依氟鸟氨酸联合舒林酸用于家族性腺瘤性息肉病的进展预防。
Eflornithine plus Sulindac for Prevention of Progression in Familial Adenomatous Polyposis.
机构信息
From the Department of Gastroenterology, Hepatology, and Nutrition, Cleveland Clinic, Cleveland (C.A.B., J.C.); the Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam (E.D., F.G.K., V.H.R.); the Department of Gastroenterology, Hepatology, and Nutrition, University of Texas M.D. Anderson Cancer Center, Houston (P.L.); the Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix (N.J.S.), and Cancer Prevention Pharmaceuticals, Tucson (A. Cohen) - both in Arizona; the Department of Gastroenterology, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, University of Barcelona, Barcelona (F.B., A. Castells); the Department of Internal Medicine I, University of Bonn (R.H., C.P.S.), and the National Center for Hereditary Tumor Syndromes (R.H., C.P.S.), Bonn, Germany; Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne (J.B., A.H.), and Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Manchester (F.L.) - both in the United Kingdom; Mount Sinai Hospital, Toronto (S. Gallinger, R.G.); the Division of Population Sciences, Dana-Farber Cancer Institute, the Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, and Harvard Medical School - all in Boston (R.L., S.S.); the Division of Gastroenterology, University of Michigan, Ann Arbor (E.M.S.); Veterans Affairs San Diego Healthcare System, San Diego, and the Division of Gastroenterology, University of California San Diego, La Jolla (S. Gupta); Huntsman Cancer Center, Salt Lake City (P.K.); the University of Pennsylvania, Philadelphia (G.G.G., A.K.R.); Mayo Clinic, Rochester, MN (F.A.S.); University Hospital Gasthuisberg, Leuven, Belgium (E.V.C.); Emory University School of Medicine, Atlanta (F.F.W.); Washington University School of Medicine, St. Louis (P.E.W.); University of Washington Medical Center, Seattle (W.M.G.); Vanderbilt University Medical Center, Nashville (M.F.); and the University of Wisconsin School of Medicine and Public Health, Madison (J.M.W.).
出版信息
N Engl J Med. 2020 Sep 10;383(11):1028-1039. doi: 10.1056/NEJMoa1916063.
BACKGROUND
The efficacy and safety of combination therapy with eflornithine and sulindac, as compared with either drug alone, in delaying disease progression in patients with familial adenomatous polyposis are unknown.
METHODS
We evaluated the efficacy and safety of the combination of eflornithine and sulindac, as compared with either drug alone, in adults with familial adenomatous polyposis. The patients were stratified on the basis of anatomical site with the highest polyp burden and surgical status; the strata were precolectomy (shortest projected time to disease progression), rectal or ileal pouch polyposis after colectomy (longest projected time), and duodenal polyposis (intermediate projected time). The patients were then randomly assigned in a 1:1:1 ratio to receive 750 mg of eflornithine, 150 mg of sulindac, or both once daily for up to 48 months. The primary end point, assessed in a time-to-event analysis, was disease progression, defined as a composite of major surgery, endoscopic excision of advanced adenomas, diagnosis of high-grade dysplasia in the rectum or pouch, or progression of duodenal disease.
RESULTS
A total of 171 patients underwent randomization. Disease progression occurred in 18 of 56 patients (32%) in the eflornithine-sulindac group, 22 of 58 (38%) in the sulindac group, and 23 of 57 (40%) in the eflornithine group, with a hazard ratio of 0.71 (95% confidence interval [CI], 0.39 to 1.32) for eflornithine-sulindac as compared with sulindac (P = 0.29) and 0.66 (95% CI, 0.36 to 1.24) for eflornithine-sulindac as compared with eflornithine. Among 37 precolectomy patients, the corresponding values in the treatment groups were 2 of 12 patients (17%), 6 of 13 (46%), and 5 of 12 (42%) (hazard ratios, 0.30 [95% CI, 0.07 to 1.32] and 0.20 [95% CI, 0.03 to 1.32]); among 34 patients with rectal or ileal pouch polyposis, the values were 4 of 11 patients (36%), 2 of 11 (18%), and 5 of 12 (42%) (hazard ratios, 2.03 [95% CI, 0.43 to 9.62] and 0.84 [95% CI, 0.24 to 2.90]); and among 100 patients with duodenal polyposis, the values were 12 of 33 patients (36%), 14 of 34 (41%), and 13 of 33 (39%) (hazard ratios, 0.73 [95% CI, 0.34 to 1.52] and 0.76 [95% CI, 0.35 to 1.64]). Adverse and serious adverse events were similar across the treatment groups.
CONCLUSIONS
In this trial involving patients with familial adenomatous polyposis, the incidence of disease progression was not significantly lower with the combination of eflornithine and sulindac than with either drug alone. (Funded by Cancer Prevention Pharmaceuticals; ClinicalTrials.gov number, NCT01483144; EudraCT number, 2012-000427-41.).
背景
与单独使用任一药物相比，联合使用依氟鸟氨酸和舒林酸治疗家族性腺瘤性息肉病患者，可延迟疾病进展，但其疗效和安全性尚不清楚。
方法
我们评估了依氟鸟氨酸和舒林酸联合应用与单独应用相比，在家族性腺瘤性息肉病成人患者中的疗效和安全性。根据最高息肉负担和手术情况对患者进行分层；分层为预结肠切除术（预计疾病进展的最短时间）、结肠切除术后直肠或回肠袋息肉（预计时间最长）和十二指肠息肉（预计时间居中）。然后，患者以 1:1:1 的比例随机分配接受依氟鸟氨酸 750 mg、舒林酸 150 mg 或两者联合每日一次，最长 48 个月。主要终点是通过时间事件分析评估的疾病进展，定义为主要手术、高级别腺瘤内镜切除术、直肠或袋内高等级发育不良的诊断或十二指肠疾病进展的复合终点。
结果
共有 171 名患者接受了随机分组。依氟鸟氨酸-舒林酸组 56 例患者中有 18 例（32%）发生疾病进展，舒林酸组 58 例患者中有 22 例（38%），依氟鸟氨酸组 57 例患者中有 23 例（40%），依氟鸟氨酸-舒林酸组与舒林酸组相比，疾病进展的风险比为 0.71（95%置信区间，0.39 至 1.32）（P=0.29），与依氟鸟氨酸相比，风险比为 0.66（95%置信区间，0.36 至 1.24）。在 37 例预结肠切除术患者中，各组的相应值为依氟鸟氨酸-舒林酸组 12 例患者中有 2 例（17%）、舒林酸组 13 例患者中有 6 例（46%）和依氟鸟氨酸组 12 例患者中有 5 例（42%）（风险比，0.30[95%置信区间，0.07 至 1.32]和 0.20[95%置信区间，0.03 至 1.32]）；在 34 例直肠或回肠袋息肉患者中，各组的相应值为依氟鸟氨酸-舒林酸组 11 例患者中有 4 例（36%）、舒林酸组 11 例患者中有 2 例（18%）和依氟鸟氨酸组 12 例患者中有 5 例（42%）（风险比，2.03[95%置信区间，0.43 至 9.62]和 0.84[95%置信区间，0.24 至 2.90]）；在 100 例十二指肠息肉患者中，各组的相应值为依氟鸟氨酸-舒林酸组 33 例患者中有 12 例（36%）、舒林酸组 34 例患者中有 14 例（41%）和依氟鸟氨酸组 33 例患者中有 13 例（39%）（风险比，0.73[95%置信区间，0.34 至 1.52]和 0.76[95%置信区间，0.35 至 1.64]）。各组的不良和严重不良事件相似。
结论
在这项涉及家族性腺瘤性息肉病患者的试验中，依氟鸟氨酸和舒林酸联合应用与单独使用任一药物相比，疾病进展的发生率并没有显著降低。（由癌症预防药物公司资助；临床试验.gov 编号，NCT01483144；EudraCT 编号，2012-000427-41）。
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