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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
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
| Original language | English |
|---|---|
| Article number | e2337494 |
| Number of pages | 10 |
| Journal | JAMA network open |
| Volume | 6 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - 17 Oct 2023 |
Bibliographical note
Funding/Support:The SELENIB study and the Bladder Cancer Prognosis Programme were funded by grant C1343/A5738 from the Cancer Research UK, the University of Birmingham, and the Birmingham & The Black Country and West Midlands North & South Comprehensive Local Research Networks. Staff at the Cancer Research UK Clinical Trials Unit are supported by core funding grant C22436/A25354 from Cancer Research UK. Pharma Nord provided the study drugs free of charge.
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- 2 Finished
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Cancer Research UK Clinical Trials Unit, Birmingham - Adult Unit
Bach, S. (Co-Investigator), Bowden, S. (Co-Investigator), Craddock, C. (Co-Investigator), Rea, D. (Co-Investigator), Kearns, P. (Principal Investigator), Wheatley, K. (Co-Investigator), Billingham, L. (Co-Investigator) & Steven, N. (Co-Investigator)
1/10/18 → 30/09/23
Project: Research
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Recurrence and Progression of Non-Muscle-Invasive Bladder Cancer
Cheng, K. (Principal Investigator), Zeegers, M. (Co-Investigator), James, N. (Co-Investigator), Billingham, L. (Co-Investigator), Hussain, S. (Co-Investigator) & Murray, P. (Co-Investigator)
Cancer Research UK, NIHR, DUDLEY GROUP OF HOSPITALS
1/05/05 → 31/08/11
Project: Research