Reference ↗
Title	Phase III randomised chemoprevention study with selenium on the recurrence of non-invasive urothelial carcinoma. The SELEnium and BLAdder cancer Trial
Topic	Selenium
Author	Goossens, ME, Zeegers, MP, van Poppel, H, Joniau, S, Ackaert, K, Ameye, F, Billiet, I, Braeckman, J, Breugelmans, A, Darras, J, Dilen, K, Goeman, L, Tombal, B, Van Bruwaene, S, Van Cleyenbreugel, B, Van der Aa, F, Vekemans, K, Buntinx, F
Year	2016
Journal	European journal of cancer
DOI	https://doi.org/10.1016/j.ejca.2016.09.021

Study Note

Brief summary

In this study, 292 subjects with non-invasive bladder cancer were divided into two groups and given either daily selenium or a placebo for around 3 years. The effects on the return of the cancer or its progression were relevant. The results show no significant differences between the two groups with regard to these points. Also, controlling the analysis performed for key demographic variables or excluding patients who had left the study made no difference. Overall, the percentage for recurrence and progression was very low and thus remained below the expected figures, which, together with the statistically insufficiently large sample, may well have contributed to the fact that a possible effect could not be found. Overall, the study is convincing with its high methodological quality, a very detailed description of the procedure, a very careful execution of the study and the testing of the subjects' selenium concentration at the beginning and end of the study.

In dieser Studie wurden 292 Probanden mit einem nichtinvasivem Harnblasenkarzinom in zwei Gruppen eingeteilt und es wurde ihnen über etwa 3 Jahre entweder täglich Selen gegeben oder sie bekamen ein Placebo. Relevant waren die Auswirkungen auf die Rückkehr der Krebserkrankung oder dessen Fortschreiten. Die Ergebnisse zeigen bezüglich dieser Punkte keine bedeutsamen Unterschiede zwischen den beiden Gruppen. Auch eine Kontrolle der durchgeführten Analyse für wichtige demographische Variablen oder den Ausschluss von Patienten, die die Studie verlassen hatten, machte keinen Unterschied. Insgesamt war der Prozentsatz für das Wiederauftreten und die Progression sehr gering und blieb damit unter den erwarteten Zahlen, was zusammen mit der statistisch nicht ausreichend großen Stichprobe durchaus dazu beigetragen haben könnte, dass ein möglicherweise vorhandener Effekt nicht gefunden werden konnte. Insgesamt überzeugt die Studie mit hoher methodischer Qualität, einer sehr detaillierten Beschreibung des Ablaufs, einer sehr sorgfältigen Durchführung dieser, sowie durch die durchgeführte Testung der Selenkonzentration der Probanden zu Beginn und Ende der Studie.

Study Design

Prospective / Retrospective Prospective: forward-looking, examples include clinical trials, cohort studies, and long-term observational studies;</br>Retrospective: backward-looking, relying on existing data, examples include case-control studies and retrospective cohort studies	Prospective
Monocentric / Multicentric Monocentric: conducted in one center/ hospital; </br>Multicentric: conducted in multiple centers/ hospitals	Multicentric
Blinding No: Open, all parties are aware of group assignments;</br>Single: one party is unaware of group assignments (generally participants);</br>Double: two parties are unaware of group assignments (generally the participants and the researchers); </br>Triple: concealing group assignment from additional parties	Double
Is randomized	Yes
Cross-over Participants alternate between different treatment groups or conditions over a specified period, allowing each participant to serve as their own control	No
Number of arms	2

Study characteristics

Inclusion criteria	underwent a transurethral resection (TUR) for a histologically confirmed low-grade or high-grade non-invasive urothelial carcinoma (transitional cell carcinoma of the bladder), stage Ta, T1, or carcinoma in situ (Tis)
Exclusion criteria	history of any type of malignancy within the past five years and other serious medical or psychiatric illness that would preclude giving informed consent
N randomized	292
Analysis PP: Per Protocol analysis, i.e. only participants included who adhered to the study protocol.</br>ITT: Intention-to-treat analysis, i.e. all randomized participants included regardless of any drop-outs or changes in assignment.</br>mITT: modified Intention-to-treat analysis can refer to analyses in which participants with missing outcome data are excluded or it can refer to analyses in which only participants who received at least one treatment dose are included. In this case, participants dropped out of the study prematurely for reasons unrelated to the treatment.	PP Analysis, ITT Analysis
Specifications on analyses	Evaluated ITT n=292, PP n=259 Sensitivity analysis n=216
Countries of data collection	Belgium
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	described unclear

Characteristics of participants

Setting Refers to cancer therapy setting.</br>- Curative therapy: aims to completely eradicate a disease and achieve a full recovery; </br>- Neo-adjuvant therapy: form of curative therapy, given before the primary treatment for cancer (usually surgery); </br>- Adjuvant therapy: form of curative therapy, given after the primary treatment for cancer (usually surgery); </br>- Palliative therapy: focuses on providing relief from symptoms and improving the quality of life for patients, without necessarily targeting the underlying disease; </br>- Active surveillance: involves close monitoring of disease progression without any intervention (typically used for prostate cancer);</br>- No therapy setting: Patients who completed therapy/are currently not in cancer treatment, cancer survivors.	No therapy setting
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Genitourinary Cancers - Bladder Cancer
Cancer stages Early Stage: generally refers to cancer that is localized to the area where it started, mostly stages I and II;</br>Advanced Stage: cancer that has spread beyond its original site, mostly stages III and IV, with stage IV indicating distant metastasis	Early Stage, Advanced Stage
Specifications on cancer stages	Transurethral resected urinary bladder carcinoma (non-invasive urinary bladder carcinoma, Ta, T1, Tis)
Comorbidities	NI
Current cancer therapies	No therapy
Specifications on cancer therapies	NA
Previous cancer therapies	Surgery
Gender	Mixed
Gender specifications	Female intervention arm: 13.2%, placebo arm: 21.3%
Age groups	Adults (18+)
Age groups specification	Median; range: 68; 46-90 years

Arms

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Intervention
Number of participants (arm) N randomized	151
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	41
Drop-out reasons	3 months follow-up: randomized in error, not meeting inclusion criteria n=6, death n=1, withdrew consent n=8; Follow-up over 3 years: adverse events n=2, withdrew consent n=24
Intervention	Selenium yeast (selenium-enriched yeast)
Dosage and regime	200 µg 1x per day, orally
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	1.095
Side effects / Interactions	Not separated between arms: Unclear cause: n=13 cystectomy (intervention arm: n=6, placebo arm: n=7), n=23 deceased (intervention arm: n=13, placebo arm: n=10); Report of side effects: intervention arm: n=7 and placebo arm: n=10, all grade 1 except n=1, grade 2 pain in the intervention arm; side effects were change in nails, back and neck pain, constipation, sleep disturbances, dizziness, and arthralgia, with one n=1 patient reporting nausea, pain, and stomach problems and another patient dizziness and diarrhea

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Placebo
Number of participants (arm) N randomized	141
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	35
Drop-out reasons	3 months follow-up: randomized in error, not meeting inclusion criteria n=10, cystectomy n= 3, withdrew consent n=5; Follow-up over 3 years: reccurence n=1, adverse events n=2, withdrew consent n=14
Intervention	Placebo
Dosage and regime	1x per day
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	1.095
Side effects / Interactions	Not separated between arms: Unclear cause: n=13 cystectomy (intervention arm: n=6, placebo arm: n=7), n=23 deceased (intervention arm: n=13, placebo arm: n=10); Report of side effects: intervention arm: n=7 and placebo arm: n=10, all grade 1 except n=1, grade 2 pain in the intervention arm; side effects were change in nails, back and neck pain, constipation, sleep disturbances, dizziness, and arthralgia, with one n=1 patient reporting nausea, pain, and stomach problems and another patient dizziness and diarrhea

Outcomes

RFS (Recurrence-Free Survival)

Outcome type As specificed by the authors	Primary
Outcome specification	NA
Type of measurement	Observation
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	ITT: intervention arm n=43 (28%; 95% CI: 0.21, 0.35) and placebo arm n=45 (32%; 95% CI: 0.24, 0.40); HR: 0.85 (95% CI: 0.56, 1.29); p=0.44, not significant PP: (all participants remaining in the study after 3 months): intervention arm n=42 and placebo arm n=39 (28%; 95% CI: 0.20, 0.35); HR: 0.96 (95% CI: 0.62, 1.48)); p=0.85, not significant No influence of age, gender, nicotine consumption, stage, selenium concentration at baseline and hospital

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	low risk
Bias due to deviation from intended intervention (assignment to intervention)	low risk
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	low risk
Bias in measurement of the outcome	some concerns
Bias in selection of the reported result	low risk
Other sources of bias	low risk
Overall RoB judgment	some concerns

PFS (Progression-Free Survival)

Outcome type As specificed by the authors	Secondary
Outcome specification	NA
Type of measurement	Observation
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Remark: After 3 months: progression in 24 patients, median progression time 22 months in both arms; Patients in intervention arm had 48% more chance of progression than those in the placebo arm, but not statistically significant (HR = 1.48 (95% CI: 0.65, 3.38); p=0.35); Progression in the intervention arm 15x, placebo arm 14x ITT: HR: 0.97 (95% CI: 0.47, 2.00); p=0.93, not significant

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	low risk
Bias due to deviation from intended intervention (assignment to intervention)	low risk
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	low risk
Bias in measurement of the outcome	some concerns
Bias in selection of the reported result	low risk
Other sources of bias	low risk
Overall RoB judgment	some concerns

Selenium level

Outcome type As specificed by the authors	Others
Outcome specification	Measured at baseline and after 3 years
Type of measurement	Blood Test
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Significant difference in selenium concentration after 3 years (n=67 (55%)): 187.6 mg/dl ± 57.7 mg/dl intervention arm vs. 88.9 mg/dl ± 22.2 mg/dl placebo arm; p=0.00

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	low risk
Bias due to deviation from intended intervention (assignment to intervention)	low risk
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	low risk
Bias in measurement of the outcome	some concerns
Bias in selection of the reported result	low risk
Other sources of bias	low risk
Overall RoB judgment	some concerns

Funding and Conflicts of Interest

Funding	“The SELEBLAT study was funded by an unconditional grant of the Agency for Innovation by Science and Technology Belgium (IWT) (project IWT 70699). (…) Drugs were supplied by PharmaNord, Vojens, Denmark and prepared according to the principles of good manufacturing practice (GMP).”
Conflicts of Interest	According to authors, no conflict of interest

Further points for assessing the study

Sample

Power analysis performed	?
- Sample size corresponds to power analysis
- Reasons for insufficient sample size based on power analysis
If no power analysis performed: at least moderate sample size (n >= 30 per arm)	?
Ethnicity mentioned	?

Alternative Explanation

Other explanations for an effect besides the investigated intervention
- Possibility of attention effects	?
- Possibility of placebo effects	?
- Other reasons	?

Statistics

Correct use of parametric and non-parametric tests Testing for normal distribution only necessary if parametric tests are used, NI: use of parametric tests without report of normal distribution testing
Correction for multiple testing	?
Measurement of compliance	?
Consistent reporting in numbers (figures, flowchart, abstract, results)	?
Comprehensive and coherent reporting	?
Cross-over
- Sufficient washout period	?
- Tested for carry-over effects	?
- Tested for sequence effects	?

Interpretation of results

Effect sizes reported (clinical vs. statistical significance)	?
Side effects systematically recorded	?
Side effects considered in result interpretation	?
Ethics votum	?

Additional Notes

PRO: Ethics approval obtained, intention-to-treat analysis and per-protocol analysis, placebo-controlled and double-blind, blinding tested with final survey, compliance checked by counting tablets, baseline selenium level measurement, power analysis, very detailed description of criteria for endpoints and cancer stage, inclusion of key demographic variables in the analysis, use of an external review committee, testing of selenium concentration difference at the end of the study

CONTRA: Sample size not adequate according to the power analysis, timeline in the study unclear: T0 is study entry and T3 is after 3 months, is there a T2?, follow-up time averaged 1½ years, this is not explained, it should have been 3 years, no information on the current treatment of patients

Additional Notes