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Title	Polaprezinc prevents oral mucositis associated with radiochemotherapy in patients with head and neck cancer
Topic	Zinc
Author	Watanabe, T, Ishihara, M, Matsuura, K, Mizuta, K, Itoh, Y
Year	2010
Journal	International journal of cancer
DOI	https://dx.doi.org/10.1002/ijc.25200

Brief summary

The study examined 31 patients with head and neck carcinoma. In addition to radiotherapy, half of the test subjects rinsed their oral cavity with a zinc solution and the other half with an azulene solution. The occurrence of inflammation of the oral mucosa (oral mucositis), pain and dry mouth (xerostomia) as well as the prevention of changes in taste, increased use of painkillers and difficulties with oral food intake were investigated. The number of daily meals was also recorded. There were significant differences in favor of the zinc arm in all points. The only exception was problems with oral food intake, in which the arms did not differ. Inflammation of the oral mucosa, pain and dry mouth occurred less frequently in the zinc arm. Furthermore, patients in the zinc arm reduced their use of painkillers and were able to eat more meals than patients in the azulene arm. The authors' conclusion regarding the intake of zinc is very positive, as it has a positive effect on the side effects of radiotherapy and has been shown to be well tolerated. However, no influence on the development of the tumor was found. From a methodological point of view, this study leaves a lot to be desired in terms of the exact study procedure and the size of the sample analyzed was very small. For these reasons, the results should only be trusted to a limited extent.

In der durchgeführten Studie wurden 31 Patienten mit Kopf-Hals Karzinom untersucht. Die Hälfte der Probanden spülte zusätzlich zur Radiotherapie ihren Mundraum mit einer Zink- und die andere mit einer Azulenlösung. Es wurden das Auftreten Entzündungen der Mundschleimhaut (oraler Mukositis), Schmerz und Mundtrockenheit (Xerostomie) untersucht sowie die Verhinderung von Geschmacksveränderungen, von zunehmendem Schmerzmittelgebrauch und Schwierigkeiten mit oraler Nahrungsaufnahme. Außerdem wurde die Anzahl an täglichen Mahlzeiten erfasst. In allen Punkten zeigten sich bedeutsame Unterschiede zugunsten des Zink-Arms. Die einzige Ausnahme bestand in Problemen der mündlichen Nahrungsaufnahme, worin sich die Arme nicht unterschieden. Mundschleimhautentzündung, Schmerz und Mundtrockenheit traten im Zink-Arm seltener auf. Des Weiteren reduzierten Patienten im Zink-Arm ihren Schmerzmittelgebrauch und konnten mehr Mahlzeiten zu sich nehmen, als Patienten im Azulen-Arm. Das Fazit der Autoren bezüglich der Einnahme von Zink fällt sehr positiv aus, da es eine positive Wirkung auf Nebenwirkungen der Radiotherapie hat und eine gute Verträglichkeit gezeigt werden konnte. Allerdings war kein Einfluss auf die Entwicklung des Tumors zu finden. Methodisch bleibt in dieser Untersuchung einiges offen, was das genaue Studienvorgehen im Verlauf angeht und die Größe der analysierten Stichprobe war sehr klein. Aus diesen Gründen sollte man den Ergebnissen nur bedingt vertrauen.

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	No
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	Patients with head and neck cancer who underwent radiotherapy or radiochemotherapy
Exclusion criteria	NI
N randomized	31
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	Japan
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	Weekly observartions

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=6 stage II, n=2 stage III, n=21 stage IV, n=2 NA
Comorbidities	NI
Current cancer therapies	Chemotherapy, Radiation therapy
Specifications on cancer therapies	Radiotherapy: n=10, Radiochemotherapy: n=21
Previous cancer therapies	Surgery
Gender	Mixed
Gender specifications	Intervention arm: 13 male, 3 female Control arm: 11 male, 4 female
Age groups	Adults (18+)
Age groups specification	Intervention arm: mean: 67.4 (53-78) Control arm: mean: 62.7 (35-86)

Arms

Duration: from the start to the end of the radiotherapy

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	16
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	Polaprezinc (zinc L-carnosine)
Dosage and regime	Orally rinsed with Polaprezinc solution (Polaprezinc granules (0.5g) were dissolved in 20 ml of 5% sodium alginate solution, a natural thickener used as food additive, by agitating intermittently for 1 hr) for 3 min 4 times in a day, the solution was swallowed after oral rinse; Duration: from the start to the end of the radiotherapy
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	NI

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Active control
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	Azulene
Dosage and regime	Orally rinsed with azulene solution (prepared by pouring 7 drops of 4% liquid solution into 100 ml water) for 3 min 4 times in a day; Duration: from the start to the end of the radiotherapy
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	NI

Outcomes

Mucositis

Outcome type As specificed by the authors	Primary
Outcome specification	Prevention of oral mucositis
Type of measurement	CTCAE (Common Terminology Criteria of Adverse Events)
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".	Oral rinse with polabrezinc significantly reduced the incidence of grade ≥2 events for oral mucositis (40% vs. 86.7%), reduced risk of oral mucositis by 56.7% (grade ≥2) and 90.6% (grade ≥3)
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	Prophylaxis of pain; Reduction in the use of analgesics for the relief of oral pain
Type of measurement	CTCAE (Common Terminology Criteria of Adverse Events)
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".	Oral rinse with polabrezinc significantly reduced the incidence of grade ≥2 events for pain (33.3% vs. 86.7% p<0.003); reduced risk of pain by 73.9% (grade ≥2) and 81.2% (grade ≥3) The frequency of the use of analgesics was reduced from 100 to 50% (p<0.0025), reduced risk of analgesics use by 50%
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	?

Xerostomia

Outcome type As specificed by the authors	Secondary
Outcome specification	Prophylaxis of xerostomia
Type of measurement	CTCAE (Common Terminology Criteria of Adverse Events)
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".	Oral rinse with polabrezinc significantly reduced the incidence of grade ≥2 events for xerostomia (13.3% vs. 73.3%, p<0.001), reduced risk of xerostomia (grade ≥2) by 83%
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	?

Taste alteration

Outcome type As specificed by the authors	Secondary
Outcome specification	Prophylaxis of taste disturbance
Type of measurement	?
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".	Oral rinse with polabrezinc significantly reduced taste disturbance (19% vs. 87%, p<0.0002), reduced risk of taste disturbance (grade ≥2) by 88.3%
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	?

Nutrition status

Outcome type As specificed by the authors	Secondary
Outcome specification	Ability to oral intake; Amount of daily meals
Type of measurement	?
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".	Reduced risk of disability to oral intake by 68.7%; Significantly larger amount of meals in intervention arm than in control arm due to the prevention from difficulty in oral intake (mean (SD): 78.8 (31.2%) of total meal vs 30.7 (37.9%), p<0.002)
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	?

Tumor response

Outcome type As specificed by the authors	Others
Outcome specification	Objective tumor response to radiochemotherapy
Type of measurement	RECIST 1.0 Criteria (Response Evaluation Criteria in Solid Tumors)
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".	The response rate was not significantly different 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	NI

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