Ertekin et al. (2004): Zinc sulfate in the prevention of radiation-induced oropharyngeal mucositis: a prospective, placebo-controlled, randomized study

Reference ↗
Title	Zinc sulfate in the prevention of radiation-induced oropharyngeal mucositis: a prospective, placebo-controlled, randomized study
Topic	Zinc
Author	Ertekin, MV, Koç, M, Karslıoğlu, I, Sezen, O
Year	2004
Journal	International journal of radiation oncology, biology, physics
DOI	http://10.1016/S0360-3016(03)01562-1

Brief summary

The study investigated the effects of zinc on the occurrence of inflammation of the oral mucosa (mucositis) in 30 patients with head and neck carcinoma during radiotherapy treatment. For this purpose, all patients were randomly divided into two arms, with one half receiving zinc and the other a placebo. The onset, duration, and severity of oral mucositis were examined over the following 13 weeks. The authors concluded that in the zinc arm, mucositis started later, was less severe, occurred only at higher radiation doses, and lasted for a shorter duration compared to the placebo arm. However, the study is critically limited by the small number of patients examined. Additionally, since various aspects of the study’s procedure and implementation remain unclear, no general conclusions about the effects of zinc should be drawn from this study.

Die Studie beschäftigte sich mit den Auswirkungen von Zink auf das Auftreten von Entzündungen der Mundschleimhaut (Mukositis) bei 30 Patienten mit Kopf-Hals Karzinom während Radiotherapiebehandlung. Zu diesem Zweck wurden alle Patienten zufällig in zwei Armen aufgeteilt, wobei die eine Hälfte Zink und die andere ein Placebo erhielt. Untersucht wurden in den darauffolgenden 13 Wochen das Einsetzen, die Dauer und die Schwere von Mundschleimhautentzündung. Die Autoren kamen zu dem Schluss, dass diese im Zink-Arm später einsetzte, weniger schwer war, erst bei höherer Strahlungsdosis entstand und weniger lange anhielt, als im Vergleichsarm mit Placebo. Kritisch an der Studie ist jedoch die geringe Anzahl der untersuchten Patienten. Aufgrund der Tatsache, dass außerdem verschiedene Aspekte zum Ablauf und Vorgehen innerhalb der Untersuchung unklar bleiben, sollte man anhand der Studie keine allgemeinen Aussagen zur Wirkung von Zink treffen.

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	Histologically proven cancer of the head and neck (Karnofsky’s performance status ≥70) who were to receive curative radiotherapy or chemoradiotherapy
Exclusion criteria	Previous history of autoimmune or chronic inflammatory disease, radiotherapy and cytotoxic chemotherapy had previously been administered, use of medicine with the aim of mucositis prophylaxis, less than one-third of buccal mucosa was in the radiotherapy region, patient refused entry
N randomized	30
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	Turkey
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T0: before radiotherapy Once a week during treatment After treatment 6 weeks after treatment

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	22 patients had undergone surgery before radiotherapy, and 8 patients were treated with radiotherapy only (telecobalt radiotherapy (Picker C-9) at 80 cm SSD using conventional fractionation of 2 Gy/fraction, five fractions weekly for 20 –35 fractions within 4 –7 weeks). According to tumor stage, localization, and histologic type, the treatment portals consisted of two lateral parallel opposing fields for the primary tumor and upper cervical lymph nodes and/or an anterior portal field for the lower cervical lymph nodes and supraclavicular lymph nodes. Immobilization with a thermoplastic mask was established for all patients, and individual lead protective blocks were used. The median radiation dose was 6400 cGy (range 4000– 7000). In the zinc sulfate arm, the median radiation dose was 6600 cGy (range 4000–7000), and in the placebo group, it was 6200 cGy (range 4000 – 6800). 3 patients in the zinc sulfate arm and 3 in the placebo arm were administered concomitant chemoradiotherapy.
Previous cancer therapies	Surgery
Gender	Mixed
Gender specifications	24 male, 6 women
Age groups	Adults (18+)
Age groups specification	Median age: 54, Range: 18-71

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	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	Zinc sulfate + local anesthetic solutions and analgesic agents were given to patients developing pain from mucositis
Dosage and regime	Three times daily at 8-hour intervals, capsules containing 50 mg zinc (Zinco 220 capsule), Duration was from first day of radiotherapy, during radiotherapy and for 6 weeks after treatment (including weekends and other times when interruption of radiotherapy was necessary)
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	3 patients with RTOG Grade 3 vomiting and nausea

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	15
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	1x died during treatment, 1x withdrew from the study, 1x not attended the 6-week control visit after treatment
Intervention	Placebo + local anesthetic solutions and analgesic agents were given to patients developing pain from mucositis
Dosage and regime	Three times daily at 8-hour intervals, empty capsules bought from the same medicine firm to be identical to the zinc sulfate capsules, Duration was from first day of radiotherapy, during radiotherapy and for 6 weeks after treatment (including weekends and other times when interruption of radiotherapy was necessary)
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 serious side effects

Outcomes

Mucositis

Outcome type As specificed by the authors	NI
Outcome specification	Duration, severity and onset of oropharyngeal mucositis according to the dose of RT
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".	Intervention arm: Mucositis developed in 13 of 15 patients; Grade 1 mucositis was found in 8 patients and Grade 2 in 5 patients; Grade 3 and 4 was not developed; dose of radiotherapy for the patients in whom mucositis developed i was 3600 cGy (range 2400-4400) Placebo arm: Grade 2 mucositis was developed in 4 patients and Grade 3 in 8 patients; Grade 4 mucositis did not occur in any patient; the median radiotherapy dose was 2000 cGy (range 1800-2800) Statistically significant differences were found in the week mucositis developed, in the severity of mucositis, and in the RT dose at which mucositis developed in favour of the intervention arm; mucositis began to appear in the second week at 1800 cGy; at the start of the third week and in the middle of the fourth week, it peaked and then began to lower; after 2400 cGy, the difference in the mucositis scores between the zinc and placebo groups was statistically significant and continued to be until 6 weeks after treatment
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".	6 weeks after treatment, mucositis was found in 1 of the patients in the intervention compared with 10 patients in the placebo arm (Fisher’s exact chi-square test 16.2, p < 0.01)

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	NI
Outcome specification	NI
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; weight loss increased as the week of radiotherapy advanced (Friedman chi-square test 40.42 p < 0.001); statistically significant difference in body weight measured before radiotherapy and the first day after radiotherapy
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".	The distinction in weight disappeared between the baseline and 6-week post-radiotherapy measurement

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	NI
- Reasons for insufficient sample size based on power analysis	NI
If no power analysis performed: at least moderate sample size (n >= 30 per arm)	?
Ethnicity mentioned	No

Alternative Explanation

Other explanations for an effect besides the investigated intervention	NI
- Possibility of attention effects	?
- 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	NI
Correction for multiple testing	?
Measurement of compliance	No
Consistent reporting in numbers (figures, flowchart, abstract, results)	?
Comprehensive and coherent reporting	No
Cross-over	NI
- 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	Yes
Side effects considered in result interpretation	No
Ethics votum	?

Additional Notes

PRO:

• Ethics vote available

CONTRA:

• Small sample
• Overall, very selective reporting: Some of the statistical parameters for described analyses are missing (concerning the weight of the patients), the type of randomization and blinding remain unclear
• No detailed description of the general conditions
• The methodology does not mention that weight should also be investigated, but this is then included in the results