Fallahi et al. (2013): Does vitamin E protect salivary glands from I-131 radiation damage in patients with thyroid cancer?

Reference ↗
Title	Does vitamin E protect salivary glands from I-131 radiation damage in patients with thyroid cancer?
Topic	Vitamin E
Author	Fallahi, B, Beiki, D, Abedi, SM, Saghari, M, Fard-Esfahani, A, Akhzari, F, Mokarami, B, Eftekhari, M
Year	2013
Journal	Nuclear medicine communications
DOI	https://doi.org/10.1097/MNM.0b013e328362b1f2

Brief summary

In this study, two different arms with thyroid cancer were examined, one half of which took vitamin E in addition to radioiodine therapy for five weeks and the other half received only a placebo instead of radioiodine therapy. The aim of this study was to investigate the protective effect of vitamin E on radiotherapy-induced functional impairment of the salivary glands (auricular and submandibular salivary glands). In both the vitamin E and the control arm, there was virtually no deterioration in the comparison before and after radioiodine therapy. Similarly, the authors found no significant group differences in the change in salivary gland function in the right and left parotid glands, with two exceptions. Points of criticism of this study are the small sample size and the fact that a large number of individual tests were carried out, which increases the likelihood of statistical differences being falsely identified.

In dieser Studie werden zwei verschiedene Gruppen mit Schilddrüsenkrebs untersucht, von denen eine Hälfte zusätzlich zur Radiojodtherapie fünf Wochen lang Vitamin E einnehmen und die andere Hälfe stattdessen zur Radiojodtherapie nur ein Placebo bekam. Das Ziel dieser Studie war es, den schützenden Effekt von Vitamin E auf die strahlentherapieinduzierte Funktionseinschränkung der Speicheldrüsen (Ohr- und Unterkieferspeicheldrüse) zu untersuchen. Sowohl im Vitamin E- als auch im Kontrollarm zeigte sich so gut wie keine Verschlechterung im Vergleich vor und nach der Radiojodtherapie. Analog dazu fanden die Autoren bis auf zwei Ausnahmen bei den rechten und linken Ohrspeicheldrüsen keine bedeutsamen Gruppenunterschiede in der Veränderung der Funktionsfähigkeit der Speicheldrüsen. Kritikpunkte an dieser Studie sind die kleine Stichprobengröße und dass sehr viele Einzeltests durchgeführt wurden, was die Wahrscheinlichkeit erhöht, dass fälschlicherweise statistische Unterschiede festgestellt 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	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	Aged less than 55 years, who were referred to our institute for 131I therapy to ablate the remnant thyroid tissue or to treat metastatic tumor, were enrolled in this study; all patients were in a hypothyroid state with serum thyroid stimulating hormone levels higher than 25 mIU/l
Exclusion criteria	Patients with xerostomia, previous salivary gland dysfunction, salivary stone or tumor, those who had undergone head and neck radiotherapy previously, who had known rheumatological diseases such as Sjögren’s disease, who had been administered 131I earlier, who had known liver disease, had taken drugs influencing salivary gland function, such as antihistaminic agents, beta-blockers, atropine, benzodiazepines, tricyclic antidepressants, and antipsychotic drugs in the past 2 weeks
N randomized	36
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 explicitly stated, but no drop-out occured.
Countries of data collection	Iran
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T0: Baseline (before radiojodtherapy) T1: 6 months after radiojodtherapy

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	NI
Specifications on cancer stages	NI
Comorbidities	NI
Current cancer therapies	Radioiodine treatment
Specifications on cancer therapies	Postsurgical ablation therapy with 3700–5550MBq 131I
Previous cancer therapies	Surgery
Gender	Mixed
Gender specifications	77.8% female
Age groups	Adults (18+)
Age groups specification	Mean (SD) = 31.1 (8.4); range: 17-48 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	19
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, 800 IU per day Start: Week -1 radioiodine therapy to 4 weeks after Duration: 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	Placebo
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	Placebo
Dosage and regime	Daily Start: Week -1 radioiodine therapy to 4 weeks after Duration: 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

Outcomes

Salivary gland function

Outcome type As specificed by the authors	Primary
Outcome specification	EE: excretion fraction; FUR: first-minute uptake ratio; MSP: maximum secretion percentage; MUR: maximum uptake ratio
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".	6 months after Radiojodtherapy: Mean (SD; Range) for each: Change in Vitamin E Arm: No significant differences between from before to 6 months after radiojodtherapy. Change in Placebo Arm: Right submandibular gland: MSP: before radiojodtherapy: 28.73 (14.59; 0.4–67.11); 6 months after: 24.53 (10.91; 4.46–45.05); p = 0.039, sign. EF: before radiojodtherapy: 47.73 (16.65; 7.60–81.50); 6 months after: 43.02 (16.69; 15.18–76.32); p = 0.015, sign. Left parotid gland : EF: before radiojodtherapy: 58.14 (7.85; 44–73.67), 6 months after: 51.99 (21.12; 4.23–76.82); p = 0.035, sign. Otherwise: not significant Comparison Vitamin E (Vitamin E arm) vs. Placebo (placebo arm): Mean (SD; Range) from before to 6 months after radiojodtherapy Right parotid gland: FUR: Vitamin E: 0.39 (0.97; –2.88-0.97); Placebo: 0.09 (0.47; –0.84-1.06); p = 0.04, sign; otherwise not significant. Right submandibular gland: No significant differences. Left Parotid gland: EF: Vitamin E: 0.43 (9.48; –15.16-23.57); Placebo: 11.15 (22.49; –13.7-60.9); p = 0.04, sign.; otherwise not significant. Left submandibular gland: No significant differences. Number of Parotid glands with more than 15% decrease in EF: Vitamin E: 3/38 (7.9%), Placebo: 9/34 (26.5%); p = 0.035, sign.

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	"This research has been supported by Tehran University of Medical Sciences grant no. 4645. The authors also thank Mohammad Reza Ramezani for his substantial contribution to the study."
Conflicts of Interest	The authors declared no conflict of interest.

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
• Double-blinded

CONTRA:

• Small sample size
• No information on dropout
• No information on compliance
• No control for multiple testing