Prevention of everolimus-related stomatitis in women with hormone receptor-positive, HER2-negative metastatic breast cancer using dexamethasone mouthwash (SWISH): a single-arm, phase 2 trial.
Stomatitis is a class effect associated with the inhibition of mTOR and is associated with everolimus therapy for breast cancer. Topical steroids might reduce stomatitis incidence and severity, and the need for dose reductions and interruptions of everolimus. Anecdotal use of topical steroid oral prophylaxis has been reported in patients with breast cancer. We aimed to assess dexamethasone-based mouthwash for prevention of stomatitis in patients with breast cancer.



This US-based, multicentre, single-arm, phase 2 prevention study enrolled women aged 18 years and older with postmenopausal status who had histologically or cytologically confirmed metastatic hormone receptor-positive, HER2-negative breast cancer. Beginning on day 1 of cycle 1, patients received everolimus 10 mg plus exemestane 25 mg daily, with 10 mL of alcohol-free dexamethasone 0·5 mg per 5 mL oral solution (swish for 2 min and spit, four times daily for 8 weeks). After 8 weeks, dexamethasone mouthwash could be continued for up to eight additional weeks at the discretion of the clinician and patient. The primary endpoint was incidence of grade 2 or worse stomatitis by 8 weeks assessed in the full analysis set (patients who received at least one dose of everolimus and exemestane and at least one confirmed dose of dexamethasone mouthwash) versus historical controls from the BOLERO-2 trial (everolimus and exemestane treatment in patients with hormone receptor-positive advanced breast cancer who were not given dexamethasone mouthwash for prevention of stomatitis). This trial is registered at ClinicalTrials.gov, number NCT02069093.



Between May 28, 2014, and Oct 8, 2015, we enrolled 92 women; 85 were evaluable for efficacy. By 8 weeks, the incidence of grade 2 or worse stomatitis was two (2%) of 85 patients (95% CI 0·29-8·24), versus 159 (33%) of 482 patients (95% CI 28·8-37·4) for the duration of the BOLERO-2 study. Overall, 83 (90%) of 92 patients had at least one adverse event. The most frequently reported grade 3 and 4 adverse events in the safety set were hyperglycaemia (seven [8%] of 92 patients), rash (four [4%]), and dyspnoea (three [3%]). Serious adverse events were reported in 20 (22%) patients; six (7%) were deemed treatment related, with dyspnoea (three [3%]) and pneumonia (two [2%]) reported most frequently. 12 (13%) of 92 patients had adverse events suspected to be related to treatment that led to discontinuation of everolimus and exemestane (the most common were rash, hyperglycaemia, and stomatitis, which each affected two [2%] patients).



Prophylactic use of dexamethasone oral solution substantially reduced the incidence and severity of stomatitis in patients receiving everolimus and exemestane and could be a new standard of oral care for patients receiving everolimus and exemestane therapy.



Novartis Pharmaceuticals Corporation.
University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA. Electronic address: hope.rugo@ucsf.edu.
Hope S
HS
Rugo
Los Angeles Cancer Network, Los Angeles, CA, USA.
Lasika
L
Seneviratne
Highlands Oncology Group, Fayetteville, AR.
J Thaddeus
JT
Beck
University of California Los Angeles School of Medicine, Los Angeles, CA, USA.
John A
JA
Glaspy
Oncology Consultants PA, Department of Research, Houston, TX, USA.
Julio A
JA
Peguero
St Luke's Cancer Institute, Kansas City, MO, USA.
Timothy J
TJ
Pluard
Cancer Treatment Centers of America, Atlanta, GA, USA.
Navneet
N
Dhillon
Kaiser Permanente Mid-Atlantic States, Gaithersburg, MD, USA.
Leon Christopher
LC
Hwang
UC Irvine Health Chao Family Comprehensive Cancer Center, Orange, CA, USA.
Chaitali
C
Nangia
Vanderbilt-Ingram Comprehensive Cancer Center, Nashville, TN, USA.
Ingrid A
IA
Mayer
Oncology and Diagnostic Sciences, Dental School and The Marlene and Stewart Greenebaum Comprehensive Cancer Center University of Maryland Medical Center, Baltimore, MD, USA.
Timothy F
TF
Meiller
The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Mark S
MS
Chambers
Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
Robert W
RW
Sweetman
Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
J Randy
JR
Sabo
The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Jennifer K
JK
Litton
D000287:Administration, Topical; D000368:Aged; D000730:Androstadienes / Q000008:administration & dosage / Q000009:adverse effects; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D003907:Dexamethasone / Q000008:administration & dosage / Q000627:therapeutic use*; D003875:Drug Eruptions / Q000209:etiology; D004417:Dyspnea / Q000139:chemically induced; D000068338:Everolimus / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D006801:Humans; D006943:Hyperglycemia / Q000139:chemically induced; D008875:Middle Aged; D009067:Mouthwashes / Q000627:therapeutic use; D009362:Neoplasm Metastasis; D011014:Pneumonia / Q000139:chemically induced; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D011960:Receptors, Estrogen / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis; D012720:Severity of Illness Index; D013280:Stomatitis / Q000139:chemically induced / Q000517:prevention & control*
D000730:Androstadienes; D000893:Anti-Inflammatory Agents; D003907:Dexamethasone; D000068338:Everolimus; D009067:Mouthwashes; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C508053:ERBB2 protein, human; C056516:exemestane