柳叶刀肿瘤学快讯：地塞米松漱口水可以预防乳腺癌女性的依维莫司相关口腔炎
编者按：2017年3月14日，美国食品药品管理局（FDA）正式批准诺华的细胞周期蛋白依赖性激酶4/6（CDK4/6）抑制剂利泊昔布（ribociclib）口服片剂联合芳香酶抑制剂（AI）用于激素受体（HR）阳性、人表皮生长因子受体2（HER2）阴性、晚期或转移性乳腺癌绝经后女性一线内分泌疗法。主要依据为2016年10月7日在线发表于《新英格兰医学杂志》的MONALEESA-2研究（N Engl J Med. 2016;375:1738-1748）。
上述消息距离中国批准比较遥远，我们言归正传，谈谈诺华另外一个在中国已经批准的药物：依维莫司。
2017年3月14日，英国《柳叶刀肿瘤学分册》在线发表旧金山加利福尼亚大学（UCSF）、洛杉矶癌症网络、海兰兹肿瘤协作组、洛杉矶加利福尼亚大学（UCLA）、休斯敦肿瘤医生集团、圣卢克癌症研究所、美国癌症治疗中心、凯泽永久医疗集团、欧文加利福尼亚大学（UCI）、范德堡英格拉姆综合癌症中心、马里兰大学、德克萨斯大学MD安德森癌症中心、美国诺华的单组Ⅱ期研究（SWISH），发现地塞米松漱口水可以预防HR阳性HER2阴性转移性乳腺癌女性的依维莫司相关口腔炎。
高大上的《柳叶刀肿瘤学分册》发表此文用意何在？
口腔炎是与哺乳动物雷帕霉素靶蛋白（mTOR）抑制有相关性的不良反应，并且与依维莫司治疗乳腺癌有相关性。局部类固醇可以减少口腔炎的发生率和严重程度，避免依维莫司的减量和停药。已有局部类固醇口服预防经验性用于乳腺癌患者的报道，故该研究对地塞米松漱口水预防乳腺癌患者口腔炎进行了评定。
该美国多中心单组Ⅱ期预防研究于2014年5月28日～2015年10月8日入组≥18岁、已停经、组织学或细胞学证实为HR阳性HER2阴性转移性乳腺癌女性92例。从第1周期第1天开始，患者每天口服依维莫司10mg＋依西美坦25mg＋无酒精的0.5mg/5mL地塞米松溶液10mL（2分钟漱口，每日4次，共8周）。8周后，可以根据临床医生和患者的判断继续使用8周地塞米松漱口水。主要终点为完全分析组（口服依维莫司、依西美坦、地塞米松漱水至少各一次的患者）与BOLERO-2研究（依维莫司＋依西美坦治疗未予地塞米松漱口水预防口腔炎的HR阳性晚期乳腺癌患者）历史对照组相比，≥2级口腔炎的发生率。该研究在美国政府临床研究网站（ClinicalTrials.gov）的注册号为：NCT02069093。
结果发现，8周期间，可评价疗效的完全分析组85例患者、BOLERO-2研究482例患者分别有2例、159例发生≥2级口腔炎，发生率分别为2%、33%（95%置信区间：0.29～8.24、28.8～37.4）。
总体而言，92例患者其中83例（90%）有至少一个不良事件。在安全性分析中，最常见的3和4级不良事件为高血糖7例（8%）、皮疹4例（4%）、呼吸困难3例（3%）。20例（22%）患者报告严重不良事件；被认为与治疗相关6例（7%），其中呼吸困难3例（3%）和肺炎2例（2%）最多见。有12例（13%）有疑似与治疗相关的不良事件，导致停用依维莫司和依西美坦，最常见为皮疹、高血糖、口腔炎，各2例（2%）。
因此，预防性使用地塞米松口服溶液大大降低了患者接受依维莫司和依西美坦的口腔炎发生率和严重程度，并且可以作为患者接受依维莫司和依西美坦治疗的口腔医疗新标准。
对此，哈佛医学院、麻省总医院癌症中心发表同期评论：类固醇漱口（SWISH-ing）是否预防依维莫司所致口腔黏膜炎的医疗新标准？
评论认为，应该赞扬SWISH研究作者开展了一项关于经济有效措施的良好研究，以防止可能导致停药或减量的不良反应。根据SWISH研究，预防性使用地塞米松漱口水应被认为是预防依维莫司所致口腔黏膜炎的可能选择。许多HR阳性转移性乳腺癌患者，尤其仅仅发生骨转移的患者，预期寿命可以年计，全身治疗目标为延长生存并且维持生活质量。因此，在靶向疗法和精确医学的时代，诸如SWISH等专门用于减轻靶向疗法不良反应以改善生活质量和耐受性的研究尤其令人耳目一新。
Lancet Oncol. 2017 Mar 14. [Epub ahead of print]
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.
Hope S Rugo, Lasika Seneviratne, J Thaddeus Beck, John A Glaspy, Julio A Peguero, Timothy J Pluard, Navneet Dhillon, Leon Christopher Hwang, Chaitali Nangia, Ingrid A Mayer, Timothy F Meiller, Mark S Chambers, Robert W Sweetman, J Randy Sabo, Jennifer K Litton.
University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA; Los Angeles Cancer Network, Los Angeles, CA, USA; Highlands Oncology Group, Fayetteville, AR; University of California Los Angeles School of Medicine, Los Angeles, CA, USA; Oncology Consultants PA, Department of Research, Houston, TX, USA; St Luke's Cancer Institute, Kansas City, MO, USA; Cancer Treatment Centers of America, Atlanta, GA, USA; Kaiser Permanente Mid-Atlantic States, Gaithersburg, MD, USA; UC Irvine Health Chao Family Comprehensive Cancer Center, Orange, CA, USA; Vanderbilt-Ingram Comprehensive Cancer Center, Nashville, TN, USA; University of Maryland Medical Center, Baltimore, MD, USA; The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
BACKGROUND: 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.
METHODS: 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.
FINDINGS: 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).
INTERPRETATION: 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.
FUNDING: Novartis Pharmaceuticals Corporation.
DOI: 10.1016/S1470-2045(17)30109-2
Lancet Oncol. 2017 Mar 14. [Epub ahead of print]
SWISH-ing steroids: new standard of care to prevent everolimus-induced oral mucositis?
Laura Spring, Aditya Bardia.
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
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. On the basis of the SWISH trial, the use of prophylactic dexamethasone mouthwash should be considered a potential option for the prevention of everolimus-induced oral mucositis. Many patients with hormone receptor-positive metastatic breast cancer, particularly those with osseous metastases only, have a life expectancy measured in years and the goals for systemic treatment are to prolong survival while maintaining quality of life.10 Accordingly, in the era of targeted therapies and 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.
DOI: 10.1016/S1470-2045(17)30106-7