Upadhyaya et al. (2017): Radioprotective effect of vitamin E on salivary glands after radioiodine therapy for differential thyroid cancer: A randomized-controlled trial

Reference ↗
Title	Radioprotective effect of vitamin E on salivary glands after radioiodine therapy for differential thyroid cancer: A randomized-controlled trial
Topic	Vitamin E
Author	Upadhyaya, A, Zhou, P, Meng, Z, Wang, P, Zhang, G, Jia, Q, Tan, J, Li, X, Hu, T, Liu, N, Wang, S, Liu, X, Wang, H, Zhang, C, Zhao, F, Yan, Z, Wang, X, Zhang, X, Zhang, W
Year	2017
Journal	Nuclear Medicine Communications
DOI	https://doi.org/10.1097/MNM.0000000000000727

Brief summary

In this study, the protective effect of vitamin E on radiotherapy-induced functional impairment of the salivary glands (auricular and submandibular salivary glands) in patients with thyroid cancer was investigated. The patients were divided into four groups, three of which took vitamin E at different doses in addition to radioiodine therapy (arm A: 100mg, arm B: 200mg and arm C: 300mg) and the control arm (arm D) received only radioiodine therapy. While a significant increase in function was observed in arms A to C, function in arm D decreased in the parotid gland. Comparing all four arms, there were significant differences between the arms in the right and left parotid glands as well as in the right and left submandibular glands. Points of criticism of this study are the small sample size. In addition, a large number of individual tests were performed, increasing the likelihood of spurious statistically significant results, and the reporting quality was rather poor (e.g. lack of information on the exact dosage of vitamin E or the failure rate over the course of the study).

In dieser Studie wurde der schützende Effekt von Vitamin E auf die strahlentherapieinduzierte Funktionseinschränkung der Speicheldrüsen (Ohr- und Unterkieferspeicheldrüse) bei Patienten mit Schilddrüsenkrebs untersucht. Die Patienten wurden in vier Gruppen aufgeteilt, von denen drei Gruppen zusätzlich zur Radiojodtherapie Vitamin E in unterschiedlicher Dosierung einnahmen (Arm A: 100mg, Arm B: 200mg und Arm C: 300mg) und der Kontrollarm (Arm D) nur Radiojodtherapie erhielt. Während im Arm A bis C ein bedeutsamer Anstieg der Funktionsfähigkeit festgestellt wurde, fiel die Funktion in Arm D in der Ohrspeicheldrüse ab. Vergleicht man alle vier Gruppen miteinander, fanden sich sowohl in der rechten und linken Ohrspeicheldrüse, als auch in der rechten und linken Unterkieferspeicheldrüse bedeutsame Unterschiede zwischen den Armen. Kritikpunkte an dieser Studie sind die kleine Stichprobengröße. Zusätzlich dazu wurden sehr viele Einzeltests durchgeführt, was die Wahrscheinlichkeit von fälschlicherweise statistisch bedeutsamen Ergebnissen erhöht, und die Berichtqualität war eher schlecht (z.B. fehlen Angaben zur genauen Dosierung von Vitamin E oder zur Ausfallrate im Laufe 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	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	Single
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	4

Study characteristics

Inclusion criteria	Definite pathological diagnosis of differentiated thyroid cancer (DTC), presented to department for 131I treatment
Exclusion criteria	Patients treated previously for any other malignancies by chemotherapy and/or radio-therapy, other head and neck cancers, patients with xerostomia because of any other reasons, other systemic disorders, patients with any deleterious habits, and patients on medications such as anticholinergics, anti-histaminics, drugs causing xerostomia, and other known radioprotective agents, and patients who received 131I other than 100 mCi doses
N randomized	82
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 not specified, but no drop-out reported.
Countries of data collection	China
LoE Level of evidence	1b Oxford 2009
Outcome timeline Data collection times	T0: -4h radioiodine therapy T1: after 6 months

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.	Adjuvant
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Head and Neck Cancers - Thyroid 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	Stages T1-3, N0-1, M0
Comorbidities	NI
Current cancer therapies	Radioiodine treatment
Specifications on cancer therapies	131I treatment
Previous cancer therapies	Surgery
Gender	Mixed
Gender specifications	75.6% female
Age groups	Adults (18+)
Age groups specification	Mean (SD) = 45.8 (12.1); range: 23-66 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	23
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	Vitamin E
Dosage and regime	Oral, 100mg Duration: week -1 radioiodine treatment until week +4 (total 5 weeks)
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.	35
Side effects / Interactions	NI

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	Vitamin E
Dosage and regime	Oral, 200mg Duration: week -1 radioiodine treatment until week +4 (total 5 weeks)
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.	35
Side effects / Interactions	NI

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	15
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	Vitamin E
Dosage and regime	Oral, 300mg Duration: week -1 radioiodine treatment until week +4 (total 5 weeks)
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.	35
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	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	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.	35
Side effects / Interactions	NI

Outcomes

Salivary gland function

Outcome type As specificed by the authors	Primary
Outcome specification	Scintigraphic parameters: Uptake fraction (UF); Uptake index (UI), Excretion fraction (EF), Excretion ratio (ER))
Type of measurement	Scintigraphy
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 6 months: Vitamin E 100mg: Increase EF right parotis (p < 0.01) and UI right submand. (p < 0.05) Vitamin E 200mg: Increase UI right parotis, both Submand. (p < 0.01) Vitamin E 300mg: Increase UF left parotis (p < 0.05) and right submand. (p < 0.01), increase UI in both submand. (p < 0.01) Usual Care: Decreasel UF in both parotis (p < 0.01) Rest: ns. All arms compared: UF: left submand.: p < 0.05 UI: right parotis: p < 0.05; both submand.: p < 0.01 ER: left parotis: p < 0.05

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

Funding and Conflicts of Interest

Funding	NI
Conflicts of Interest	According to authors none.

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:

• Ethical approval obtained.

CONTRA:

• Single-blinded only.
• Small sample size without power analysis.
• No information on dropout.
• No control for multiple testing.
• No pairwise intergroup comparisons to determine the optimal dosage.
• No information on compliance.
• Poor reporting quality (e.g., no indication of how often vitamin E should be taken).