Lin et al. (2009): Effects of zinc supplementation on the survival of patients who received concomitant chemotherapy and radiotherapy for advanced nasopharyngeal carcinoma: follow-up of a double-blind randomized study with subgroup analysis

Reference ↗
Title	Effects of zinc supplementation on the survival of patients who received concomitant chemotherapy and radiotherapy for advanced nasopharyngeal carcinoma: follow-up of a double-blind randomized study with subgroup analysis
Topic	Zinc
Author	Lin, Y-S, Lin, L-C, Lin, S-W
Year	2009
Journal	The Laryngoscope
DOI	http://10.1002/lary.20524

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 and a subgroup-analysis of 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.

Brief summary

This study was dedicated to the investigation of 34 patients with nasopharyngeal carcinoma who were removed from a larger sample of a 2006 study to investigate the effect of zinc on overall survival and time interval to local tumor recurrence or distant metastasis after 5 years. The results suggest that zinc had a positive effect on overall survival, time to tumor recurrence or metastasis, and time to local tumor progression. Methodologically, however, this study must be viewed critically, as it only included a very small sample and did not make sure before the analyses whether the conditions for the respective calculations were valid. In addition, in their study from the previous year, Lin and colleagues found exactly opposite results with regard to the same examination points in the total sample of 97 patients, namely that zinc had no effect on the general survival time or the time until the occurrence of local or distant metastases. For this reason, it remains unclear to what extent the findings of the subsample analyzed here can be transferred and applied to other types of cancer.

Diese Studie widmete sich der Untersuchung von 34 Patienten mit Nasopharynxkarzinom, die aus einer größeren Stichprobe einer Untersuchung aus dem Jahr 2006 herausgenommen wurden, um den Effekt von Zink auf die allgemeine Überlebensdauer und die Zeitintervalle bis zu einem lokalen Wiederauftreten des Tumors oder einem Auftreten entfernter Metastasen nach 5 Jahren zu untersuchen. Die Ergebnisse legen nahe, dass Zink die allgemeine Überlebensdauer, das Zeitintervall bis zu einem Wiederauftreten eines Tumors oder Metastasen und die Zeitspanne bis zum Fortschreiten des lokalen Tumors positiv beeinflusste. Methodisch muss man diese Studie jedoch kritisch betrachten, da sie eine nur sehr kleine Stichprobe einschließt und sich vor den Analysen nicht vergewissert, ob die Voraussetzungen für die jeweiligen Berechnungen gelten. Hinzu kommt, dass Lin und Kollegen in ihrer Studie aus dem Vorjahr gemessen an der Gesamtstichprobe von 97 Patienten bezüglich der gleichen Untersuchungspunkte genau gegensätzliche Ergebnisse fanden, nämlich dass Zink keine Auswirkungen auf die allgemeine Überlebensdauer oder die Zeitspanne bis zum Auftreten lokaler oder entfernter Metastasen hatte. Aus diesem Grund bleibt unklar, inwiefern man die Befunde der hier analysierten Teilstichprobe übertragen und auch auf andere Krebsarten beziehen 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, pathologically established stages III and IV advanced nasopharyngeal carcinoma (NPC), concomitant chemotherapy and radiotherapy (CCRT)
Exclusion criteria	Previous radiotherapy for head and neck cancer, double cancers, diabetes mellitus
N randomized	34
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 of 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	Follow-up period of 5 years (followed up on once a month during the first year of study and then every 3 months 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, Adjuvant
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	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	Advanced Stage
Specifications on cancer stages	stages III (n=5) and IV (n=29)
Comorbidities	NI
Current cancer therapies	Chemotherapy, Radiation therapy
Specifications on cancer therapies	Daily fraction was 180 cGy to 200 cGy in five weekly fractions, total dose prescribed was 7,000 cGy; No significant difference in the radiation dose, fraction, and duration was identified between intervention and placebo arm; all patients received concomitant chemotherapy with 5-fluorouracil and cis-platinum
Previous cancer therapies	NI
Gender	Mixed
Gender specifications	Intervention arm: n=14 male, n=3 female Placebo arm: n=13 male, n=4 female
Age groups	Adults (18+)
Age groups specification	Intervention arm: mean (SD): 49.53 (13.75) Placebo arm: mean (SD): 50.88 (10.01)

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	17
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	17
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

"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	The period between the time of treatment and the time of death; Subgroup analysis: no significant difference between the arms for the 5-year OS among the patients with stages III to IV head and neck cancers other than nasopharyngeal carcinoma (p = .357)
Type of measurement	?
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 duration was 32 months (6–68 months): patients in the intervention arm have better rates of OS than those in placebo arm (p = .044)

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	Between the time of first treatment and the time of local recurrence or distant metastases; Subgroup analysis: no significant difference between the arms for the 5-year DFS among the patients with stages III to IV head and neck cancers other than nasopharyngeal carcinoma (p = .752)
Type of measurement	?
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 duration was 32 months (6–68 months): patients in the intervention arm have better rates of DFS than those in placebo (p = .033)

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), between the time of the first treatment and the time when 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".	Median follow-up duration was 32 months (6–68 months): patients in the intervention arm have better rates of LFS than those in intervention arm (p = .007); Subgroup analysis: no significant difference between the arms for the 5-year LFS among the patients with stages III to IV head and neck cancers other than nasopharyngeal carcinoma (p = .467)

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	?
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".	The difference of pretreatment serum zinc levels between the arms was not statistically significant, significant differences posttreatment with higher levels in the intervention arm (mean (SD): 138.76 (32.71) vs. 114.06 (26.08), p = .023)
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	?

Nutrition status

Outcome type As specificed by the authors	Others
Outcome specification	Serum transferrin 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".	No statistically difference between the two patient arms pre-treatment and post-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".	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	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
• Double blinding
• Given comparability of the groups (also regarding the zinc level)

CONTRA:

• Lack of clarity about the time of randomization (already in the 2006 study or again after 5 years?)
• Small sample (no testing of normal distribution)
• Results only reported in a short sentence stating the p-values, MFS is only taken up again in the discussion section - but represents the endpoint that was the only one that did not become significant (focus on significant results)
• Report on NW is not comprehensible ("none of the commonly reported side effects accompanied by orally administered Zinc was observed among patients in the control group")