Büntzel et al. (2010): Limited effects of selenium in the prevention of radiation-associated toxicities - results of a randomized study in head neck cancer patients

Reference ↗
Title	Limited effects of selenium in the prevention of radiation-associated toxicities - results of a randomized study in head neck cancer patients
Topic	Selenium
Author	Buentzel, J, Riesenbeck, D, Glatzel, M, Berndt-Skorka, R, Riedel, T, Muecke, R, Kisters, K, Schoenekaes, KG, Schaefer, U, Bruns, F, Micke, O
Year	2010
Journal	Anticancer research
DOI	https://ar.iiarjournals.org/content/30/5/1829.short

Brief summary

In this study, 39 patients with advanced head and neck tumors and selenium deficiency were randomly divided into two arms. One arm (22 participants) received selenium during radiotherapy and another arm (17 participants) received nothing in addition to radiotherapy. It was investigated whether selenium administration can influence the side effects of radiotherapy. At the end of radiotherapy, no differences were found between the arms for the maximum severity of the radiotherapy-induced symptoms “dry mouth”, “inflammation of the oral mucosa”, “loss of sense of taste” and “nutritional deficiency”. No differences were found in terms of frequency either. Only at week seven, the last week of radiotherapy, were the symptoms of “nutritional deficiency” more pronounced in the control arm than in the selenium arm. Overall, the study provides a very clear description of the procedure and the results. However, important demographic data such as concomitant diseases and tumor stage of the patients are not given and therefore cannot be considered in the analysis. Furthermore, as no placebo was used, it was not possible to blind the subjects or the investigators.

In dieser Studie wurden 39 Probanden mit fortgeschrittenen Kopf-Hals Tumoren und Selendefizit zufällig in zwei Gruppen eingeteilt. Eine Gruppe (22 Probanden) bekamen Selen während der Radiotherapie und eine andere Gruppe (17 Probanden) erhielt nichts Zusätzliches zur Radiotherapie. Untersucht wurde ob Selengabe die Nebenwirkungen der Radiotherapie beeinflussen kann. Am Ende der Radiotherapie konnten bezügliche den Radiotherapie verursachten Symptomen „Trockener Mund“, „Entzündung der Mundschleimhaut“, „Verlust des Geschmackssinnes“ und „Ernährungsdefizit“ keine Unterschiede zwischen den Gruppen für die maximale Ausprägung gefunden werden. Es konnten auch keine Unterschiede bezüglich der Häufigkeit gefunden werden. Nur zu Woche sieben und der damit letzten Woche der Radiotherapie waren die Symptome des „Ernährungsdefizits“ in der Kontrollgruppe stärker ausgeprägt als in der Selen-Gruppe. Insgesamt gibt die Studie eine sehr übersichtliche Beschreibung des Ablaufs und auch der Ergebnisse. Allerdings werden wichtige demographische Angaben wie Begleiterkrankungen und Tumorstadium der Patienten nicht angegeben und können deshalb auch nicht in der Analyse berücksichtigt werden. Da kein Placebo eingesetzt wurde, konnte zudem keine Verblindung der Probanden oder der Prüfungsleiter durchgeführt werden.

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	No
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 squamous cell carcinoma of the head and neck region; atom absorption spectrometry showed a deficiency in selenium and the radiation field included 75% of the major salivary glands
Exclusion criteria	NI
N randomized	39
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	ITT-analysis not specified, but no drop-out occured
Countries of data collection	Germany
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	Selenium concentration measured at baseline, after 4 weeks, after the end of Radiotherapy and 6 weeks after the end of Radiotherapy Outcome assessed at baseline and then once a week and 6 weeks after Radiotherapy

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, Adjuvant
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	Advanced Stage
Specifications on cancer stages	NI
Comorbidities	Selenium deficit
Current cancer therapies	Radiation therapy
Specifications on cancer therapies	NI
Previous cancer therapies	Surgery
Gender	Mixed
Gender specifications	Male n=31, female n=8
Age groups	Adults (18+)
Age groups specification	Mean(SD) = 63.5(9.31) 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	22
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	0
Drop-out reasons	NA
Intervention	Sodium selenite
Dosage and regime	500µg sodium selenite 2 days before the start of radiotherapy and on days with radiotherapy; and 300 µg sodium selenite on days without radiotherapy (weekends and vacations), orally as a liquid 1 hour before radiotherapy
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	Passive control
Number of participants (arm) N randomized	17
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	0
Drop-out reasons	NA
Intervention	Usual care
Dosage and regime	NA
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	NA

Outcomes

Toxicity

Outcome type As specificed by the authors	Primary
Outcome specification	Grade of radiotherapy-associated side effects: Xerostomia, stomatitis, ageusia, and dysphagia
Type of measurement	RTOG Acute Radiation Morbidity Scoring Criteria (Radiation Therapy Oncology Group)
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".	Maximum toxicity intervention vs. control arm: dysphagia 22.7% vs. 35.3%, ageusia 22.7% vs. 47.1%, xerostomia 22.7% vs. 23.5%, and stomatitis 36.4% vs. 23.5%; no significant differences; Significant mean difference between arms only for dysphagia at week 7: mean intervention arm 1.533 vs. control 2.167 (p=0.05)
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".	No significant differences; overall number of serious adverse events, not significantly different: intervention arm 23x and control arm 22x (p=0.476)

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)	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	some concerns
Other sources of bias	some concerns
Overall RoB judgment	some concerns

Funding and Conflicts of Interest

Funding	Sponsored by biosyn Arzneimittel GmbH, Fellbach, Germany
Conflicts of Interest	NI

Further points for assessing the study

Sample

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

Alternative Explanation

Other explanations for an effect besides the investigated intervention	Yes
- Possibility of attention effects	NA
- Possibility of placebo effects	Yes
- Other reasons	No information about the comparability of the groups at baseline in the results section, nor information on how this was achieved – especially considering the unequal group sizes No detailed description of the data collection in the individual clinics and whether they were comparable

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	No
Measurement of compliance	NI
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.
• Clear presentation of results.
• Detailed description of the research question and selenium level testing.

CONTRA:

• Unequal arm sizes despite randomization.
• No power analysis.
• No placebo and thus no blinding possible.
• Unclear randomization process.
• No information on the comparability of arms at baseline in the results section or how this was achieved—especially considering the unequal arm sizes.
• Lack of additional demographic variables such as comorbidities, tumor stage, etc.
• No detailed description of the assessments in the individual clinics and whether they were comparable.