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.
摘要
背景。哺乳动物雷帕霉素靶向基因 (mTOR) 抑制剂相关口腔炎 (mlAS) 是一种与 mTOR 抑制剂疗法相关的常见不良反应(AE)，可能影响治疗依从性。本研究旨在评估两种基于类固醇的漱口液对于使用依维莫司进行转移性乳腺癌(MBC)治疗的患者预防/改善mlAS的效果。
材料和方法。这项前瞻性 II 期随机研究选取美国肿瘤网络中的 100 名激素受体阳性 MBC 的绝经后患者，均已开始芳香化酶抑制剂+依维莫司治疗(AIE; 10 mg/天)。患者随机接受使用其中一种漱口液的预防性治疗 [组 1:神奇漱口水 (MMW)480 mL 处方:320 mL 口服苯海拉明(苯海拉明，强生公司，美国新泽西州新布伦瑞克)，2 g四环素，80 mg氢化可的松，40 mL制霉菌素混悬剂，水；或组 2:强的松龙(P)，15 mg/5 mL口服液， 1.8% 酒精浓度]。按照指示，患者从 AIE 治疗第一天开始，含漱/吐出 10 mL指定漱口液，每次 1‐2 分钟，每日四次，持续治疗 12 周。
结果。总计 100 名患者接受了治疗(49 人使用 MMW；51 人使用 P)。使用 MMW 和 P 前 12 周的口腔炎/口腔AE发生率分别为 35% (n = 17/49) 和 37% (19/51)。使用 MMW 和 P 的二级口腔AE发生率分别为 14% (7/49) 和 12% (6/51)。另有两例三级口腔AE(MMW 组)，没有四级事件。在前 12 周治疗中，出现一例依维莫司剂量减少 (MMW) 和六例剂量延迟(4 例 MMW，2 例 P)，以及一例剂量减少+延迟(MMW)。没有患者因漱口液相关毒性而停止类固醇漱口水治疗。
结论。预防性使用含有类固醇的漱口液可以防止/改善接受 AIE 治疗的MBC患者的mIAS。MMW+氢化可的松和地塞米松漱口液都是价格合理的治疗选择。
对实践的启示:该前瞻性 II 期研究显示，两种含有类固醇的漱口液大幅度降低了各级别及二级(含)以上口腔炎和相关口腔不良反应的发生率，也减少了接受依维莫司治疗联合芳香酶抑制剂的转移性乳腺癌(MBC)患者中依维莫司剂量延迟和/或剂量减少的数量。两种漱口液都具备良好耐受性，且功效相似。
预防性使用类固醇漱口液提供了经济适用的选项，大幅度降低 mTOR 抑制剂相关口腔炎和相关口腔不良反应的发生率和严重程度，以及接受 mTOR 抑制剂治疗的MBC患者对剂量改变的需求。
Keywords: Aromatase inhibitor; Everolimus; Mouthwash; Prednisolone; Stomatitis.
© AlphaMed Press 2019.