Sangthawan et al. (2015): Effects of zinc sulfate supplementation on cell-mediated immune response in head and neck cancer patients treated with radiation therapy

Reference ↗
Title	Effects of zinc sulfate supplementation on cell-mediated immune response in head and neck cancer patients treated with radiation therapy
Topic	Zinc
Author	Sangthawan, D, Phungrassami, T, Sinkitjarurnchai, W
Year	2015
Journal	Nutrition and cancer
DOI	https://dx.doi.org/10.1080/01635581.2015.1004735

Study Note

This study is a follow-up analysis of Sangthawan et al. (2013): 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.

Brief summary

The present study dealt with the question of the extent to which zinc supplementation influences the survival of patients with head and neck cancer. Seventy patients undergoing radiotherapy at the same time were randomly divided into two arms, one of which received zinc and the other a placebo. Annual measurements were taken of general survival and disease-free interval. The tolerability of zinc was also investigated. It was found that zinc had no effect on overall survival and the time interval until recurrence of the disease. At the same time, however, no side effects were observed from the administration of zinc.

Die vorliegende Studie beschäftigte sich mit der Frage, inwiefern eine Nahrungsergänzung durch Zink Einfluss auf das Überleben und die von Patienten mit Kopf-Hals Karzinomen auswirkt. Man untersuchte 70 Patienten, die sich zur gleichen Zeit einer Radiotherapie unterziehen mussten und teilte diese zufällig in zwei Armen auf, von der die eine Zink und die andere ein Placebo erhielt. Es fanden jährliche Messungen bzgl. des allgemeinen Überlebens und krankheitsfreien Intervalls statt. Außerdem wurde die Verträglichkeit von Zink untersucht. Es wurde festgestellt, dass Zink keine Auswirkungen auf das allgemeine Überleben und das Zeitintervall bis zu einem erneuten Auftreten der Erkrankung hatte. Gleichzeitig wurden aber auch keine Nebenwirkungen durch die Gabe von Zink festgestellt.

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	72

Study characteristics

Inclusion criteria	Older than 18 years, had a histologically docu- mented diagnosis of head and neck cancer, and had a Karnof- sky Performance Status Scale score of at least 70
Exclusion criteria	A previous diagnosis of cancer, a concomitant cancer, distant metastases or recurrent cancer, prior radiation therapy or chemotherapy, pregnancy, an autoimmune disease, or drugs received that contained zinc
N randomized	72
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	70 received the complete treatment
Countries of data collection	Thailand
LoE Level of evidence	1b Oxford 2009
Outcome timeline Data collection times	Follow-ups: at the first month after completion of radiation therapy, every 3 month to 2 year, every 6 month to 5 year, annually thereafter

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	Early Stage, Advanced Stage
Specifications on cancer stages	n=28 stage I-II, n=38 stage III-IV, n=6 unknown
Comorbidities	NI
Current cancer therapies	Radiation therapy
Specifications on cancer therapies	All patients treated with Cobalt 60 or 6 MV photon treatment machines, the daily fractionation was 2 Gy in 5 weekly fractions
Previous cancer therapies	Surgery
Gender	Mixed
Gender specifications	Intervention arm: 33 (92%) male, 3 (8%) female Placebo arm: 31 (86%) male, 5 (14%) female
Age groups	Adults (18+)
Age groups specification	Intervention arm: mean: 62 (43–78) Placebo arm: mean: 60 (29–77)

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	36
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	Refused the radiation therapy
Intervention	Zinc sulfate
Dosage and regime	Oral syrup that consisted of elemental zinc at a concentration of 5 mg per cc, self-administered at 50 mg (10 cc) per meal, 3 times a day at meal times, Duration: on the first day of radiation and 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	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	32
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	Personal reasons
Intervention	Placebo
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 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	Vomiting

Outcomes

Zinc level

Outcome type As specificed by the authors	Others
Outcome specification	Serum zinc level
Type of measurement	Blood Test
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".	Serum zinc level of the intervention arm increased during radiation therapy and was significantly higher than that of the placebo arm (p < 0.001)
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	?

PFS (Progression-Free Survival)

Outcome type As specificed by the authors	Secondary
Outcome specification	NI
Type of measurement	Observation
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".	NA
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".	There were no significant differences in the 1-, 3- and 5-year progression-free survival percentages

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	?

OS (Overall Survival)

Outcome type As specificed by the authors	Secondary
Outcome specification	NI
Type of measurement	Observation
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".	NA
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".	Median follow-up times were 33 month (3.8-79 month) for the intervention arm and 18.6 month (3-79 month) for the placebo arm: the 1-, 3- and 5-year overall survival percentages were not significantly different

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	The study was supported by a grant from the Faculty of Medicine, Prince of Songkla University, Thailand.
Conflicts of Interest	NI

Further points for assessing the study

Sample

Power analysis performed	?
- 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	?

Alternative Explanation

Other explanations for an effect besides the investigated intervention	NI
- 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	NI
Correction for multiple testing	?
Measurement of compliance	?
Consistent reporting in numbers (figures, flowchart, abstract, results)	?
Comprehensive and coherent reporting	?
Cross-over	NI
- 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

PRO:

• Ethics vote available
• Given comparability of the groups
• Testing of patient compliance
• Investigation of adverse events
• Intention-to-treat analyses
• Double blinding