Bladder Cancer Research Centre, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.
Cancer Research UK Clinical Trials Unit, Institute of Cancer and Genomic Sciences, University of Birmingham, United Kingdom.
JAMA Netw Open. 2023 Oct 2;6(10):e2337494. doi: 10.1001/jamanetworkopen.2023.37494.
Selenium and vitamin E have been identified as promising agents for the chemoprevention of recurrence and progression of non-muscle-invasive bladder cancer.
To determine whether selenium and/or vitamin E may prevent disease recurrence in patients with newly diagnosed NMIBC.
DESIGN, SETTING, AND PARTICIPANTS: This multicenter, prospective, double-blinded, placebo-controlled, 2 × 2 factorial randomized clinical trial included patients with newly diagnosed NMIBC recruited from 10 secondary or tertiary care hospitals in the UK. A total of 755 patients were screened for inclusion; 484 did not meet the inclusion criteria, and 1 declined to participate. A total of 270 patients were randomly assigned to 4 groups (selenium plus placebo, vitamin E plus placebo, selenium plus vitamin E, and placebo plus placebo) in a double-blind fashion between July 17, 2007, and October 10, 2011. Eligibility included initial diagnosis of NMIBC (stages Ta, T1, or Tis); randomization within 12 months of first transurethral resection was required.
Oral selenium (200 μg/d of high-selenium yeast) and matched vitamin E placebo, vitamin E (200 IU/d of d-alfa-tocopherol) and matched selenium placebo, selenium and vitamin E, or placebo and placebo.
Recurrence-free interval (RFI) on an intention-to-treat basis (analyses completed on November 28, 2022).
The study randomized 270 patients (mean [SD] age, 68.9 [10.4] years; median [IQR] age, 69 [63-77] years; 202 male [75%]), with 65 receiving selenium and vitamin E placebo, 71 receiving vitamin E and selenium placebo, 69 receiving selenium and vitamin E, and 65 receiving both placebos. Median overall follow-up was 5.5 years (IQR, 5.1-6.1 years); 228 patients (84%) were followed up for more than 5 years. Median treatment duration was 1.5 years (IQR, 0.9-2.5 years). The study was halted because of slow accrual. For selenium (n = 134) vs no selenium (n = 136), there was no difference in RFI (hazard ratio, 0.92; 95% CI, 0.65-1.31; P = .65). For vitamin E (n = 140) vs no vitamin E (n = 130), there was a statistically significant detriment to RFI (hazard ratio, 1.46; 95% CI, 1.02-2.09; P = .04). No significant differences were observed for progression-free interval or overall survival time with either supplement. Results were unchanged after Cox proportional hazards regression modeling to adjust for known prognostic factors. In total, 1957 adverse events were reported; 85 were serious adverse events, and all were considered unrelated to trial treatment.
In this randomized clinical trial of selenium and vitamin E, selenium supplementation did not reduce the risk of recurrence in patients with NMIBC, but vitamin E supplementation was associated with an increased risk of recurrence. Neither selenium nor vitamin E influenced progression or overall survival. Vitamin E supplementation may be harmful to patients with NMIBC, and elucidation of the underlying biology is required.
isrctn.org Identifier: ISRCTN13889738.
硒和维生素 E 已被确定为非肌肉浸润性膀胱癌复发和进展的有前途的化学预防剂。
确定硒和/或维生素 E 是否可能预防新诊断为非肌层浸润性膀胱癌患者的疾病复发。
设计、地点和参与者：这是一项多中心、前瞻性、双盲、安慰剂对照、2×2 析因随机临床试验，纳入了在英国 10 家二级或三级护理医院新诊断为非肌层浸润性膀胱癌的患者。共有 755 名患者接受了包括标准，其中 484 名不符合纳入标准，1 名拒绝参加。270 名患者于 2007 年 7 月 17 日至 2011 年 10 月 10 日期间以双盲方式随机分为 4 组（硒加安慰剂、维生素 E 加安慰剂、硒加维生素 E 和安慰剂加安慰剂）。入选标准包括非肌层浸润性膀胱癌（Ta、T1 或Tis 期）的初始诊断；需要在首次经尿道膀胱肿瘤切除术 12 个月内进行随机分组。
口服硒（高硒酵母 200μg/d）和匹配的维生素 E 安慰剂、维生素 E（d-α-生育酚 200IU/d）和匹配的硒安慰剂、硒和维生素 E 或安慰剂和安慰剂。
意向治疗基础上的无复发生存期（RFI）（2022 年 11 月 28 日完成分析）。
该研究共纳入 270 名患者（平均[标准差]年龄 68.9[10.4]岁；中位数[IQR]年龄 69[63-77]岁；202 名男性[75%]），其中 65 名接受硒和维生素 E 安慰剂，71 名接受维生素 E 和硒安慰剂，69 名接受硒和维生素 E，65 名接受两种安慰剂。中位总体随访时间为 5.5 年（IQR，5.1-6.1 年）；228 名患者（84%）随访时间超过 5 年。中位治疗持续时间为 1.5 年（IQR，0.9-2.5 年）。由于招募缓慢，该研究停止。与无硒（n=136）相比，硒组（n=134）的 RFI 无差异（危险比，0.92；95%CI，0.65-1.31；P=0.65）。与无维生素 E（n=130）相比，维生素 E 组（n=140）的 RFI 显著降低（危险比，1.46；95%CI，1.02-2.09；P=0.04）。两种补充剂对无进展生存期或总生存期均无显著影响。在调整已知预后因素的 Cox 比例风险回归模型后，结果保持不变。共报告了 1957 例不良事件，其中 85 例为严重不良事件，均被认为与试验治疗无关。
在这项关于硒和维生素 E 的随机临床试验中，硒补充剂并未降低非肌层浸润性膀胱癌患者的复发风险，但维生素 E 补充剂与复发风险增加相关。硒和维生素 E 均不影响进展或总生存。维生素 E 补充剂可能对非肌层浸润性膀胱癌患者有害，需要阐明其潜在生物学机制。
国际临床试验注册平台标识符：ISRCTN82163046。
