Gorgu et al. (2013): The effect of zinc sulphate in the prevention of radiation induced oral mucositis in patents with head and neck cancer

Reference ↗
Title	The effect of zinc sulphate in the prevention of radiation induced oral mucositis in patents with head and neck cancer
Topic	Zinc
Author	Gorgu, SZ, Ilknur, AF, Sercan, O, Rahsan, H, Nalan, A
Year	2013
Journal	International Journal of Radiation Research
DOI	http://ijrr.com/article-1-1036-en.html

Brief summary

In this study, Gorgu and colleagues investigated the effects of zinc administration on the occurrence of oral mucositis and esophagitis in 40 head and neck cancer patients. In addition to radiotherapy, 16 of the 40 patients received zinc. The patients in the second arm received only radiotherapy without any other treatment and thus formed a control arm without placebo. At the end of the study, there were no differences in the occurrence of oral mucosal inflammation. Zinc was therefore unable to reduce the incidence of oral mucositis or inflammation of the esophagus. However, the zinc level in the control arm was significantly lower than in the zinc arm, which was able to maintain its zinc level. In general, the statistical tests of this study were unable to demonstrate any effects of zinc. However, the study has several serious methodological flaws, making the results difficult to interpret. Due to the lack of information on the duration of zinc administration or the method by which the patients were divided into arms, the study cannot be reconstructed. In addition, the sample was very small and, above all, not large enough for the calculated analyses. The difference between the two study arms, which existed from the outset, may also have influenced the results. Overall, this study must be viewed with caution.

Gorgu und Kollegen untersuchten in der vorliegenden Studie die Auswirkungen der Gabe von Zink auf das Auftreten von Mundschleimhautentzündung (Mukositis) und Entzündung der Speiseröhre (Ösophagitis) bei 40 Kopf-Hals-Karzinom Patienten. Zusätzlich zur Radiotherapie erhielten 16 der 40 Patienten Zink. Die Patienten des zweiten Arms bekamen nur die Radiotherapie ohne jegliche andere Behandlung und bildeten somit einen Kontrollarm ohne Placebo. Am Ende der Untersuchung zeigten sich keine Unterschiede im Auftreten einer Mundschleimhautentzündung. Zink konnte also weder das Auftreten von Mundschleimhautentzündung noch von einer Entzündung der Speiseröhre reduzieren. Der Zinkspiegel war im Kontrollarm jedoch deutlich geringer, als im Zink-Arm, die ihren Zinkspiegel halten konnten. Generell konnten die statistischen Testungen dieser Studie keine Effekte von Zink nachweisen. Allerdings weist die Untersuchung mehrere schwerwiegende methodische Mängel auf, wodurch die Ergebnisse kaum interpretierbar sind. Durch das Fehlen von Angaben zur Dauer der Zinkgabe oder dem Verfahren, nach dem die Patienten in die Arme aufgeteilt wurden, kann die Studie nicht nachvollzogen werden. Hinzu kommt, dass die Stichprobe sehr klein und vor allem für die berechneten Analysen nicht ausreichend groß war. Auch der schon von Beginn an bestehende Unterschied zwischen den beiden Untersuchungsarmen, kann die Ergebnisse beeinflusst haben. Insgesamt muss man diese Studie mit Vorsicht betrachten.

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	NI
Exclusion criteria	NI
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.	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	Turkey
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T0: before radiotherapy Once a week during radiotherapy After radiotherapy

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	Radiotherapy field >33% of the buccal mucosa and ECOG 0‐2
Comorbidities	NI
Current cancer therapies	Chemotherapy, Radiation therapy
Specifications on cancer therapies	Median radiation dose in all the patients was 6440 cGy (range: 4600‐7000 cGy); intervention arm: 6625 cGy (range: 6000‐7000 cGy) vs. control arm: 6316 cGy (range: 4600‐7000 cGy); n=20 with concurrent chemotherapy; n=24 with surgery before radiotherapy
Previous cancer therapies	Surgery
Gender	Mixed
Gender specifications	Intervention arm: n=15 male and n=1 female Control arm: n=24 male, n=0 female
Age groups	Adults (18+)
Age groups specification	Intervention arm: 42-74 (median: 56) Control arm: 41-73 (median: 58)

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	16
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	NI
Drop-out reasons	NI
Intervention	Zink sulphate
Dosage and regime	4 Zinco‐C 25‐mg tablets daily
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	Passive control
Number of participants (arm) N randomized	24
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	NI
Drop-out reasons	NI
Intervention	No treatment
Dosage and regime	NA
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	NI
Type of measurement	RTOG Acute Radiation Morbidity Scoring Criteria (Radiation Therapy Oncology Group)
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".	Grade 0, 1, 2, and 3 mucositis were observed in 37.5%, 32.5%, 27.5%, and 2.5% of the patients; Grade 4 mucositis was not noted in any of the patients; there was no relationship between zinc replacement and mucositis (p = 0.159); incidence of mucositis was lower in the patients with normal serum zinc levels before and after RT, though that was not statistically signifiicant (p = 0.476)
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	?

Esophagitis

Outcome type As specificed by the authors	NI
Outcome specification	NI
Type of measurement	NI
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 statistical relationship between the administration of zinc and esophagitis (p = 0.596); incidence of esophagitis was lower in the patients with normal serum zinc levels before and after RT, but that was not statistically signifiicant (p = 0.351)
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	?

Zinc level

Outcome type As specificed by the authors	Others
Outcome specification	NI
Type of measurement	NI
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".	Post‐treatment serum zinc levels were signifiicantly lower in the control group than in the treatment group (p = 0.05)
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	No
- 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)	No
Ethnicity mentioned	No

Alternative Explanation

Other explanations for an effect besides the investigated intervention
- Possibility of attention effects	Yes
- Possibility of placebo effects	NA
- 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	No
Consistent reporting in numbers (figures, flowchart, abstract, results)	?
Comprehensive and coherent reporting	No
Cross-over
- Sufficient washout period	NA
- Tested for carry-over effects	NA
- Tested for sequence effects	NA

Interpretation of results

Effect sizes reported (clinical vs. statistical significance)	No
Side effects systematically recorded	No
Side effects considered in result interpretation	No
Ethics votum	?