Laali et al. (2020): Effect of Selenium on Incidence and Severity of Mucositis during Radiotherapy in Patients with Head and Neck Cancer

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.