Selenium and Vitamin E for Prevention of Non-Muscle-Invasive Bladder Cancer Recurrence and Progression: A Randomized Clinical Trial

Abstract

Importance: Selenium and vitamin E have been identified as promising agents for the chemoprevention of recurrence and progression of non-muscle-invasive bladder cancer.

Objective: 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.

Interventions: 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.

Main outcome and measures: Recurrence-free interval (RFI) on an intention-to-treat basis (analyses completed on November 28, 2022).

Results: 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.

Conclusions and relevance: 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.

Trial registration: isrctn.org Identifier: ISRCTN13889738.

Figure 1.. SELENIB Trial Profile

Trial profile of the 4 arms and comparisons analyzed within the SELENIB trial. BCPP indicates Bladder Cancer Prognosis Programme.

Figure 2.. Recurrence-Free Interval

Kaplan-Meier 5-year analyses of recurrence-free intervals, defined as the time from date of study entry to date of recurrence, for selenium and vitamin E. For patients not observed to have experienced recurrence at the time of analysis, the interval was censored at the date last known to be recurrence free. HR indicates hazard ratio.

Figure 3.. Progression-Free Interval

Kaplan-Meier 5-year analyses of progression-free intervals as time from date of study entry to date of progression, for selenium and vitamin E. Progression was defined as recurrence with an increase in grade from grade 1 or grade 2 to grade 3 or an increase in T stage (determined by histopathologic analysis) or the new occurrence of carcinoma in situ (CIS) in a bladder previously free from CIS or the new occurrence of multiple urothelial tumors following the initial diagnosis of a solitary urothelial tumor. Progression was also reported if there was the need for a cystectomy because of refractory disease or the new development of nodal and/or distant metastases (determined by imaging). For those patients not observed to have experienced progression by the time of analysis, the interval was censored at the date last known to be progression free. HR indicates hazard ratio.

Figure 4.. Overall Survival Analysis

Kaplan-Meier 5-year analyses of overall survival time defined as time from the date of randomization to the date of death from any cause, for selenium and vitamin E. Patients alive at the time of analysis were censored at the date last known to be alive. For patients not observed to have experienced recurrence at the time of analysis, the interval was censored at the date last known to be recurrence free. HR indicates hazard ratio.