Selenium and Vitamin E for Prevention of Non–Muscle-Invasive Bladder Cancer Recurrence and Progression

Key Points Question Can selenium and vitamin E supplementation prevent recurrence and progression of non–muscle-invasive bladder cancer (NMIBC)? Findings In this randomized clinical trial of 270 adults, supplementation with selenium was not associated with a decreased risk of NMIBC recurrence; vitamin E supplementation was associated with a significantly increased risk of recurrence. Neither selenium nor vitamin E was associated with progression or overall survival. Meaning These findings suggest that vitamin E supplements may be harmful to patients with NMIBC.


Introduction
Bladder cancer is the 12th most common cancer worldwide 1 ; in high-income countries, more than 90% are transitional cell carcinomas of urothelial origin, and most patients (75%-85%) present with non-muscle-invasive bladder cancer (NMIBC) (Union for International Cancer Control stages Ta, T1, and Tis). 2 Patients with NMIBC are initially treated by transurethral resection of bladder tumor and adjuvant intravesical therapy. 3Recurrence occurs in up to 80% of patients 4 ; progression to muscleinvasive bladder cancer (stages T2 or higher) occurs in up to 45% of patients diagnosed with initial stage T1 disease. 5ven the frequency of recurrence and progression and the chronic nature of the disease, NMIBC may be amenable to chemoprevention. 6Selenium and vitamin E have previously been identified as promising agents [7][8][9] ; notwithstanding, more recent clinical trials of selenium and/or vitamin E in the primary and secondary cancer prevention settings have shown no effect 10,11 or a detrimental effect. 12Between 2005 and 2007, we established a trial protocol with the aim of providing important insights into the use of selenium and vitamin E as adjuvant therapies for NMIBC (SELENIB trial).

Study Design and Participants
From July 17, 2007, to October 10, 2011, SELENIB recruited patients with newly diagnosed NMIBC to a double-blinded, placebo-controlled, 2 × 2 factorial randomized clinical trial from 10 UK hospitals.
Eligible patients were 18 years or older with newly diagnosed, pathologically confirmed urothelial NMIBC who were able to give informed consent.Ethnicity data were not collected because they were not considered to be relevant for a study of this nature.Patients were required to be randomized within 12 months of initial transurethral resection of bladder tumor.All patients provided written informed consent.SELENIB was coordinated by the Cancer Research UK Clinical Trials Unit at the University of Birmingham.The trial was conducted in accordance with the principles of the Good Clinical Practice guidelines and the Declaration of Helsinki. 13It was approved by the UK Medicines and Healthcare Products Regulatory Agency.Research ethics approval was gained from East Midlands-Derby Research Ethics Committee, and the trial was overseen by an independent data monitoring committee.This report follows the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline. 14The trial protocol can be found in Supplement 1.

Randomization, Blinding, and Interventions
Patients were randomly assigned equally to 1 of 4 groups: oral selenium (200 μg/d of high selenium yeast, 364% recommended daily allowance 15 ) and matched vitamin E placebo, vitamin E (200 IU/d D-alfa-tocopherol, 600% recommended daily allowance 16 ) and matched selenium placebo, selenium and vitamin E, or placebo and placebo.Treatment allocations were blinded.Randomization was stratified by recurrence risk group (high vs low or intermediate 17 ) and treatment center.Patients took 1 tablet (selenium or placebo) and 1 capsule (vitamin E or placebo) once daily with food for up to 5 years.Patients were otherwise treated according to contemporaneous European Association of Urology guidelines. 17Patients attended a SELENIB follow-up clinic every 6 months for up to 5 years after randomization during which treatment adherence, toxic effects, and disease status were recorded.

Outcomes
The primary outcome was recurrence-free interval (RFI), measured as the time from study entry to recurrence.For patients without recurrence at the time of analysis, the interval was censored at the date the patient was last known to be recurrence free.Recurrences at the first 3-month cystoscopy checkup were excluded.Secondary outcome measures included progression-free interval and overall survival (eMethods in Supplement 2).Quality of life was assessed at each follow-up visit.

Statistical Analysis
The primary hypothesis was addressed on an intention-to-treat basis.As a 2 × 2 factorial design, analysis consisted of 2 comparisons: (1) those patients randomized to selenium vs those randomized to the associated placebo, stratifying by vitamin E allocation; and (2) those patients randomized to vitamin E vs those randomized to the associated placebo, stratifying by selenium allocation.
Interaction was not expected.Treatment groups were compared by Kaplan-Meier estimates of recurrence-free and progression-free interval; log-rank tests were used to test the hypothesis of no difference between treatments.Hazard ratios (HRs) from Cox proportional hazards regression models compared treatments, both unadjusted and adjusted for known prognostic factors.Similar methods were used for secondary outcomes.These analyses were completed on November 28, 2022.
All tests used a 2-sided P < .05 to indicate statistical significance, and all analysis was performed in R software, version 4.2.0 (R Foundation for Statistical Computing) using lmtest, survival, survminer and cowplot, ggplot2, and RColorBrewer for graphs.

Participants
The study randomized 270 patients (mean [SD] age, 68.9 [10.4]  receiving vitamin E and selenium placebo, 69 receiving selenium and vitamin E, and 65 receiving both placebos (Figure 1).Baseline characteristics are shown in the Table .A total of 256 (95%) of all tumors were pure transitional cell carcinomas, and 226 (84%) had papillary morphology (eTable 1 in Supplement 2).The trial failed to recruit to its prespecified target of 515 patients and was halted because of slow accrual.Two hundred twenty-eight patients were followed up for more than 5 years.

Treatment
Across 3 approaches to assess adherence (returned tablets or capsules, diary, and patient recollection), the median percentage of days taking trial treatment was more than 95% (IQR, 90%-99%) (eTables 2 and 3 in Supplement 2).The median treatment duration was 1.5 years (IQR, 0.9-2.5 years).Of 270 participants, 264 (98%) had more than 3 years of follow-up or died within 3 years of randomization.Standard-of-care treatments received by participants are detailed in eTables 4 to 6 in Supplement 2.

Primary Outcome
Of 122 recurrences, 60 (49%) occurred in the selenium arm and 62 (51%) in the placebo arm.For selenium, there was no statistically significant difference in RFI (HR, 0.92; 95% CI, 0.65-1.31;P = .65);median RFI was not reached in either arm (Figure 2A).Of the recurrences, 72 (59%) occurred in the vitamin E arm and 50 (41%) in the placebo arm.Vitamin E was associated with a statistically significant decrease in RFI (HR, 1.46; 95% CI, 1.02-2.09;P = .04);median RFI was 3.3 years (IQR, 0.89 years to not reached) for vitamin E and was not reached for the placebo arm (Figure 2B).
Recurrence-free survival estimates at yearly intervals for each treatment comparison are shown in eTable 10 in Supplement 2. We observed a 13% difference in RFI at 5 years for placebo vs vitamin E (59.6% vs 46.5%), with the study originally designed for an absolute difference of 12% at 5 years.
Adjusted analyses of the primary outcome were also undertaken (eTables 11 and 12 in Supplement 2).

Secondary Outcomes
Overall, 37 patients had disease progression; no significant differences in progression-free interval were observed with selenium or vitamin E (Figure 3).Fifty-three patients died, and no significant  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.
differences in overall survival were observed with either selenium or vitamin E (Figure 4).No significant differences in quality of life were observed between the arms (eFigure in Supplement 2).

Discussion
We observed no benefit of selenium for recurrence, progression, or overall survival in patients with NMIBC.We observed an association between vitamin E supplementation and an increased risk of recurrence but no association with progression or overall survival.The assumptions of the factorial trial design were demonstrated to be correct.The randomization used contemporary risk categorization as a stratification factor; over time, risk categorization has changed. 3,17For enabling  8) 112 ( 12) 108 ( 15) 102 ( 16) 92 ( 16) 134 (0) 124 ( 8) 115 (11)  106 (17)  98 (20) 76 (20) 130 (0) 120 ( 7) 108 ( 11) 101 ( 15) 95 ( 17) 77 ( 17) 140 (0) 129 ( 9) 119 ( 12) 113 ( 17) 105 (19)  91 (19)   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.3) 120 ( 13) 119 ( 14) 113 ( 16) 100 (20) 134 (0) 132 ( 1) 124 ( 7) 119 ( 12) 114 ( 13) 91 (17)   130 (0) 126 ( 2) 114 ( 12) 109 ( 17) 105 ( 17) 84 ( 21) 140 (0) 138 ( 2) 130 ( 8) 129 ( 9) 122 ( 12) 107 ( 16) 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.

Figure 4
Figure 4. Overall Survival Analysis

Table . Baseline
Characteristics of the Study Participants a a Data are presented as number (percentage) of patients unless otherwise indicated.Baseline risk groups are not the same as those used for stratification.bIncalculatingbaselinerisk group, carcinoma in situ is assumed absent if not confirmed present.JAMA Network Open | OncologySelenium and Vitamin E for Non-Muscle-Invasive Bladder Cancer JAMA Network Open.2023;6(10):e2337494. doi:10.1001/jamanetworkopen.2023.37494(Reprinted) October 17, 2023 4/10 Downloaded From: https://jamanetwork.com/ on 10/22/2023 intervention of the COVID-19 pandemic, ongoing follow-up beyond this time point became unfeasible.All patients are included in the analysis.

com/ on 10/22/2023 up
Selenium and Vitamin E for Non-Muscle-Invasive Bladder Cancer -to-date risk categorization and applicability to current practice, data were collected on each of the contributory factors.SELENIB is, to our knowledge, the first trial to investigate the use of selenium and vitamin E for preventing recurrence and progression in patients newly diagnosed with NMIBC.In 2011, the Selenium and Vitamin E Cancer Prevention Trial (SELECT) concluded that dietary supplementation with vitamin E (400 IU/d all-rac-α-tocopheryl acetate) significantly increased the risk of prostate This study has some limitations, including the fact that patient accrual fell below the intended 515 due to an unexpectedly high proportion of ineligible patients, the elderly age of the patient population with accompanying comorbidities and medication, and the proposed trial duration.Furthermore, trial funding was withdrawn in 2010, resulting in the decision to end recruitment and treatment in 2011.Consequently, study participants received considerably less selenium and vitamin E than intended, and 245 fewer patients than required were recruited; thus, these analyses are underpowered.In this randomized clinical trial of selenium and vitamin E in patients with newly diagnosed NMIBC, selenium supplementation did not reduce the risk of disease recurrence, whereas vitamin E supplementation was associated with an increased risk of recurrence.Neither selenium nor vitamin E influenced progression or overall survival.These findings suggest that vitamin E supplementation may be harmful to patients with NMIBC, and elucidation of the underlying biology is required.Tumour Pathology of Patients Within the SELENIB Trial eTable 2. Trial Treatment Compliance eTable 3. Trial Treatment Duration eTable 4. Overview of Standard Treatments Received by Patients Within the SELENIB Trial eTable 5. Intravesical BCG Treatment Received by Patients Within the SELENIB Trial eTable 6. Intravesical Chemotherapy Received by Patients Within the SELENIB Trial eTable 7. Adverse Events by CTCAE Grade eTable 8. Adverse Events Occurrence and Incidence During the SELENIB Trial eTable 9. Serious Adverse Events Occurrence and Incidence During the SELENIB Trial eTable 10.Recurrence-Free Survival Estimates at Yearly Intervals for Each Treatment Comparison eTable 11.Recurrence-Free Interval Cox Model Estimates Adjusted for Prognostic Factors eTable 12. Recurrence-Free Interval Cox Model Estimates Adjusted for EAU Risk Group eFigure.Quality-of-Life Analysis eReferences JAMA Network Open | Oncology Selenium and Vitamin E for Non-Muscle-Invasive Bladder Cancer JAMA Network Open.2023;6(10):e2337494. doi:10.1001/jamanetworkopen.2023.37494(Reprinted) October 17, 2023 6/10 Downloaded From: https://jamanetwork.JAMA Network Open.2023;6(10):e2337494. doi:10.1001/jamanetworkopen.2023.37494(Reprinted) October 17, 2023 9/10 Downloaded From: https://jamanetwork.com/ on 10/22/2023