Najafizade et al. (2013): Preventive effects of zinc sulfate on taste alterations in patients under irradiation for head and neck cancers: A randomized placebo-controlled trial

Reference ↗
Title	Preventive effects of zinc sulfate on taste alterations in patients under irradiation for head and neck cancers: A randomized placebo-controlled trial
Topic	Zinc
Author	Najafizade, N, Hemati, S, Gookizade, A, Berjis, N, Hashemi, M, Vejdani, S, Ghannadi, A, Shahsanaee, A, Arbab, N
Year	2013
Journal	Journal of research in medical sciences : the official journal of Isfahan University of Medical Sciences
DOI	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3724372/?report=printable

Brief summary

The study described here observed the effect of zinc on taste changes during radiotherapy treatment in 35 patients with head and neck carcinoma. In the arm that received a placebo instead of zinc, there was a deterioration in all four taste sensations: sweet, salty, sour, and bitter, meaning the threshold needed to recognize these tastes increased. In the zinc arm, however, only the sense of sour taste decreased. Even one month after the therapy, the threshold for recognizing the four tastes had significantly increased in the placebo arm, whereas in the zinc arm, only the perception of salty taste had worsened. However, due to the lack of an arm comparison and thus no proven difference in taste changes between the arms, the results are not conclusive but merely suggest a possible positive effect of zinc.

Die hier beschriebene Untersuchung beobachtete an 35 Patienten mit Kopf-Hals Karzinom die Wirkung von Zink, bezogen auf Geschmacksveränderungen während der Radiotherapie Behandlung. In den Armen, die statt Zink ein Placebo erhielt, zeigte sich eine Verschlechterung in allen vier Geschmacksrichtungen süß, salzig, sauer und bitter, d.h. der Schwellenwert, der zur Erkennung dieser Geschmäcker nötig war stieg an. In dem Zink-Arm hatte sich hingegen nur der Sinn für sauer verringert. Auch einen Monat nach der Therapie war der Schwellenwert zur Erkennung der vier Geschmäcker im Placebo-Arm deutlich angestiegen, wohingegen sich der Zink-Arm nur in der Geschmackswahrnehmung salzig verschlechtert hatte. Aufgrund der fehlenden Durchführung eines Armvergleichs und damit keinem nachgewiesenen Unterschied in den Geschmacksveränderungen zwischen den Armen sind die Ergebnisse allerdings nicht aussagekräftig, sondern geben höchstens einen Hinweis auf die positive Wirkung von Zink.

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	Head and neck cancers who were on schedule for radiotherapy with at least 2000 Gy ot >30% of oral cavity, with or without chemotherapy
Exclusion criteria	Oral candidiasis or other oral lesions (e.g., stomatitis, necrosis, and ulcers), cranial nerve injuries, and metabolic/endocrine disorders that may have effects on taste perception
N randomized	35
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	The specific analysis method is not stated in the study, however, according to the authors, all included patients were evaluated at the end of the study.
Countries of data collection	Iran
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T0: Baseline T1: at the end of radiotherapy Follow-Up: a month later

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	Early Stage, Advanced Stage
Specifications on cancer stages	Cancer Grade II - IV
Comorbidities	NI
Current cancer therapies	Chemotherapy, Radiation therapy
Specifications on cancer therapies	Al the patients were treated with daily fractions of 180 to 200 Gy lasting from 5to 9weeks, for atotal dose of 6000 to 7000 cGy. The radiation fields were the same for al patients, and the tongue was always included.
Previous cancer therapies	NI
Gender	Mixed
Gender specifications	60% male
Age groups	Adults (18+)
Age groups specification	Mean (SD): 59.2 (16.5)

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	20
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	Zinc sulfate
Dosage and regime	Zinc sulfate capsules: 50 mg, three times a day, after meals, Duration of intervention: started with beginning of radiotherapy and continued one month after completion of irradiation
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.	-999
Side effects / Interactions	No side effects

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	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	Placebo
Dosage and regime	Capsules three times a day, after meals, Duration of intervention: started with beginning of radiotherapy and continued one month after completion of irradiation
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.	-999
Side effects / Interactions	No side effects

Outcomes

Taste alteration

Outcome type As specificed by the authors	Primary
Outcome specification	Taste acuity: detection and recognition thresholds for four taste qualities (sweet, salty, sour, and bitter)
Type of measurement	Three-stimulus drop technique (by Henkin)
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".	T0: Similar ini baseline taste perception threshold for the four tastes, T1: at the end of radiation therapy, there was a significant increase in taste perception threshold for biter (p = 0.003), salty (p = 0.002), sweet (p = 0.002), and sour (p = 0.002) tastes in the placebo arm, in the intervention arm threshold did not change significantly at the end of radiation, except the sour taste perception (p = 0.038)
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".	One month after completion of radiotherapy: taste perception threshold was increased in the placebo arm for al four tastes (p = 0.001), in the intervention arm, there was only slight increase in threshold for perception of the salty taste (p = 0.046)

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	Supported by agrant (project number 290088) from Isfahan University of Medical Sciences.
Conflicts of Interest	None declared

Further points for assessing the study

Sample

Power analysis performed	?
- Sample size corresponds to power analysis	NI
- Reasons for insufficient sample size based on power analysis	NI
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	NI
- 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	NI
Correction for multiple testing	?
Measurement of compliance	?
Consistent reporting in numbers (figures, flowchart, abstract, results)	?
Comprehensive and coherent reporting	?
Cross-over	NI
- 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:

• Ethics vote available
• Given comparability to baseline in general characteristics and outcome parameters
• Testing of taste via sweet, salty, sour and bitter solutions
• Investigation of the adverse events (weekly demand)
• Investigation of the influence of third-party variables on the outcome
• Double blinding
• Examination of patient compliance (weekly inquiry) and use of other mouthwashes etc.

CONTRA:

• Small sample size
• No examination of zinc levels - neither at the beginning nor at the end of the study
• Group comparison is not reported, only changes within the two arms, therefore results are not meaningful (although statistical test for group comparison is announced beforehand - selective reporting?)
• No information on zinc levels in the two groups