a very low incidence of mouth sores with the use of the steroid mouthwash.

"Since everolimus-induced mucositis is associated with a prodrome, treatment with steroid rinses at the earliest indication of stomatitis, rather than upfront, could be considered," Dr Bardia suggested. A better understanding of the risk factors for oral mucositis would also be helpful for targeting patients at high risk with a more individualized approach, he said.

When asked to respond, Dr Rugo said that data from SWISH "demonstrates that prophylaxis works, and patients had no difficulty swishing as instructed." She agreed that better understanding of the 'optimal frequency of swishing each day' is needed. Whether the mouthwash could be just as effective when initiated after the onset of initial symptoms rather than used as prophylaxis also needs to be determined. "A study is planned with the Alliance for Clinical Trials in Oncology to evaluate just these questions," Dr Rugo told Medscape Medical News.  

Details of the Mouthwash Regimen 

In the SWISH trial, in addition to treatment with everolimus 10 mg plus exemestane 25 mg daily, participants received 10 mL of alcohol-free dexamethasone, 0.5 mg per 5 mL oral solution, with instructions to swish for 2 minutes and spit, four times a day for 8 weeks. They were also given an educational video about stomatitis and instructions on twice-daily tooth brushing, daily flossing, and other oral hygiene maintenance tips. Patients kept track of their swish-and-spit adherence, rated oral pain, and kept lists of the most "difficult" foods they could eat.

The only adverse events associated with the mouthwash was oral candidiasis in two patients. After 8 weeks, SWISH-ers were given the option of continuing the mouthwash for another 8 weeks and 74% decided to go for it. While this suggests "a benefit in the prevention or treatment of a later event of stomatitis with minimal risk," it remains unknown whether the incidence of candidiasis would increase if the mouthwash were used for a longer time, the researchers point out.

This study was funded by Novartis Pharmaceuticals Corporation. Dr Rugo reports financial relationships with Genomic Health, Novartis, Plexxikon, Macrogenics, OBI Pharma, Eisai, Pfizer, Lilly, GlaxoSmithKline, Genentech, Celsion, Nektar, and Merck. Several coauthors also report financial ties with pharmaceutical companies, as detailed in the paper.

Dr Bardia reports financial relationships with Novartis and Genentech, and Dr Spring has disclosed no relevant financial relationships.

Lancet Oncol. Published online March 14, 2017.