Lin et al. (2008): Effects of zinc supplementation on clinical outcomes in patients receiving radiotherapy for head and neck cancers: a double-blinded randomized study

Reference ↗
Title	Effects of zinc supplementation on clinical outcomes in patients receiving radiotherapy for head and neck cancers: a double-blinded randomized study
Topic	Zinc
Author	Lin, L-C, Que, J, Lin, K-L, Leung, HW-C, Lu, C-L, Chang, C-H
Year	2008
Journal	nternational journal of radiation oncology, biology, physics
DOI	http://10.1016/j.ijrobp.2007.06.073

Study Note

This study is a follow-up 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

In this study, Lin and colleagues investigated the effect of zinc during radiotherapy treatment on overall survival time, the time intervals until local recurrence of the tumor, local recurrence of metastases and the occurrence of distant metastases in head and neck carcinoma patients. Half of the patients were given zinc, the other half a placebo consisting of soybean oil. It was found that the administration of zinc had no effect on the general lifespan or the time until the appearance of local or distant metastases and that there were no significant differences between the zinc and placebo arms. Only cancer growth tended to be delayed by zinc, although this was particularly true for patients with stage III-IV cancer and receiving chemotherapy at the same time as radiotherapy. Accordingly, the results of the study can only be generalized to a very limited extent, as many analyses were only calculated for very specific subgroups (such as stage III-IV cancer patients receiving chemotherapy at the same time). The extent to which the various subgroups are comparable and the size of each arm remains unclear. Furthermore, the results described focus strongly on those that showed a difference due to the administration of zinc. The three other factors investigated remain relatively unnoticed in the evaluation, but their results indicate that zinc has no positive influence on the lifespan or growth of distant metastases in head and neck cancer patients.

Lin und Kollegen untersuchten in dieser Studie die Wirkung von Zink während der Radiotherapie-Behandlung auf die allgemeine Überlebenszeit, die Zeitintervalle bis zu einem lokalen Wiederauftreten des Tumors, einem lokalen Wiederauftreten von Metastasen und dem Auftreten entfernter Metastasen bei Kopf-Hals- Karzinom Patienten. Eine Hälfte der Patienten bekam dafür Zink, die andere ein, aus Sojabohnenöl bestehendes, Placebo verabreicht. Es stellte sich heraus, dass die Gabe von Zink keine Auswirkungen auf die allgemeine Lebenszeit oder die Dauer bis zum Auftreten lokaler oder entfernter Metastasen hatte und es zwischen dem Zink- und Placebo-Arm zu keinen bedeutsamen Unterschieden kam. Allein das Krebswachstum konnte durch Zink tendenziell hinausgezögert werden, wobei dies v.a. für Patienten mit einem Krebsstadium von III-IV und gleichzeitig zur Radiotherapie stattfindender Chemotherapie galt. Dementsprechend lassen sich die Ergebnisse der Studie nur sehr beschränkt verallgemeinern, da viele Analysen für nur ganz bestimmte Teilgruppen berechnet wurden (wie Krebspatienten im Stadium III-IV und gleichzeitig erhaltener Chemotherapie). Inwiefern die verschiedenen Teilgruppen vergleichbar sind und welche Größe sie jeweils umfassten bleibt dabei unklar. Des Weiteren konzentrieren sich die beschrieben Ergebnisse stark aus solche, die einen Unterschied durch die Gabe von Zink erbrachten. Die drei weiteren untersuchten Faktoren bleiben in der Auswertung relativ unbeachtet, deuten in ihren Ergebnissen aber darauf hin, dass Zink keinen positiven Einfluss bei Kopf-Hals-Karzinom Patienten auf die Lebensspanne oder das Wachstum entfernter Metastasen hat.

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	2b Oxford 2009
Outcome timeline Data collection times	T0: after radiotherapy Follow-Up: every 3 months after therapy

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, 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: mean (SD): 50 (11) Placebo arm: mean (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

"LFS (Local-Free Survival)" is not in the list (Anorexia/Cachexia, Anxiety, Appetite, Cerebral oedema, Cognitive functioning, Cognitive impairment, Depression, Dermatitis, Distress, Dysgeusia, ...) of allowed values for the "Outcome name" property.

"MFS (Metastases-Free Survival)" is not in the list (Anorexia/Cachexia, Anxiety, Appetite, Cerebral oedema, Cognitive functioning, Cognitive impairment, Depression, Dermatitis, Distress, Dysgeusia, ...) of allowed values for the "Outcome name" property.

OS (Overall Survival)

Outcome type As specificed by the authors	Primary
Outcome specification	Time from the first day of treatment to death
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 duration of follow-up was 22.3 months (1- 47 months): no significant differences

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	?

DFS (Disease-Free Survival)

Outcome type As specificed by the authors	Secondary
Outcome specification	More specifically: LFS (Local-Free Survival), from the date of the first treatment until the date local tumor progression was documented
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".	Patients with recurrent disease had significantly worse LFS than patients with primary disease (HR, 2.23; 95% CI, 1.17–4.26, p = 0.015) and worse LFS than patients with primary Stages I–II disease (HR, 9.4; 95% CI, 1.22–72.39, p = 0.031), completion of radiotherapy was a significantly beneficial factor for LFS (HR, 6.84; 95% CI, 2.62–17.86, p < 0.001); Univariate analysis for patients receiving concurrent chemoradiotherapy: poorer prognosis of patients with recurrent disease than for those with primary disease (HR, 5.25; 95% CI, 2.06–13.42, p = 0.001), better LFS with completion of radiotherapy (HR, 12.49; 95% CI, 2.4–65, p = 0.003), worse LFS of patients in placebo arm than patients in intervention arm (HR, 3.01; 95% CI, 1.1–8.23, p = 0.032); Multivariate analysis: placebo arm (HR, 5.25; 95% CI, 1.73–15.88, p = 0.003) and recurrent disease (HR, 8.83; 95% CI, 3.13–24.88, p < 0.001) emerged as independent predictors of poor LFS

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	?

DFS (Disease-Free Survival)

Outcome type As specificed by the authors	Secondary
Outcome specification	The date of the first treatment to local recurrence or distant metastases
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".	No significant differences between intervention and placebo arm

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	?

DFS (Disease-Free Survival)

Outcome type As specificed by the authors	Secondary
Outcome specification	More specifically: MFS (Metastases-Free Survival), from the date of the first treatment until the date distant metastases occurred
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".	No significant differences

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	?

Additional Notes

PRO:

• Ethics vote available
• Given comparability of the two groups in all important characteristics and zinc levels
• Large sample size
• Double blinding

CONTRA:

• No information on reasons for attrition (3%)
• Selectively reported: Reference is made to the tables for the results, the focus in the results section is only on endpoint 2, lack of information on statistical parameters (focus on significant results)
• Multiple testing in repeatedly different group comparisons, whereby it is not clear how many patients the individual groups comprise in each case
• Results of significant subgroup analyses are only mentioned for the first time in the discussion section
• No mention of reasons for exclusion of patients