Reference ↗
Title	Discrepancy of the effects of zinc supplementation on the prevention of radiotherapy-induced mucositis between patients with nasopharyngeal carcinoma and those with oral cancers: subgroup analysis of a double-blind, randomized study
Topic	Zinc
Author	Lin, Y-S, Lin, L-C, Lin, S-W, Chang, C-P
Year	2010
Journal	Nutrition and cancer
DOI	https://dx.doi.org/10.1080/01635581003605532

Study Note

This study is a retrospective subgroup-analysis of Lin et al. (2006): Zinc supplementation to improve mucositis and dermatitis in patients after radiotherapy for head-and-neck cancers: a double-blind, randomized study.

Brief summary

The analyses conducted in this publication included 83 patients with nasopharyngeal carcinoma (NPC) or oral carcinoma (OC), which were removed from a sample of Lin from 2006 with originally 100 patients. The occurrence of oral mucositis during radiotherapy was investigated, for which 44 patients received a zinc preparation (of which 21 patients had NPC and 23 had OC) and the remaining 39 patients received an identical-looking placebo of soybean oil (19 NPC, 20 OC). In the subgroup of patients with oral carcinoma, there was a later onset of 2nd and 3rd degree oral mucositis as a result of zinc intake. Compared with the placebo group, the duration of severe inflammation of the oral mucosa was also shorter in the patients who had taken zinc. In the subgroup of patients with nasopharyngeal carcinoma, however, no differences were found - neither in the occurrence of 2nd or 3rd degree inflammation of the oral mucosa nor in its duration. In summary, it can be said that according to this study, zinc only has a positive effect on patients with oral carcinoma, regardless of which radiotherapy they received. In the subgroup of patients with nasopharyngeal carcinoma, however, no differences were found - neither in the occurrence of grade 2 or 3 oral mucositis nor in its duration. In summary, it can be said that according to this study, zinc only has a positive effect on patients with oral carcinoma, regardless of which radiotherapy they received. In contrast, there appear to be no benefits of zinc intake in cancer patients with nasopharyngeal carcinoma. However, a critical aspect of this study is that various information on the analyses is not reported and the number of patients in the individual subgroups is relatively small, meaning that the accuracy of the results can only be assessed as limited.

Die in dieser Veröffentlichung durchgeführten Analysen umfassten 83 Patienten mit Nasopharynxkarzinom (NPK) oder oralen Karzinom (OK), die aus einer Stichprobe von Lin aus dem Jahr 2006 mit ursprünglich 100 Patienten herausgenommen wurden. Untersucht wurde das Auftreten von Mundschleimhautentzündung (Mukositis) während Radiotherapie, wofür 44 Patienten ein Zinkpräparat (davon hatten 21 Patienten ein NPK und 23 ein OK) und die übrigen 39 Patienten ein identisch aussehendes Placebo aus Sojaöl (19 NKP, 20 OK) bekamen. In der Teilgruppe der Patienten mit Oralkarzinom zeigte sich ein späteres Einsetzen von Mundschleimhautentzündung 2. und 3. Grades in Folge der Zinkeinnahme. Verglichen mit der Placebo-Gruppe war auch die Dauer der schweren Entzündung der Mundschleimhaut bei den Patienten, die Zink eingenommen hatten kürzer. In der Subgruppe der Patienten mit Nasopharynxkarzinom ließen sich hingegen keine Unterschiede feststellen – weder im Auftreten der Mundschleimhautentzündung 2. oder 3. Grade, noch in ihrer Dauer. Zusammenfassend lässt sich sagen, dass laut dieser Untersuchung Zink nur auf Patienten mit Oralkarzinom eine positive Wirkung hat und dies unabhängig davon, welche Radiotherapie sie bekamen. Bei Krebspatienten mit Nasopharynxkarzinom scheinen sich hingegen keine Vorteile einer Zinkeinnahme zu ergeben. Kritisch an dieser Studie ist jedoch, dass verschiedene Informationen zu den Analysen nicht berichtet werden und es sich um relativ geringe Patientenzahlen in den einzelnen Subgruppen handelt, sodass die Genauigkeit der Ergebnisse nur als eingeschränkt bewertet werden kann.

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	Aged >18 years, had a radiotherapy field covering more than one-third of the buccal mucosa
Exclusion criteria	Previous radiotherapy of the head and neck; diabetes
N randomized	83
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 in the subgroup analysis were evaluated at the end of the study
Countries of data collection	Taiwan
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T0: before radiotherapy 1st Follow-Up at 3 months after radiotherapy 2nd Follow-Up at 12 months 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.	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 - Oral Cancer, Head and Neck Cancers - Nasopharyngeal 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	Early Stage, Advanced Stage
Specifications on cancer stages	Stage II-IV and recurrent cancer
Comorbidities	NI
Current cancer therapies	Chemotherapy, Radiation therapy
Specifications on cancer therapies	Nasopharyngeal Cancer: daily fractionations of 180 cGy to 200 cGy in 5 weekly fractions; total dose: 7000 cGy Oral Cancer: 7000 cGy was given to patients without surgery and 6000 cGy was prescribed as adjuvant treatment if they received an operation, unilateral irradiation was performed for cancers arising from retromolar, unilateral gum, lip, or single focus of buccal mucosa; whereas bilateral irradiation was done for tumors arising from mouth floor or multiple foci of buccal mucosa
Previous cancer therapies	Surgery
Gender	Mixed
Gender specifications	Nasopharyngeal cancer: intervention arm: 17 (81.0%) male, 4 (19.0%) female Nasopharyngeal cancer: placebo arm: 15 (78.9%) male, 4 (21.1%) female Oral cancer: intervention arm: 19 (83.0%) male, 4 (17%) female Oral cancer: placebo arm: 20 (100%) male
Age groups	Adults (18+)
Age groups specification	Nasopharyngeal cancer: intervention arm: mean (SD): 50.60 (14.17) Nasopharyngeal cancer: placebo arm: mean (SD): 52.63 (11.28) Oral cancer: intervention arm: mean (SD): 50.48 (9.10) Oral cancer: placebo arm: mean (SD): 51.30 (10.81)

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	44
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
Dosage and regime	Oral zinc (25 mg Pro-Z), three capsules per day
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.	56
Side effects / Interactions	No side effects

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	42
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	Placebo
Dosage and regime	Three capsule containing soybean oil per day
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.	56
Side effects / Interactions	No side effects

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".	SEVERITY For the entire group of patients with head and neck cancers, Grade 2 mucositis (p = 0.009) and Grade 3 mucositis (p = 0.001) appeared sooner in the placebo arm than in the intervention arm; Subgroup analyses by disease type: Oral cancer: Grade 2 mucositis (p < 0.001) and Grade 3 mucositis (p < 0.001) appeared sooner in the placebo arm than in the intervention arm Nasopharyngeal cancer: no significant difference in the development of Grade 2 and Grade 3 mucositis; Hazard ratio (placebo vs. experimental) in patients with oral cancer was 2.60 times the corresponding hazard ratio in patients with nasopharyngeal cancer (p = 0.036) in the development of Grade 2 mucositis and 5.95 times in the development of Grade 3 mucositis DURATION For the entire group of patients, a statistically significant difference was found (intervention arm: 3.55 vs. placebo arm: 4.46 wk, p = 0.033); Subgroup analyses by disease type: Oral cancer: significant difference for the average durations of severe mucositis between the intervention and placebo arm (3.12 vs. 5.14 wk, p = 0.001), Nasopharyngeal cancer: no significant difference for the average durations of severe mucositis 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	?

Zinc level

Outcome type As specificed by the authors	Others
Outcome specification	NI
Type of measurement	Atomic absorption
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".	Same serum zinc and transferrin levels prior to therapy; Both patient arms exhibited a large value of fluctuation, with a wide range of SD, trends of zinc level of the intervention and placebo arm during treatment also varied significantly
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