Stratton et al. (2010): Oral Selenium Supplementation Has No Effect on Prostate- Specific Antigen Velocity in Men Undergoing Active Surveillance for Localized Prostate Cancer

Reference ↗
Title	Oral Selenium Supplementation Has No Effect on Prostate-Specific Antigen Velocity in Men Undergoing Active Surveillance for Localized Prostate Cancer
Topic	Selenium
Author	Stratton, MS, Algotar, AM, Ranger-Moore, J, Stratton, SP, Slate, EH, Hsu, CH, Thompson, PA, Clark, LC, Ahmann, FR
Year	2010
Journal	Cancer prevention research
DOI	https://doi.org/10.1158/1940-6207.CAPR-09-0143

Brief summary

In this study, data from 140 men with low-grade non-metastatic prostate cancer were included, who had decided against active therapy and instead opted for a watchful waiting therapy. The participants were randomly assigned to three arms, in which they received either 200 μg or 800 μg of selenium daily, or a placebo. The study investigated whether the PSA value, as an indicator for the development and thus worsening of the participants' prostate cancer, changed over the following years. After five years, no difference in the PSA value was found between the arms. Neither between the selenium arms and the placebo arm, nor between the two selenium arms. It was only shown that men who already had a high selenium plasma level at the start of the study and then took 800 μg daily over the course of the study showed a significantly higher PSA value after five years compared to the placebo arm. However, this is a very small subgroup of the original sample, so the result should be interpreted with caution. Overall, the study shows great statistical and planning care, but fails to provide important information about the randomization and blinding process, which could call the study's framework into question. It is also noteworthy that the selenium concentration of the participants at baseline was already on average (SD) 134.5 (41.5) ng/mL, which is considered very high. Therefore, a dose of 200 or even 800 μg daily can be considered an overdose of selenium.

In dieser Studie wurden die Daten von 140 Männern mit niedrig-gradigem nicht metastasierendem Prostatakrebs eingeschlossen, welche sich gegen eine aktive Therapie und stattdessen für eine abwartende Überwachungs-Therapie entschieden haben. Die Probanden wurden zufällig in drei Gruppen eingeteilt, in derer sie entweder täglich 200 μg oder 800 μg Selen bekamen, oder ein Placebo. Untersucht wurde, ob sich der PSA Wert, als Indikator für die Entwicklung und damit Verschlechterung des Prostatakrebses der Probanden über die kommenden Jahre verändert. Nach fünf Jahren konnte zwischen den Gruppen kein Unterschied bezüglich der Höhe des PSA-Wertes festgestellt werden. Weder zwischen den Selen-Gruppen und der Placebo-Gruppe, noch zwischen den beiden Selen-Gruppen. Es konnte nur gezeigt werden, dass Männer, welche schon zu Beginn der Studie einen hohen Selen-Plasma-Wert hatten und dann über die Zeit der Studie täglich 800 μg zu sich nahmen nach fünf Jahren einen bedeutsam höheren PSA-Wert aufzeigten als die Placebo-Gruppe. Doch hier handelt es sich um eine sehr kleine Untergruppe der ursprünglichen Stichprobe, weshalb das Ergebnis mit Vorsicht zu interpretieren ist. Insgesamt wartet die Studie mit großer statistischer und planungsmäßiger Sorgfalt auf, versäumt hingegen wichtige Informationen über den Randomisierungs- und Verblindungsprozess zu liefern, womit die Rahmenbedingungen der Studie in Frage gestellt werden könnten. Es zudem anzumerken, dass die Selenkonzentration der Probanden zur Baseline bereits im Mittel (SD) bei 134.5 (41.5) ng/mL lag, was schon als sehr hoch anzusehen ist. Wodurch eine Gabe von 200 oder sogar 800µg täglich als eine Überdosierung von Selen zu werten ist.

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	3

Study characteristics

Inclusion criteria	Biopsy-proven localized (nonmetastatic) prostate cancer documented within 48 months before enrolling in the trial, Gleason score of <8, serum PSA level of <50 ng/mL, age <85 years, life expectancy of ≥3 years, elected to forgo front-line therapy and chose to be followed by active surveillance, limited daily selenium supplementation to no more than 50 μg from non-study sources
Exclusion criteria	NI
N randomized	140
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.	ITT Analysis
Specifications on analyses	NI
Countries of data collection	United States
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	Baseline; then every 3 months for 5 years

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.	Active surveillance
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Prostate 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
Specifications on cancer stages	Biopsy-proven localized (nonmetastatic) prostate cancer
Comorbidities	NI
Current cancer therapies	Active surveillance
Specifications on cancer therapies	NA
Previous cancer therapies	NI
Gender	Male
Gender specifications	100% male
Age groups	Adults (18+)
Age groups specification	Mean: 72.8 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	47
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	38
Drop-out reasons	9 completed study; 18 reached study endpoint, 7 on study at study end, 2 died, 2 concurrent illness, 4 withdrew for reasons not study-related, 5 withdrew for other study-related reasons
Intervention	Selenium
Dosage and regime	200 μg selenium per day (yeast selenium); Follow-up duration (mean (SD); median): 33.4 (20.3); 33.3 years
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.	1.826
Side effects / Interactions	The incidences of brittle hair and brittle nail (grade 1 or 2 and possibly, probably, or definitely related to the intervention) were 6 (12.8%) and the incidences of garlic breath and liver/kidney function test abnormalities (grade 1 and possibly, probably, or definitely related to the intervention) were 0 (0.0%), no significant difference between 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	47
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	12 completed study; 13 reached study endpoint, 6 on study at study end, 2 died, 2 concurrent illness, 6 withdrew for reasons not study-related, 6 withdrew for other study-related reasons
Intervention	Selenium
Dosage and regime	800 μg selenium per day (yeast selenium); Follow-up duration (mean (SD); median): 33.3 (23.3); 33.8 years
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.	1.826
Side effects / Interactions	The incidences of brittle hair and brittle nail (grade 1 or 2 and possibly, probably, or definitely related to the intervention) were 8 (17.0%) and the incidences of garlic breath and liver/kidney function test abnormalities (grade 1 and possibly, probably, or definitely related to the intervention) were 4 (8.5%); no significant difference between the arms

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	46
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	38
Drop-out reasons	8 completed study; 14 reached study endpoint, 14 on study at study end, 1 died, 2 concurrent illness, 4 withdrew for reasons not study-related, 3 withdrew for other study-related reasons
Intervention	Placebo
Dosage and regime	Placebo; Follow-up duration (mean (SD); median): 36.3 (20.7); 38.4 years
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.	1.826
Side effects / Interactions	The incidences of brittle hair and brittle nail (grade 1 or 2 and possibly, probably, or definitely related to the intervention) were 10 (21.7%) and the incidences of garlic breath and liver/kidney function test abnormalities (grade 1 and possibly, probably, or definitely related to the intervention) were 5 (10.9%), no significant difference between arms

Outcomes

PSA level (Prostate-Specific Antigen)

Outcome type As specificed by the authors	Primary
Outcome specification	Change over 5 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".	After 5 years: selenium arms not significantly different to placebo arm (p=0.32 and p=0.61) or to each other Subgroup of high-selenium arm with high selenium value at baseline shows higher PSA values than placebo arm (p=0.018)

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	NA
Overall RoB judgment	some concerns

Funding and Conflicts of Interest

Funding	“Public Health Service grants CA079080 and CA023074. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.“
Conflicts of Interest	According to authors, no conflict of interest

Further points for assessing the study

Sample

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

Alternative Explanation

Other explanations for an effect besides the investigated intervention	No
- Possibility of attention effects	NA
- Possibility of placebo effects	NA
- Other reasons	NA

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	Yes
Correction for multiple testing	NA
Measurement of compliance	Yes
Consistent reporting in numbers (figures, flowchart, abstract, results)	Yes
Comprehensive and coherent reporting	Yes
Cross-over	No
- Sufficient washout period	NA
- Tested for carry-over effects	NA
- Tested for sequence effects	NA

Interpretation of results

Effect sizes reported (clinical vs. statistical significance)	No
Side effects systematically recorded	Yes
Side effects considered in result interpretation	Yes
Ethics votum	Yes

Additional Notes

PRO:

• Ethics approval obtained.
• Participants were tested for 30 days to assess adherence to the intake protocol before randomization.
• Only those with over 80% adherence were randomized.
• Extensive prior questioning and recording of all medical factors related to potential selenium risk.
• Detailed information on expected side effects provided.
• Use of a "Data and Safety Monitoring Committee" to monitor protocols, side effects, etc.
• Intent-to-treat analysis conducted.
• Adequate and participant-adjusted analysis considering: Duration of participation in the study, Skin color, Baseline plasma selenium, Age, BMI, Nicotine consumption, PSA assay, Gleason score
• Power analysis performed.
• Arm comparability achieved except for BMI, which was adjusted in the analysis.

CONTRA:

• Participants could still take 50 μg of selenium outside of the study.
• Unclear if baseline blood samples were taken before the test run of pill intake.
• Baseline selenium differences between arms with p=0.07 were already close to significance.
• The 800 μg selenium arm had a significantly higher descriptive level at 146 ng/mL compared to 128 ng/mL in the placebo arm.
• Unclear randomization and blinding process.
• Analysis of a subgroup from the 800 μg selenium arm resulted in very few participants.