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

Reference ↗
Title	Zinc supplementation to improve mucositis and dermatitis in patients after radiotherapy for head-and-neck cancers: a double-blind, randomized study
Topic	Zinc
Author	Lin, L-C, Que, J, Lin, L-K, Lin, F-C
Year	2006
Journal	International journal of radiation oncology, biology, physics
DOI	http://10.1016/j.ijrobp.2006.01.015

Brief summary

The study investigated 100 patients with head and neck carcinoma who were treated with radiotherapy. Fifty percent of the patients were randomly assigned to an arm receiving daily zinc, while the other half received a placebo made of soybean oil. The study observed the time interval until the onset, severity, and duration of mucositis (inflammation of the oral mucosa) and dermatitis (eczema). Both mucositis and eczema occurred later and were less severe in the zinc arm. However, two weeks after completing radiotherapy, similar improvements were seen in both arms. Additionally, the authors reported that zinc had no impact on the duration of concurrent chemotherapy, though there was a tendency towards a smoother course. Zinc did not cause additional side effects and was well tolerated. Overall, this study suggests a positive effect of zinc during radiotherapy.

Die Studie beschäftigte sich mit der Untersuchung von 100 Kopf-Hals-Karzinom Patienten, die mit Radiotherapie behandelt wurden. 50% der Patienten wurden zufällig in einen Arm eingeteilt, die täglich Zink erhielt, die andere Hälfte bekam ein Placebo aus Sojaöl. Im weiteren Verlauf wurden das Zeitintervall bis zum Auftreten, die Schwere und die Dauer von Mundschleimhautentzündung (Mukositis) und Ekzemen (Dermatitis) beobachtet. Sowohl eine Entzündung der Mundschleimhaut als auch Ekzeme traten im Zink-Arm später auf und waren von geringerer Schwere. Zwei Wochen nach Beenden der Radiotherapie zeigten sich jedoch ähnliche Verbesserungen in beiden Armen. Als zusätzliche Ergebnisse berichten die Autoren, dass Zink keine Auswirkungen auf die Länge einer zusätzlich stattfindenden Chemotherapie hatte, die Tendenz aber auf einen reibungsloseren Verlauf hindeutete. Zink verursachte keine zusätzlichen Nebenwirkungen, sondern wurde gut vertragen. Anhand dieser Studie kann man insgesamt auf eine positive Wirkung von Zink während Radiotherapie schließen.

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 mellitus
N randomized	100
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	Taiwan
LoE Level of evidence	1b Oxford 2009
Outcome timeline Data collection times	T0: before radiotherapy T1: after 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.	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	Stages I-IV and primary and recurrent tumors
Comorbidities	NI
Current cancer therapies	Chemotherapy, Radiation therapy
Specifications on cancer therapies	Intervention arm: Dose of radiotherapy (cGy): 6,824 (463.5), Placebo arm: Dose of radiotherapy (cGy): 6,651 (1,056.3); Intervention arm: Duration of radiotherapy: 56 (8.7), Placebo arm: Duration of radiotherapy: 54 (11.8); Intervention arm: concurrent chemotherapy: 20 (41) Placebo arm: concurrent chemotherapy: 20 (42)
Previous cancer therapies	NI
Gender	Mixed
Gender specifications	Intervention arm: n=40 (81.6%) male, n=9 (18.4%) female Placebo arm: n=43 (89.6%) male, n=5 (10.4%) female
Age groups	Adults (18+)
Age groups specification	Intervention arm: MW (SD): 50 (11) Placebo arm: MW (SD): 51 (11)

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	50
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	Voluntary withdrawal
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	50
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	2
Drop-out reasons	Voluntary withdrawal
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

"Weight" is not in the list (AQoL-8D (Assessment of Quality of Life), ASAT (Auditory Sustained Attention Test), BIA (Bioelectrical impedance analysis), BPI-SF (Brief Pain Inventory - Short Form), CTCAE (Common Terminology Criteria of Adverse Events), ESAS (Edmonton Symptom Assessment Scale), FAACT (Functional Assessment of Anorexia-Cachexia Therapy), FACIT (Functional Assessment of Chronic Illness Therapy), FLIE (Functional Living Index for Emesis), Genitourinary atrophy self-assessment tool, ...) of allowed values for the "Type of measurement" property.

Mucositis

Outcome type As specificed by the authors	NI
Outcome specification	Incidence and severity
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 2 mucositis (p = 0.017) appeared earlier in the placebo arm than in the intervention arm, a similarly significant difference was observed in the development of Grade 3 mucositis (p = 0.0003); mucositis ( p = 0.003) seemed to be milder in the intervention arm than in the placebo arm
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".	2 weeks after the completion of therapy, the conditions of mucositis seemed to have similar improvement in both arms

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	?

Dermatitis

Outcome type As specificed by the authors	NI
Outcome specification	incidence and severity
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 2 dermatitis (p = 0.014) appeared earlier in the placebo group than in the experimental group, a similarly significant difference was observed in the development of Grade 3 dermatitis (p = 0.0092); dermatitis ( p = 0.003) seemed to be milder in the intervention arm than in the placebo arm
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".	2 weeks after the completion of therapy, the conditions of dermatitis seemed to have similar improvement in both arms

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	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".	No significant differences before therapy, in the last week: significant difference of serum zinc levels between the two arm: intervention arm: 20.5 (39.9) vs. placebo arm: -1.5 (39.1), p = 0.02
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".	?

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	?

Interaction with cancer treatment

Outcome type As specificed by the authors	Others
Outcome specification	Effects on concurrent chemotherapy
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".	Zinc not provide a benefit: patients in the intervention arm were unable to tolerate more courses of weekly chemotherapy than patients in the placebo arm
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	?

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".	Weight loss in the two groups was very similar
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	Sponsored by the Chi-Mei Foundation Medical Center (CMFHR9201)
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	?