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|Reference=Publication: Effect of Selenium on Incidence and Severity of Mucositis during Radiotherapy in Patients with Head and Neck Cancer
|Reference=Publication: Effect of Selenium on Incidence and Severity of Mucositis during Radiotherapy in Patients with Head and Neck Cancer
}}
}}
{{Study Note}}
=Brief summary=
=Brief summary=
In this study, 84 patients with pre-existing head and neck tumours were included. These patients were randomly divided into two groups. One group (37 patients) received 400 micrograms of selenium daily while the other group (34 patients) received placebo tablets. Both groups received the regular combined radiochemotherapy in addition to the tablets. The occurrence of inflammation of the oral mucosa, which is a common side effect of radiochemotherapy, was investigated. For this purpose, both the blood selenium level and the current condition of the oral mucosa were recorded at the beginning of the study. While taking the tablets, the oral cavity was examined weekly and the degree of inflammation of the mucous membranes was assessed. No significant difference was found between the two groups with regard to the occurrence of oral mucosal inflammation. No differences between the selenium levels of the two groups were found at the end of the study either. Overall, the study had a small number of participants and the number of patients included in the final analysis is not clearly presented.  
In this study, 84 patients with pre-existing head and neck tumours were included. These patients were randomly divided into two arms. One arm (37 patients) received 400 micrograms of selenium daily while the other arm (34 patients) received placebo tablets. Both arms received the regular combined radiochemotherapy in addition to the tablets. The occurrence of inflammation of the oral mucosa, which is a common side effect of radiochemotherapy, was investigated. For this purpose, both the blood selenium level and the current condition of the oral mucosa were recorded at the beginning of the study. While taking the tablets, the oral cavity was examined weekly and the degree of inflammation of the mucous membranes was assessed. No significant difference was found between the two arms with regard to the occurrence of oral mucosal inflammation. No differences between the selenium levels of the two arms were found at the end of the study either. Overall, the study had a small number of participants and the number of patients included in the final analysis is not clearly presented.  
 


In dieser Studie wurden 84 Patienten mit bereits bestehenden Kopf-Hals-Tumoren eingeschlossen. Diese Patienten wurden zufällig in zwei Gruppen eingeteilt. Die eine Gruppe (37 Patienten) erhielt täglich 400 Mikrogramm Selen während die andere Gruppe (34 Patienten) Placebotabletten bekam. Beide Gruppen erhielten neben den Tabletten die reguläre kombinierte Radiochemotherapie. Untersucht wurde das Auftreten von Entzündungen der Mundschleimhaut, welche eine häufige Nebenwirkung der Radiochemotherapie darstellt. Dazu wurden am Anfang der Studie sowohl der Blutselenspiegel als auch der aktuelle Zustand der Mundschleimhäute erhoben. Während der Einnahme der Tabletten wurde wöchentlich die Mundhöhle untersucht und der Grad der Schleimhautentzündung eingeschätzt. Es konnte kein bedeutsamer Unterschied zwischen den beiden Gruppen festgestellt werden, was das Auftreten von Mundschleimhautentzündungen betrifft. Auch konnten am Ende der Studie keine Unterschiede zwischen den Selenspiegeln der beiden Gruppen festgestellt werden. Die Studie hat insgesamt eine geringe Teilnehmeranzahl und die Anzahl der Patienten, die am Ende in die Analyse eingeschlossen wurden ist nicht nachvollziehbar dargestellt.
In dieser Studie wurden 84 Patienten mit bereits bestehenden Kopf-Hals-Tumoren eingeschlossen. Diese Patienten wurden zufällig in zwei Gruppen eingeteilt. Die eine Gruppe (37 Patienten) erhielt täglich 400 Mikrogramm Selen während die andere Gruppe (34 Patienten) Placebotabletten bekam. Beide Gruppen erhielten neben den Tabletten die reguläre kombinierte Radiochemotherapie. Untersucht wurde das Auftreten von Entzündungen der Mundschleimhaut, welche eine häufige Nebenwirkung der Radiochemotherapie darstellt. Dazu wurden am Anfang der Studie sowohl der Blutselenspiegel als auch der aktuelle Zustand der Mundschleimhäute erhoben. Während der Einnahme der Tabletten wurde wöchentlich die Mundhöhle untersucht und der Grad der Schleimhautentzündung eingeschätzt. Es konnte kein bedeutsamer Unterschied zwischen den beiden Gruppen festgestellt werden, was das Auftreten von Mundschleimhautentzündungen betrifft. Auch konnten am Ende der Studie keine Unterschiede zwischen den Selenspiegeln der beiden Gruppen festgestellt werden. Die Studie hat insgesamt eine geringe Teilnehmeranzahl und die Anzahl der Patienten, die am Ende in die Analyse eingeschlossen wurden ist nicht nachvollziehbar dargestellt.
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{{RCT study general properties
{{RCT study general properties
|Inclusion criteria=Patients with head and neck cancer, who were due to receive radiation on at least two-thirds of the oral cavity; aged 18-85 years with a normal renal function (creatinine clearence > 60ml/min) and an acceptable performance status (Karnofsky performance status > 70%) without any history of RT were eligible for this study
|Inclusion criteria=Patients with head and neck cancer, who were due to receive radiation on at least two-thirds of the oral cavity; aged 18-85 years with a normal renal function (creatinine clearence > 60ml/min) and an acceptable performance status (Karnofsky performance status > 70%) without any history of radiotherapy were eligible for this study
|Exclusion criteria=NI
|Exclusion criteria=NI
|N randomized=84
|N randomized=84
|Analysis=PP Analysis
|Analysis=PP Analysis
|Specifications on analyses=Occurrence, duration and severity of oral mucositis (WHO: grade 0-4, weekly check of oral status during RT, then monthly by doctor and an author)
|Specifications on analyses=Occurrence, duration and severity of oral mucositis (WHO: grade 0-4, weekly check of oral status during radiotherapy, then monthly by doctor and an author);
 
log rank analysis
log rank analysis
|Countries of data collection=Iran
|Countries of data collection=Iran
Line 32: Line 31:
|Outcome timeline=Oral mucositis
|Outcome timeline=Oral mucositis
T0: Baseline
T0: Baseline
Follow up: weekly for 7 weeks
Follow up: weekly for 7 weeks


Selenium level
Selenium level
T0: Baseline
T0: Baseline
T1: End of radiation
T1: End of radiation
}}
}}
Line 41: Line 44:


{{Characteristics of participants
{{Characteristics of participants
|Setting=NI
|Setting=Curative
|Types of cancer=Head and Neck Cancers
|Types of cancer=Head and Neck Cancers
|Stage cancer=NI
|Stage cancer=NI
Line 48: Line 51:
|Current cancer therapy=Chemotherapy, Radiation therapy
|Current cancer therapy=Chemotherapy, Radiation therapy
|Specifications on cancer therapies=* Radiation therapy: 5 fractions per week at 60-70 Gy cumulative doses over 6 weeks to 7 weeks   
|Specifications on cancer therapies=* Radiation therapy: 5 fractions per week at 60-70 Gy cumulative doses over 6 weeks to 7 weeks   
* Chemotherapy: 18 (48.6%) patients from the selenium group and 16 (47.1%) from the placebo group with cisplatin (30-50mg/m2 weekly, during radiation)
* Chemotherapy: 18 (48.6%) patients from the selenium and 16 (47.1%) from the placebo arm with cisplatin (30-50mg/m2 weekly, during radiation)
* Grade of neutropenia and renal failure was evaluated based on the NCI CTCAE
* Grade of neutropenia and renal failure was evaluated based on the NCI CTCAE
* Creatinine level increase of > 0.3 mg/dL or 1.5–2.0 mg/dL above baselinewas considered as renal failure and a neutrophil count decrease to 1000–500 mm3 was considered as grade 3 of this toxicity
* Creatinine level increase of > 0.3 mg/dL or 1.5–2.0 mg/dL above baselinewas considered as renal failure and a neutrophil count decrease to 1000–500 mm3 was considered as grade 3 of this toxicity
* After 7 weeks no differencences in the incidence of other adverse effects related to chemoradiation such as neutropenia and renal failure in the selenium group and the placebo group
* After 7 weeks no differencences in the incidence of other adverse effects related to chemoradiation such as neutropenia and renal failure in the selenium arm and the placebo arm
|Previous cancer therapies=NI
|Previous cancer therapies=NI
|Gender=Mixed
|Gender=Mixed
|Gender specifications=Male n(%) per group:
|Gender specifications=Male n(%) per arm:
selenium group: 25 (67.9), placebo group: 25 (73.5)
Selenium arm: 25 (67.9), placebo arm: 25 (73.5)
 


Female n(%) per group:
Female n(%) per arm:
selenium group: 12 (32.1), placebo group: 9 (26.5)
Selenium arm: 12 (32.1), placebo arm: 9 (26.5)
|Age groups=Adults (18+)
|Age groups=Adults (18+)
|Age groups specification=Age in years, mean (min-max) per group:
|Age groups specification=Age in years, mean (min-max) per arm:
selenium group: 52.14 (22-81), placebo group: 54.74 (18-81)
Selenium arm: 52.14 (22-81), placebo arm: 54.74 (18-81)
}}
}}
=Arms=
=Arms=
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|Number of participants (arm)=42
|Number of participants (arm)=42
|Drop-out=9
|Drop-out=9
|Drop-out reasons=Did not receive allocated intervention (not to accept contributing) (n=1)
|Drop-out reasons=Did not receive allocated intervention (not to accept contributing): n=1
Lost to follow-up: discontinued tablets (n=1); discontinued radiation due to individual preferences (n=4)
Lost to follow-up: discontinued tablets (n=1); discontinued radiation due to individual preferences: n=4


Inconsistencies in the number of drop-outs in the Selenium group: flowchart reports analyzed n=33 from n=42, but only reports drop-out reasons for n=6 (reasons missing n=3); table of baseline characteristics reports data of n=37
Inconsistencies in the number of drop-outs in the selenium arm: flowchart reports analyzed n=33 from n=42, but only reports drop-out reasons for n=6 (reasons missing n=3); table of baseline characteristics reports data of n=37
|Intervention=Selenium  
|Intervention=Selenium  
+ all participants received: application of oral saline rinse and oral hygiene; dental status check before first treatment
+ all participants received: application of oral saline rinse and oral hygiene; dental status check before first treatment
Line 80: Line 84:
|Side Effects / Interactions=NI
|Side Effects / Interactions=NI
|Order number=1
|Order number=1
|Arm topic=Selenium
}}
}}
{{Arm
{{Arm
Line 85: Line 90:
|Number of participants (arm)=42
|Number of participants (arm)=42
|Drop-out=8
|Drop-out=8
|Drop-out reasons=Did not receive allocated intervention (not to accept contributing) (n=4)
|Drop-out reasons=Did not receive allocated intervention (not to accept contributing): n=4
Lost to follow-up: discontinued radiation due to individual preferences (n=4)
Lost to follow-up: discontinued radiation due to individual preferences: n=4
|Intervention=Placebo
|Intervention=Placebo
+ all participants received: application of oral saline rinse and oral hygiene; dental status check before first treatment
+ all participants received: application of oral saline rinse and oral hygiene; dental status check before first treatment
|Dosage and regime=2x placebo tablets daily from the first day until the end of radiation (including days without radiation exposure)
|Dosage and regime=2x placebo tablets daily from the first day until the end of radiation (including days without radiation exposure)
|One-time application=No
|One-time application=No
|Duration in days=49
|Duration in days=49
|Side Effects / Interactions=NI
|Side Effects / Interactions=NI
|Order number=2
|Order number=2
|Arm topic=Selenium
}}
}}
{{Arm Overview}}
{{Arm Overview}}
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|Outcome name=Mucositis
|Outcome name=Mucositis
|Outcome specification=Inflammation of the oral mucosa (mucositis) due to radiotherapy
|Outcome specification=Inflammation of the oral mucosa (mucositis) due to radiotherapy
|Type of measurement=WHO-Scale (World Health Organisation)
|Results during intervention=Significant difference for incidence of severe mucositis at week 3: selenium arm 9.8% vs. placebo arm 42.0% (p=0.017)
|Results after intervention=After 7 weeks no significant differences between the selenium arm and the placebo arm for:
* mean duration of oral mucositis (grade 1–4) (p=0.27)
* onset of oral mucosits (p =0.31)
* recovery (day after radiation completion (p=0.80)
* cumulative incidence of oral mucusitis (grade 1–4) (p=0.79)


Grade of oral mucositis (WHO Toxicity Scale):
grade 0 = normal, no oral mucosits;
grade 1 = soreness and erythema;
grade 2 = erythema, ulcers, can eat solids;
grade 3 = ulcers, requires liquid diet only;
grade 4 = alimentation not possible


The assessments were performed by an assigned oral medicine specialist and one author, who were both blind to groups
Severe oral mucositis (grade 3 or 4) was seen in 25 patients in the selenium arm and in 20 patients in the placebo arm.
|Type of measurement=WHO-Scale (World Health Organisation)
|Results during intervention=Significant difference for incidence of severe mucositis at week 3: selenium group 9.8% vs. placebo group 42.0% (p=0.017)
|Results after intervention=After 7 weeks no significant differences between the selenium group and the placebo group for:
- mean duration of oral mucositis (grade 1–4) (p=0.27)
- onset of oral mucosits (p =0.31)
- recovery (day after radiation completion (p=0.80)
- cumulative incidence of oral mucusitis (grade 1–4) (p=0.79)


Severe oral mucositis (grade 3 or 4) was seen in 25 patients in the selenium group and in 20 patients in the placebo group.


Addition: Development of oral mucositis in patients with selenium levels >65 mcg/l significantly delayed from baseline (p=0.04, no further explanation given)
Addition: Development of oral mucositis in patients with selenium levels >65 mcg/l significantly delayed from baseline (p=0.04, no further explanation given)
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|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=some concerns
|Bias due to missing outcome data=some concerns
|Bias in measurement of the outcome=low risk
|Bias in measurement of the outcome=some concerns
|Bias in selection of the reported result=low risk
|Bias in selection of the reported result=some concerns
|Other sources of bias=low risk
|Other sources of bias=some concerns
|Overall RoB judgment=high risk
|Overall RoB judgment=high risk
|Order number=1
|Order number=1
|Outcome topic=Selenium
}}
}}
{{Outcome
{{Outcome
Line 138: Line 138:
|Type of measurement=GFAAS (Graphite Furnace Atomic Absorption Spectrometry)
|Type of measurement=GFAAS (Graphite Furnace Atomic Absorption Spectrometry)
|Results during intervention=NA
|Results during intervention=NA
|Results after intervention=At the end of radiation (after 7 weeks) there was no difference in the mean serum selenium level between the selenium group and placebo group (p=0.24)
|Results after intervention=At the end of radiation (after 7 weeks) there was no difference in the mean serum selenium level between the selenium arm and placebo arm (p=0.24)


Based on the selenium level before radiation, developing severe oral mucositis was statistically significant postponed in patients who had selenium levels ≥ 65 mcg/L (p=0.04)
Based on the selenium level before radiation, developing severe oral mucositis was statistically significant postponed in patients who had selenium levels ≥ 65 mcg/L (p=0.04)
|Bias arising from the randomization process=some concerns
|Bias arising from the randomization process=NA
|Bias due to deviation from intended intervention (assignment to intervention)=high risk
|Bias due to deviation from intended intervention (assignment to intervention)=NA
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to deviation from intended intervention (adhering to intervention)=NA
|Bias due to missing outcome data=some concerns
|Bias due to missing outcome data=NA
|Bias in measurement of the outcome=low risk
|Bias in measurement of the outcome=NA
|Bias in selection of the reported result=low risk
|Bias in selection of the reported result=NA
|Other sources of bias=low risk
|Other sources of bias=NA
|Overall RoB judgment=high risk
|Overall RoB judgment=NA
|Order number=3
|Order number=2
|Outcome topic=Selenium
}}
}}
{{Outcome Overview}}
{{Outcome Overview}}
Line 161: Line 162:


{{Further points for assessing the study
{{Further points for assessing the study
|Samples sufficiently large=?
|power analysis performed=Yes
|power analysis performed=?
|Sample size corresponds to power analysis=Yes
|Reasons given for samples being too small according to power analysis=NA
|Samples sufficiently large=NA
|Ethnicity mentioned=No
|Other explanations for an effect besides the investigated intervention=Yes
|Possibility of attention effects=NA
|Possibility of placebo effects=NA
|Other reasons=* Selenium levels in intervention arm were not significantly higher than in placebo arm after supplementation and selenium levels in placebo arm also increased over the course of the study
|Correct use of parametric and non-parametric tests=NI
|Correction for multiple testing=NA
|Measurement of compliance=NI
|Consistent reporting in numbers=No
|Comprehensive and coherent reporting=No
|Cross-over=No
|sufficient washout period=NA
|Tested for carry-over effects=NA
|Were sequence effects tested=NA
|Effect sizes reported=No
|Were side effects systematically recorded=NI
|Side effects taken into account in the interpretation of the results=NA
|Ethics / CoI / Funding=Yes
|reasons given for samples being too small according to power analysis=?
|reasons given for samples being too small according to power analysis=?
|Ethnicity mentioned=?
|Possibility of attention effects=?
|Possibility of placebo effects=?
|Other reasons=?
|Testing for normal distribution=?
|Testing for normal distribution=?
|Correct application of statistical tests=?
|Correct application of statistical tests=?
|Correction for multiple testing=?
|Measurement of compliance=?
|Blinding reliable=?
|Blinding reliable=?
|Check whether blinding was successful=?
|Check whether blinding was successful=?
|Consistent reporting in numbers=?
|sufficient washout period=?
|Tested for carry-over effects=?
|Were sequence effects tested=?
|Comprehensive and coherent reporting=?
|Were side effects systematically recorded=?
|Effect sizes reported=?
|Side effects taken into account in the interpretation of the results=?
|mono- or multicentric=?
|mono- or multicentric=?
|Ethics / CoI / Funding=?
}}
}}
{{Additional Notes
{{Additional Notes
|Additional Notes=PRO: Ethics approval obtained, power analysis conducted, selenium levels measured at the beginning and end of radiotherapy, adherence checked via self-report
|Additional Notes=PRO:
* Ethics approval obtained.
* Power analysis conducted.
* Selenium levels measured at the beginning and end of radiotherapy.
* Adherence checked via self-report.
 


CONTRA: No intent-to-treat analysis conducted, authors state baseline characteristics are comparable but do not provide statistical analysis, no explanation of how double-blinding was ensured, unclear whose baseline values are reported—apparent discrepancy in patient numbers between intervention (34 patients evaluated) and placebo arm (37 patients' characteristics reported but only 33 evaluated according to flow diagram), inconsistencies in patient numbers and dropout not clearly presented for intervention arm, small sample size, selenium levels in intervention arm were not significantly higher after supplementation compared to placebo, and selenium levels in gplacebo arm increased during the study, analyses in the results section are unclear and most are not reported in the methodology (post-hoc analyses), results are presented without supporting tables or explanation of the analysis, making them difficult to interpret, timeline of the study is unclear as it's uncertain when the values for "end of study" were taken—intervention was only 7 weeks but Kaplan-Meier curve is presented up to week 12
CONTRA:
* No intent-to-treat analysis conducted.
* Authors state baseline characteristics are comparable but do not provide statistical analysis.
* No explanation of how double-blinding was ensured.
* Unclear whose baseline values are reported—apparent discrepancy in patient numbers between intervention (34 patients evaluated) and placebo arm (37 patients' characteristics reported but only 33 evaluated according to flow diagram).
* Inconsistencies in patient numbers and dropout not clearly presented for the intervention arm.
* Small sample size.
* Selenium levels in the intervention arm were not significantly higher after supplementation compared to placebo, and selenium levels in the placebo arm increased during the study.
* Analyses in the results section are unclear and most are not reported in the methodology (post-hoc analyses).
* Results are presented without supporting tables or explanation of the analysis, making them difficult to interpret.
* Timeline of the study is unclear as it's uncertain when the values for "end of study" were taken—intervention was only 7 weeks but Kaplan-Meier curve is presented up to week 12.
}}
}}

Latest revision as of 14:33, 25 November 2024


Reference ↗
Title Effect of Selenium on Incidence and Severity of Mucositis during Radiotherapy in Patients with Head and Neck Cancer
Topic Selenium
Author Laali, E, Manifar, S, Kazemian, A, Jahangard-Rafsanjani, Z, Gholami, K
Year 2020
Journal Oral Health Preventive Dentistry
DOI https://doi.org/10.3290/j.ohpd.a45080

Brief summary

In this study, 84 patients with pre-existing head and neck tumours were included. These patients were randomly divided into two arms. One arm (37 patients) received 400 micrograms of selenium daily while the other arm (34 patients) received placebo tablets. Both arms received the regular combined radiochemotherapy in addition to the tablets. The occurrence of inflammation of the oral mucosa, which is a common side effect of radiochemotherapy, was investigated. For this purpose, both the blood selenium level and the current condition of the oral mucosa were recorded at the beginning of the study. While taking the tablets, the oral cavity was examined weekly and the degree of inflammation of the mucous membranes was assessed. No significant difference was found between the two arms with regard to the occurrence of oral mucosal inflammation. No differences between the selenium levels of the two arms were found at the end of the study either. Overall, the study had a small number of participants and the number of patients included in the final analysis is not clearly presented.


In dieser Studie wurden 84 Patienten mit bereits bestehenden Kopf-Hals-Tumoren eingeschlossen. Diese Patienten wurden zufällig in zwei Gruppen eingeteilt. Die eine Gruppe (37 Patienten) erhielt täglich 400 Mikrogramm Selen während die andere Gruppe (34 Patienten) Placebotabletten bekam. Beide Gruppen erhielten neben den Tabletten die reguläre kombinierte Radiochemotherapie. Untersucht wurde das Auftreten von Entzündungen der Mundschleimhaut, welche eine häufige Nebenwirkung der Radiochemotherapie darstellt. Dazu wurden am Anfang der Studie sowohl der Blutselenspiegel als auch der aktuelle Zustand der Mundschleimhäute erhoben. Während der Einnahme der Tabletten wurde wöchentlich die Mundhöhle untersucht und der Grad der Schleimhautentzündung eingeschätzt. Es konnte kein bedeutsamer Unterschied zwischen den beiden Gruppen festgestellt werden, was das Auftreten von Mundschleimhautentzündungen betrifft. Auch konnten am Ende der Studie keine Unterschiede zwischen den Selenspiegeln der beiden Gruppen festgestellt werden. Die Studie hat insgesamt eine geringe Teilnehmeranzahl und die Anzahl der Patienten, die am Ende in die Analyse eingeschlossen wurden ist nicht nachvollziehbar dargestellt.

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 Monocentric
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 Patients with head and neck cancer, who were due to receive radiation on at least two-thirds of the oral cavity; aged 18-85 years with a normal renal function (creatinine clearence > 60ml/min) and an acceptable performance status (Karnofsky performance status > 70%) without any history of radiotherapy were eligible for this study
Exclusion criteria NI
N randomized 84
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
Specifications on analyses Occurrence, duration and severity of oral mucositis (WHO: grade 0-4, weekly check of oral status during radiotherapy, then monthly by doctor and an author);

log rank analysis

Countries of data collection Iran
LoE Level of evidence Level 2 Oxford 2011
Outcome timeline Data collection times Oral mucositis

T0: Baseline

Follow up: weekly for 7 weeks


Selenium level

T0: Baseline

T1: End of radiation

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. Curative
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included Head and Neck Cancers
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 NI
Specifications on cancer stages NI
Comorbidities NI
Current cancer therapies Chemotherapy, Radiation therapy
Specifications on cancer therapies
  • Radiation therapy: 5 fractions per week at 60-70 Gy cumulative doses over 6 weeks to 7 weeks
  • Chemotherapy: 18 (48.6%) patients from the selenium and 16 (47.1%) from the placebo arm with cisplatin (30-50mg/m2 weekly, during radiation)
  • Grade of neutropenia and renal failure was evaluated based on the NCI CTCAE
  • Creatinine level increase of > 0.3 mg/dL or 1.5–2.0 mg/dL above baselinewas considered as renal failure and a neutrophil count decrease to 1000–500 mm3 was considered as grade 3 of this toxicity
  • After 7 weeks no differencences in the incidence of other adverse effects related to chemoradiation such as neutropenia and renal failure in the selenium arm and the placebo arm
Previous cancer therapies NI
Gender Mixed
Gender specifications Male n(%) per arm:

Selenium arm: 25 (67.9), placebo arm: 25 (73.5)


Female n(%) per arm: Selenium arm: 12 (32.1), placebo arm: 9 (26.5)

Age groups Adults (18+)
Age groups specification Age in years, mean (min-max) per arm:

Selenium arm: 52.14 (22-81), placebo arm: 54.74 (18-81)

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 42
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date 9
Drop-out reasons Did not receive allocated intervention (not to accept contributing): n=1

Lost to follow-up: discontinued tablets (n=1); discontinued radiation due to individual preferences: n=4

Inconsistencies in the number of drop-outs in the selenium arm: flowchart reports analyzed n=33 from n=42, but only reports drop-out reasons for n=6 (reasons missing n=3); table of baseline characteristics reports data of n=37

Intervention Selenium

+ all participants received: application of oral saline rinse and oral hygiene; dental status check before first treatment

Dosage and regime 2x 200 mcg tablets of selenium (Webber Naturals, Coquitlam, BC, Canada) daily from the first day until the end of radiation (including days without radiation exposure)
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. 49
Side effects / Interactions NI
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 42
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date 8
Drop-out reasons Did not receive allocated intervention (not to accept contributing): n=4

Lost to follow-up: discontinued radiation due to individual preferences: n=4

Intervention Placebo

+ all participants received: application of oral saline rinse and oral hygiene; dental status check before first treatment

Dosage and regime 2x placebo tablets daily from the first day until the end of radiation (including days without radiation exposure)
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. 49
Side effects / Interactions NI

Outcomes

Mucositis

Outcome type As specificed by the authors NI
Outcome specification Inflammation of the oral mucosa (mucositis) due to radiotherapy
Type of measurement WHO-Scale (World Health Organisation)
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". Significant difference for incidence of severe mucositis at week 3: selenium arm 9.8% vs. placebo arm 42.0% (p=0.017)
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 7 weeks no significant differences between the selenium arm and the placebo arm for:
  • mean duration of oral mucositis (grade 1–4) (p=0.27)
  • onset of oral mucosits (p =0.31)
  • recovery (day after radiation completion (p=0.80)
  • cumulative incidence of oral mucusitis (grade 1–4) (p=0.79)


Severe oral mucositis (grade 3 or 4) was seen in 25 patients in the selenium arm and in 20 patients in the placebo arm.


Addition: Development of oral mucositis in patients with selenium levels >65 mcg/l significantly delayed from baseline (p=0.04, no further explanation given)

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

Selenium level

Outcome type As specificed by the authors NI
Outcome specification NA
Type of measurement GFAAS (Graphite Furnace Atomic Absorption Spectrometry)
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". At the end of radiation (after 7 weeks) there was no difference in the mean serum selenium level between the selenium arm and placebo arm (p=0.24)

Based on the selenium level before radiation, developing severe oral mucositis was statistically significant postponed in patients who had selenium levels ≥ 65 mcg/L (p=0.04)

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

Funding and Conflicts of Interest

Funding No funding
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 No

Alternative Explanation

Other explanations for an effect besides the investigated intervention Yes
- Possibility of attention effects NA
- Possibility of placebo effects NA
- Other reasons
  • Selenium levels in intervention arm were not significantly higher than in placebo arm after supplementation and selenium levels in placebo arm also increased over the course of the study

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 NI
Correction for multiple testing NA
Measurement of compliance NI
Consistent reporting in numbers (figures, flowchart, abstract, results) No
Comprehensive and coherent reporting No
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 NI
Side effects considered in result interpretation NA
Ethics votum Yes


Additional Notes

PRO:

  • Ethics approval obtained.
  • Power analysis conducted.
  • Selenium levels measured at the beginning and end of radiotherapy.
  • Adherence checked via self-report.


CONTRA:

  • No intent-to-treat analysis conducted.
  • Authors state baseline characteristics are comparable but do not provide statistical analysis.
  • No explanation of how double-blinding was ensured.
  • Unclear whose baseline values are reported—apparent discrepancy in patient numbers between intervention (34 patients evaluated) and placebo arm (37 patients' characteristics reported but only 33 evaluated according to flow diagram).
  • Inconsistencies in patient numbers and dropout not clearly presented for the intervention arm.
  • Small sample size.
  • Selenium levels in the intervention arm were not significantly higher after supplementation compared to placebo, and selenium levels in the placebo arm increased during the study.
  • Analyses in the results section are unclear and most are not reported in the methodology (post-hoc analyses).
  • Results are presented without supporting tables or explanation of the analysis, making them difficult to interpret.
  • Timeline of the study is unclear as it's uncertain when the values for "end of study" were taken—intervention was only 7 weeks but Kaplan-Meier curve is presented up to week 12.
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