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

Rugo, Hope S.; Seneviratne, Lasika; Beck, J. Thaddeus; Glaspy, John A.; Peguero, Julio Antonio; Pluard, Timothy; Dhillon, Navneet K.; Hwang, Leon; Nangia, Chaitali Singh; Mayer, Ingrid A.; Meiller, Timothy F.; Chambers, Mark S.; Sweetman, Robert; Sabo, John; Litton, Jennifer K.

doi:10.1016/s1470-2045(17)30109-2

Cited by 166 publications

(116 citation statements)

References 20 publications

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“…Our results are consistent with recently reported results from the SWISH study, which evaluated use of a dexamethasonecontaining mouth rinse in a similar population of 92 postmenopausal women with MBC who were receiving treatment with everolimus plus exemestane [15]. The incidence of allgrade stomatitis or related oral AEs observed during the first 12 weeks of our study (MMW: 35%; P: 37%) was comparable with the 27% incidence of all-grade stomatitis reported in the SWISH study.…”

Section: © Alphamed Press 2019supporting

confidence: 91%

Evaluation of Miracle Mouthwash plus Hydrocortisone Versus Prednisolone Mouth Rinses as Prophylaxis for Everolimus-Associated Stomatitis: A Randomized Phase II Study

et al. 2019

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Background Mammalian target of rapamycin (mTOR) inhibitor‐associated stomatitis (mIAS) is a frequent adverse event (AE) associated with mTOR inhibitor therapy and can impact treatment adherence. The objectives are to evaluate two steroid‐based mouthrinses for preventing/ameliorating mIAS in patients with metastatic breast cancer (MBC) treated with everolimus. Materials and Methods This prospective, randomized phase II study enrolled 100 postmenopausal patients with hormone receptor‐positive MBC within the US Oncology Network who were initiating therapy with an aromatase inhibitor + everolimus (AIE; 10 mg/day). Patients were randomized to prophylactic therapy with one of two oral rinses (Arm 1: Miracle Mouthwash [MMW] 480 mL recipe: 320 mL oral Benadryl [diphenhydramine; Johnson & Johnson, New Brunswick, NJ, USA], 2 g tetracycline, 80 mg hydrocortisone, 40 mL nystatin suspension, water; or Arm 2: prednisolone [P] 15 mg/5 mL oral solution, 1.8% alcohol). Patients were instructed to swish/expectorate 10 mL of the assigned rinse for 1–2 minutes four times daily starting with day 1 of AIE treatment, for the first 12 weeks. Results A total of 100 patients received treatment (49 MMW; 51 P). The incidence of stomatitis/oral AEs during the first 12 weeks was 35% (n = 17/49) and 37% (19/51) in the MMW and P arms, respectively. The incidence of grade 2 oral AEs was 14% (7/49) and 12% (6/51) with MMW or P, respectively. There were two grade 3 oral AEs (MMW arm) and no grade 4 events. There was one everolimus dose reduction (MMW) and six dose delays (four MMW, two P) and one dose reduction + delay (MMW) during the first 12 weeks of treatment. No patients stopped steroid mouthwash therapy because of rinse‐related toxicity. Conclusion Prophylactic use of steroid‐containing oral rinses can prevent/ameliorate mIAS in patients with MBC treated with AIE. MMW + hydrocortisone is an affordable option, as is dexamethasone oral rinse. Implications for Practice This prospective phase‐II study showed that two steroid‐containing mouthrinses substantially reduced incidences of all‐grade and grade ≥2 stomatitis and related oral adverse events (AEs), and the number of everolimus dose‐delays and/or dose‐reduction in metastatic breast cancer (MBC) patients receiving everolimus treatment plus an aromatase inhibitor. Both oral rinses were well tolerated and demonstrated similar efficacy. Prophylactic use of steroid mouth rinse provides a cost‐effective option that substantially decreases the incidence and severity of mammalian target of rapamycin (mTOR) inhibitor‐associated stomatitis and related oral AEs as well as the need for dose modification in MBC patients undergoing treatment with an mTOR inhibitor.

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Section: © Alphamed Press 2019supporting

confidence: 91%

Evaluation of Miracle Mouthwash plus Hydrocortisone Versus Prednisolone Mouth Rinses as Prophylaxis for Everolimus-Associated Stomatitis: A Randomized Phase II Study

et al. 2019

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“…The combination with vinblastine may be more tolerable at lower temsirolimus dose levels, and future trials may focus on identifying an optimum biologic dose for this combination, rather than an MTD. A prophylactic oral dexamethasone‐based mouthwash may also help reduce mTOR inhibitor–associated stomatitis, as has been shown for breast cancer patients receiving everolimus . This trial was published after the initiation of the current study, and hence the use of mouthwash prophylaxis was not incorporated into the trial protocol.…”

Section: Discussionmentioning

confidence: 99%

Phase I study of vinblastine and temsirolimus in pediatric patients with recurrent or refractory solid tumors: Canadian Cancer Trials Group Study IND.218

Deyell

Rassekh

et al. 2018

Pediatric Blood & Cancer

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Combining mammalian target of rapamycin (mTOR) inhibitors and vinca alkaloids has shown therapeutic synergy in xenograft models of pediatric cancers. This phase I study assessed safety and toxicity of temsirolimus in combination with vinblastine in children. Procedure Patients ≥ 1 and ≤ 18 years with recurrent/refractory solid or CNS tumors were eligible. Vinblastine (4 mg/m2) and temsirolimus (15 mg/m2) were administered i.v. weekly, with planned dose escalation of vinblastine using a rolling six phase I design. Pharmacokinetic and pharmacodynamic data were collected. Results Seven patients with median age 12 years (range, 8–18 years) were enrolled; all were evaluable for toxicity and six for response. At dose level 1, four of six patients developed grade 3 mucositis, of which one met duration criteria for dose‐limiting toxicity (DLT). Four patients required dose omissions for grade 3 or 4 hematologic toxicity, including one prolonged neutropenia DLT. A subsequent patient was enrolled on dose level −2 (temsirolimus 10 mg/m2, vinblastine 4 mg/m2) with no protocol‐related toxicity > grade 1, except grade 2 neutropenia. Two serious adverse events (SAE) occurred—an allergic reaction to temsirolimus (grade 2) and an intracranial hemorrhage in a CNS tumor patient (grade 3)—unlikely related to study therapy. Soluble VEGFR2 was reduced at cycle 1, day 36 in keeping with inhibition of angiogenesis. Four patients achieved prolonged stable disease for a median of 5.0 months (range, 3.1–8.3 months). Conclusion The combination of weekly temsirolimus (15 mg/m2) and vinblastine (4 mg/m2) exceeds the maximum tolerated dose in children, with frequent oral mucositis and hematologic toxicity.

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“…The use of dexamethasone mouth rinse may be considered to prevent stomatitis in potentially susceptible patients, based on the findings of the SWISH trial in postmenopausal women with breast cancer receiving everolimus and exemestane. The study demonstrated a lower incidence of stomatitis (2.4% grade > 2 stomatitis at 8 weeks), compared with 33% in a historical control) when concomitant dexamethasone mouth rinse was used [39]. …”

Section: Targeted Therapymentioning

confidence: 99%

ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Neoplasms: Systemic Therapy - Biotherapy and Novel Targeted Agents

et al. 2017

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Systemic therapies established in the management of patients with neuroendocrine tumors (NETs) include somatostatin analogs and interferon-α, also referred to as biotherapy. Recent randomized controlled studies have extended the knowledge on the frequency of side effects associated with biotherapy. More recently, novel targeted drugs, such as the mammalian target of rapamycin inhibitor everolimus and the multiple tyrosine kinase inhibitor sunitinib, have been introduced in the management of NETs. Although targeted drugs are generally well tolerated, with most adverse events being of mild to moderate severity and manageable, novel targeted drugs exhibit a distinct adverse event profile that warrants guidance for appropriate diagnostic and therapeutic management. This is particularly important given the widespread and potentially long-term use of everolimus in a broad spectrum of NETs and of sunitinib in pancreatic NETs. This review will focus on the most relevant toxicities associated with biotherapy and novel targeted drugs and on their management. For each drug class indication, administration and dosing schedule, most frequent adverse events, actions and dose adjustments for adverse events as well as their monitoring are presented. This review further covers the evaluation of treatment effect, patient information, drug interactions, and information on pregnancy.

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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

Cited by 166 publications

References 20 publications

Evaluation of Miracle Mouthwash plus Hydrocortisone Versus Prednisolone Mouth Rinses as Prophylaxis for Everolimus-Associated Stomatitis: A Randomized Phase II Study

Evaluation of Miracle Mouthwash plus Hydrocortisone Versus Prednisolone Mouth Rinses as Prophylaxis for Everolimus-Associated Stomatitis: A Randomized Phase II Study

Phase I study of vinblastine and temsirolimus in pediatric patients with recurrent or refractory solid tumors: Canadian Cancer Trials Group Study IND.218

ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Neoplasms: Systemic Therapy - Biotherapy and Novel Targeted Agents

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