Reference ↗
Title	A randomized double-blind, placebo-controlled trial of zinc sulfate supplementation for alleviation of radiation-induced oral mucositis and pharyngitis in head and neck cancer patients
Topic	Zinc
Author	Sangthawan, D, Phungrassami, T, Sinkitjarurnchai, W
Year	2013
Journal	Journal of the Medical Association of Thailand = Chotmaihet thangphaet
DOI

Study Note

Brief summary

The 2013 study by Sangthawan and colleagues examined 144 patients with head and neck cancer. By random allocation, 50% of the patients were given zinc and the other half a placebo to take alongside radiotherapy. In the following weeks of treatment, the main focus was on the occurrence of oral mucositis and pharyngitis with severity greater than or equal to grade 2. In addition, pain in the mouth and throat as well as side effects and other possible side effects of the zinc intervention were recorded. The results showed that both the inflammation of the oral mucosa and the pharynx increased over the course of the radiotherapy treatment, but that there were no differences between the arms in terms of occurrence, severity or the change in radiation dose due to side effects. There were also no differences in pain or other side effects of the therapy, such as weight loss. This suggests that zinc does not reduce the incidence, severity or duration of mucositis and pharyngitis during radiotherapy and has no effect on perceived pain or weight. This study is convincing with statistical rigor and a large sample size.

Die Studie von Sangthawan und Kollegen von 2013 untersuchte 144 Patienten mit Kopf-Hals Karzinom. Durch eine zufällige Aufteilung bekamen 50% der Patienten Zink und die andere Hälfte ein Placebo, was sie neben der Radiotherapie zu sich nehmen sollten. Hauptaugenmerk lag in den folgenden Wochen der Behandlung auf dem Auftreten von Mundschleimhautentzündung (orale Mukositis) und Rachenentzündung (Pharyngitis) mit Ausprägungen größer oder gleich 2. Grades. Außerdem wurden Schmerzen im Mund und Hals sowie Nebenwirkungen und mögliche weitere Begleiterscheinungen der Zink-Intervention erhoben. Im Ergebnis sah man, dass sowohl die Entzündung der Mundschleimhaut als auch des Rachens über die Zeit der Radiotherapie Behandlung zunahm, sich aber keine Unterschiede im Auftreten, in der Schwere oder in der aufgrund von Nebenwirkungen veränderten Strahlendosis zwischen den Armen zeigten. Auch die Schmerzen oder andere Begleiterscheinungen der Therapie, wie Gewichtsverlust unterschieden sich nicht. Dies deutet darauf hin, dass Zink das Auftreten, die Schwere oder die Dauer von Mukositis und Pharyngitis während einer Radiotherapie nicht verringert und keinen Einfluss auf die empfundenen Schmerzen oder das Gewicht hat. Diese Studie überzeugt mit statistischer Sorgfalt und einer großen Stichprobe.

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	Older than 18 years, had histologically documented diagnosis of head and neck cancer, had a Kanofsky performance status at least 70
Exclusion criteria	Previously diagnosed with cancer, had other concomitant cancers, distant metastases or recurrent cancer, had undergone prior radiation therapy or chemotherapy, or had received drug containing zinc
N randomized	144
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	139 patients received the complete treatment
Countries of data collection	Thailand
LoE Level of evidence	1b Oxford 2009
Outcome timeline Data collection times	T0: before radiation weekly during radiation Follow-Up: 1 month after completion of radiation

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.	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	Early Stage, Advanced Stage
Specifications on cancer stages	n=55 stage I-II, n=139 stage III-IV, n=8 unknown
Comorbidities	NI
Current cancer therapies	Radiation therapy
Specifications on cancer therapies	Radiation therapy alone or as postoperative radiation therapy, all patients were treated with Cobalt-60 or 6 MV photon machine, daily fractionation was 1.8 to 2 Gy, a total dose of 50 to 70 Gy over 5 to 7 weeks was administered
Previous cancer therapies	Surgery
Gender	Mixed
Gender specifications	Intervention arm: 65 (90%) male, 7 (10%) female Placebo arm: 60 (83%) male, 12 (17%) female
Age groups	Adults (18+)
Age groups specification	Intervention arm: mean (SD): 62 (13) Placebo arm: mean (SD): 60 (12)

Arms

Duration: on the first day of radiation and to continue daily including weekends until the completion of radiation

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	72
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	1
Drop-out reasons	Died during the course of radiation
Intervention	Zinc sulfate + allmparticipants: Xylocain viscous and analgesic medication (classified according to WHO analgesic ladder) whenever considered necessary, antibiotics and antifungal agents whenever infection was documented or suspected
Dosage and regime	Oral syrup of an elemental zinc at a concentration of 5 mg per cc, self-administered at 10 cc per meal, three times a day at meal times, Duration: on the first day of radiation and to continue daily including weekends until the completion of radiation
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	Nausea, vomiting

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	72
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	n=1 died during the course of radiation, n=1 denied radiation therapy, n=1 left the study due to personal reason
Intervention	Placebo + allmparticipants: Xylocain viscous and analgesic medication (classified according to WHO analgesic ladder) whenever considered necessary, antibiotics and antifungal agents whenever infection was documented or suspected
Dosage and regime	Oral syrup, identical in taste and consistency, self-administered at 10 cc per meal, three times a day at meal times, Duration: on the first day of radiation and to continue daily including weekends until the completion of radiation
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

Mucositis

Outcome type As specificed by the authors	Primary
Outcome specification	Frequency of development of greater than or equal to grade 2 oral mucositis
Type of measurement	NCI-CTC v.2 (National Cancer Institute-Common Toxic Criteria)
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".	In the second week, the patients in both arms began to experience greater than or equal to grade 2 oral mucositis, there were no statistically significant differences in frequency of patients experiencing greater than or equal to grade 2 oral mucositis for every week between the two groups, no significant differences in developing grade 3 oral mucositis between the arms, there was no observation of grade 4 oral mucositis in either arm, No significant differences in the mean radiation doses in developing of greater than or equal to grade 2 oral mucositis
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".	NI

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	?

Pharyngitis

Outcome type As specificed by the authors	Primary
Outcome specification	Frequency of development of greater than or equal to grade 2 pharyngitis
Type of measurement	NCI-CTC v.2 (National Cancer Institute-Common Toxic Criteria)
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".	In the second week, the patients in both arms began to experience greater than or equal to grade 2 pharyngitis, there were no statistically significant differences in frequency of patients experiencing greater than or equal to grade 2 pharyngitis for every week between the two groups, no significant differences in developing grade 3 pharyngitis between the arms, there was no observation of grade 4 pharyngitis in either arm, No significant differences in the mean radiation doses in developing of greater than or equal to grade 2 pharyngitis
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".	NI

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	?

Pain

Outcome type As specificed by the authors	Secondary
Outcome specification	oral and throat pain
Type of measurement	VAS (Visual Analogue 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".	No baseline differences concerning oral pain, but significant differences in the mean scores of throat pain (placebo: 0.17 (SD 0.75) vs. intervention: 0.36 (SD 1.21), p<0.05), there were no statistically significant differences between the two arms during radiation time; The frequency of using analgesic medication were not significantly different between arms
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".	NI

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	?

Weight

Outcome type As specificed by the authors	Secondary
Outcome specification	Body weight
Type of measurement	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".	No statistically significant difference was noted between the arms
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".	NI

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 potential conflicts 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