Arbabi-kalati et al. (2012): Evaluation of the efficacy of zinc sulfate in the prevention of chemotherapy-induced mucositis: A double-blind randomized clinical trial

Reference ↗
Title	Evaluation of the efficacy of zinc sulfate in the prevention of chemotherapy-induced mucositis: A double-blind randomized clinical trial
Topic	Zinc
Author	Arbabi-kalati, F, Deghatipour, M, Moghaddam, AA
Year	2012
Journal	Archives of Iranian Medicine
DOI	https://journalaim.com/Article/327

Brief summary

In this study, 50 patients with different types of cancer were randomly divided into two arms. One arm received zinc treatment in addition to chemotherapy and the other received a placebo. The occurrence of inflammation of the oral mucosa (mucositis) and dry mouth (xerostomia) as well as pain and the quality of life of the patients were examined. It was shown that although the duration of oral mucosal inflammation did not differ between the arms, it was significantly milder in the zinc arm than in the placebo arm and improved more strongly over the 20-week study period. The same was true for dry mouth. Furthermore, patients in the zinc arm complained of less pain. There were no differences between the arms in terms of quality of life. According to the results of this study, zinc cannot prevent the occurrence of oral mucosal inflammation and dryness, but it can reduce their severity and intensity. In general, however, the statements made in this study should be viewed with caution, as several methodological deficiencies can be identified in its implementation. On the one hand, no data on the patients' cancers is provided, nor is the zinc level before the start of the examination. Therefore, differences in these points could already have existed in the arms regardless of the intervention and influenced the result. On the other hand, it remains unclear how long the individual patients were treated with chemotherapy, which is why it is uncertain whether every patient was recorded at every point in time. For this reason, the results can only be trusted to a limited extent.

In dieser Studie wurden 50 Patienten mit verschiedenen Krebserkrankungen zufällig in zwei Arme aufgeteilt. Ein Arm erhielt dabei zusätzlich zur Chemotherapie eine Zinkbehandlung und die andere ein Placebo. Untersucht wurden das Auftreten von Mundschleimhautentzündung (Mukositis) und Mundtrockenheit (Xerostomie) sowie Schmerzen und die Lebensqualität der Patienten. Man zeigte, dass sich die Dauer der Mundschleimhautentzündung zwischen den Armen zwar nicht unterschied, im Zink Arm aber deutlich leichter ausfiel, als imPlacebo-Arm und sich über den Untersuchungszeitraum der 20 Wochen stärker verbesserte. Das Gleiche galt für Mundtrockenheit. Des Weiteren klagten Patienten des Zink-Arms über weniger Schmerzen. Die Lebensqualität betreffend fanden sich keine Unterschiede zwischen den Armen. Zink kann laut den Ergebnissen dieser Studie also zwar nicht das Auftreten von Mundschleimhautentzündung und -trockenheit verhindern, jedoch aber ihre Schwere und Intensität verringern. Generell sollte man die Aussagen dieser Untersuchung aber mit Vorsicht betrachten, da man mehrere methodische Mängel in ihrer Durchführung feststellen kann. Zum einen werden keine Daten zu den Krebserkrankungen der Patienten angegeben, noch der Zinkspiegel vor Beginn der Untersuchung. Somit könnten in diesen Punkten bereits unabhängig von der Intervention Unterschiede in den Armen bestanden und das Ergebnis beeinflusst haben. Zum anderen bleibt unklar, wie lange die einzelnen Patienten mit der Chemotherapie behandelt wurden, weshalb ungewiss ist, ob jeder Patient zu jedem Zeitpunkt erhoben wurde. Aus diesem Grund kann 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	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	Chemotherapy treatment by a regimen with the same mucositis probability, including cyclophosphamide, doxorubicin, dacarbazine, gemcitabine, methotrexate, and 5-fluorouracil; Karnofsky performance status 60 or above; life expectancy equal to or more than 6 months; white blood cell (WBC) count equal to or more than 1500cell/ml platelet counts equal to greater than 100000 μL
Exclusion criteria	Previous or simultaneous radiotherapy in the head and neck region, including the nasopharynx, oropharynx, and larynx; previous head and neck surgery due to malignancy; use of dentures; pregnancy; infection
N randomized	50
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.	NI
Specifications on analyses	Information is missing about how many patients were measured to the different time points
Countries of data collection	Iran
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T0: Baseline (before chemotherapy) T1: after 2 weeks T2: after 4 weeks T3: after 6 weeks T4: after 8 weeks T5: after 10 weeks T6: after 12 weeks T7: after 14 weeks T8: after 16 weeks T9: after 18 weeks T10: after 20 weeks

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.	NI
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Breast Cancer, Gastrointestinal Cancers - Esophageal Cancer, Head and Neck Cancers - Nasopharyngeal Cancer, Hematologic Cancers, Lung Cancer, Prostate Cancer, Stomach Cancer
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
Specifications on cancer therapies	Chemotherapy treatment by a regimen including cyclophosphamide, doxorubicin, dacarbazine, gemcitabine, methotrexate, and 5-fluorouracil
Previous cancer therapies	NI
Gender	Mixed
Gender specifications	Intervention arm: n=12 female, n=13 male Placebo arm: n=12 female, n=13 male
Age groups	Adults (18+)
Age groups specification	Intervention arm: MW (SD): 51.5 (3.3), Range: 18-70 Placebo arm: MW (SD): 47.2 (3.5), Range: 18-79

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	25
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	Zinc sulfate
Dosage and regime	3x 220mg zinc sulfate capsules, 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.	140
Side effects / Interactions	NI

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	25
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	Placebo
Dosage and regime	3x placebo capsules, daily (similar in shape, taste, and color)
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.	140
Side effects / Interactions	NI

Outcomes

Mucositis

Outcome type As specificed by the authors	NI
Outcome specification	Mucositis intensity; mucositis recovery and time effects
Type of measurement	WHO-Scale (World Health Organisation)
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 week 2, 4 and 6 no statistically significant differences in mucositis intensity between arms; in the 8th, 12th, 16th, and 20th week of chemotherapy there were statistically significant differences between both arms (p < 0.005) No statistically significant difference in the mucositis treatment period between both arms Increased drug effect with decreased mucositis intensity over increased time in the intervention arm (p < 0.005).
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	NI
Outcome specification	Xerostomia intensity, xerostomia recovery and time effects
Type of measurement	LENT SOMA Scale (Late Effects on Normal Tissues/ Subjective Objective Management Analysis)
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".	During 2nd week no statistically significant differences in the arms; during 4th week the intensity of xerostomia in the drug arm was less than the placebo arm (p < 0.005), a trend which continued until the 16th week of treatment; during 18th week no differences; during 20th week significantly lower in the intervention arm (p < 0.005) No significant differences in terms of xerostomia treatment Increased drug effect with decreased xerostomia intensity over increased time in the intervention arm (p < 0.005).
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	NI
Outcome specification	Pain intensity and time effects
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".	From the 6th week until the 20th week less pain intensity in the intervention arm than in the placebo arm (p < 0.005) Increased drug effect with decreased degree of pain over increased time in the intervention arm (p < 0.005)
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	?

Quality of life

Outcome type As specificed by the authors	NI
Outcome specification	Specification of type of measurement: EORTC QLQ-OES18 (Oesophageal module)
Type of measurement	EORTC QLQ (European Organisation for Research and Treatment of Cancer Core/ Quality of Life questionnaire)
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 differences 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	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	No
- Possibility of placebo effects	No
- 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	No
Measurement of compliance	No
Consistent reporting in numbers (figures, flowchart, abstract, results)	No
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	Informations are missing"Informations are missing" is not in the list (Yes, No, NI, ?) of allowed values for the "Ethics / CoI / Funding" property.