Reference ↗
Title	Oral zinc sulphate and prevention of radiation-induced oropharyngealmucositis in patients with head and neck cancers: A double blind, randomized controlled clinical trial
Topic	Zinc
Author	Moslemi, D, Babaee, N, Damavandi, M, Pourghasem, M, Moghadamnia AA
Year	2014
Journal	International Journal of Radiation Research
DOI	https://ijrr.com/browse.php?a_id=1281&sid=1&slc_lang=en

Study Note

Brief summary

In this study, Moslemi and colleagues investigated the effects of zinc on inflammation of the oral mucosa (mucositis). 40 patients with head and neck carcinoma were randomly divided into two arms, one receiving zinc and the other a placebo. The zinc arm showed that the patients were affected less early by inflammation of the oral mucosa and that, when it did occur, it was less intense than in the placebo arm. The study can be rated as good overall in terms of methodology, as it looked at which factors in addition to zinc may have had an influence on the inflammation of the oral mucosa and provided a good explanation of the course of events and patient failures. However, a major weakness is that they did not check the comparability of the two arms with regard to zinc levels. In addition, the statistical analysis is not fully comprehensible due to missing values, unclear procedures and superficial reporting of results.

Moslemi und Kollegen untersuchten in der vorliegenden Studie die Auswirkungen von Zink auf Mundschleimhautentzündungen (Mukositis). 40 Patienten mit Kopf-Hals Karzinom wurden zufällig in zwei Arme aufgeteilt, wobei einer Zink erhielt und der andere ein Placebo. In den Zink-Arm zeigte sich dass die Patienten weniger früh von Entzündungen der Mundschleimhaut betroffen waren und dass sie, wenn sie auftrat, in ihrer Intensität geringer war, als im Placebo-Arm. Die Studie ist methodisch zwar insgesamt als gut zu bewerten, da sie geschaut hat, welche Faktoren zusätzlich zu Zink evtl. Einfluss auf die Mundschleimhautentzündung genommen haben könnten und den Ablauf und Ausfälle von Patienten gut begründet. Eine große Schwachstelle ist jedoch, dass sie die Vergleichbarkeit der beiden Arme hinsichtlich der Zinkspiegel nicht überprüfen. Zudem ist die statistische Auswertung aufgrund fehlender Werte, unklarer Vorgehensweise und oberflächlicher Ergebnisberichtung nicht in Gänze nachvollziehbar.

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	Karnofsky’s performance status ≥70, receiving curative radiotherapy or chemoradiotherapy, planned treatment was at least 6000cGy total radiation dose of external beam radiotherapy to at least one third of the oral cavity
Exclusion criteria	concurrent disease (diabetes mellitus, hypertension, autoimmunedisorder, chronic infllammation, cardiac disease, etc.), previously administration of cytotoxic chemotherapy or radiotherapy, patients refusal, infection of mouth and systemic infection and patients with interruption in the treatment
N randomized	40
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	NI
Countries of data collection	Iran
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	During treatment until 2 weeks after treatment, weekly

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, Neo-adjuvant, 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	NI
Specifications on cancer stages	NI
Comorbidities	NI
Current cancer therapies	Chemotherapy, Radiation therapy
Specifications on cancer therapies	Radiotherapy doses (cGy) Range: 4000-7000; concurrent chemoradiotherapy: n=32
Previous cancer therapies	Surgery
Gender	Mixed
Gender specifications	Intervention arm: n=12 male, n=8 female placebo arm: n=9 male, n=8 female
Age groups	Adults (18+)
Age groups specification	Intervention arm: mean (SD): 49.5 (17.47), Range: 18–78 placebo arm: mean (SD): 52.82 (14.03), Range: 22 –71

Arms

Duration of intervention: started 10 days before beginning of treatment and continued to 8 weeks after the end of treatment

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 suphate
Dosage and regime	Zinc sulphate capsules (30 mg) three times daily at 8 hours interval, Duration of intervention: started 10 days before beginning of treatment and continued to 8 weeks after the end of treatment
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	20
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	3
Drop-out reasons	Sever mucositis and interruption of treatment
Intervention	Placebo
Dosage and regime	Capsules filled with starch and designed same medicine firm, form and color to zinc sulphate, three times daily at 8 hours interval, Duration of intervention: started 10 days before beginning of treatment and continued to 8 weeks after the end of treatment
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	NA

Outcomes

Mucositis

Outcome type As specificed by the authors	NI
Outcome specification	Severity, duration and commencement of radiotherapy induced mucositis
Type of measurement	OMAS (Oral Mucositis Assessment Scale)
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".	Sex, age, histological type, disease, treatment modalities, and chemotherapy regimen didn’t make statistically signiicant differences; Mean of oral and pharyngeal mucositis severities had been increased after commencement of radiotherapy and reached to maximum tendency at 4th week; placebo arm showed highest severity in mucositis (p < 0.0001); in weeks2‐7 and 8, the severity of oral and pharyngeal mucositis were lower in the zinc group (p < 0.003) Mucositis has been expressed during the first week in both arms but the prevalence of mucositis were 40% and 70.5% in intervention and placebo arm, respectively at the end of this week (p < 0.0001)
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".	2 weeks after end of the treatment, difference between results of intervention and placebo arm were statistically significant (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	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