Revision as of 09:01, 4 July 2024

Reference ↗
Title	Does zinc sulfate prevent therapy-induced taste alterations in head and neck cancer patients? Results of phase III double-blind, placebo-controlled trial from the North Central Cancer Treatment Group (N01C4)
Topic	Zinc
Author	Halyard, MY, Jatoi, A, Sloan, JA, Bearden, JD, Vora, SA, Atherton, PJ, Perez, EA, Soori, G, Zalduendo, AC, Zhu, A, Stella, PJ, Loprinzi, CL
Year	2007
Journal	International journal of radiation oncology, biology, physics
DOI	http://10.1016/j.ijrobp.2006.10.046

Study Note

Brief summary

Halyard et al. conducted a study on 169 patients with head and neck carcinoma to investigate the influence of zinc on changes in taste perception (dysgeusia), quality of life, and weight during radiotherapy treatment. They also examined the tolerability of zinc. Patients were randomly assigned to receive either zinc or a placebo. The results showed that zinc did not improve the time interval until the onset of taste changes, the overall frequency of these changes, or the time span until symptom recovery. There was also no improvement in quality of life. Side effects were comparable in both arms in terms of frequency and severity, except for swallowing disorders, which were significantly more common in the zinc arm. The findings suggest that zinc has no positive impact on taste changes during radiotherapy. The authors carefully considered the necessary sample size for their analyses and studied a large number of patients. The arms were tested for comparability at the beginning, reducing the likelihood of biased results. The main criticism of this study is the dropout rate of patients over time. It remains unclear when and for what reasons participants left the study, and the study's framework conditions are inadequately described.

Halyard und Kollegen untersuchten in ihrer Studie an 169 Patienten mit Kopf-Hals Karzinom den Einfluss von Zink auf Veränderungen des Geschmackssinns (Dysgeusie), die Lebensqualität und das Gewicht während der Behandlung durch Radiotherapie. Zusätzlich wurde die Verträglichkeit von Zink betrachtet. Patienten bekamen dafür zufällig entweder Zink oder ein Placebo verabreicht. Es stellte sich heraus, dass durch Zink weder das Zeitintervall bis zum Auftreten von Geschmacksveränderungen, noch die generelle Häufigkeit oder die Zeitspanne bis zu einer Erholung der Symptome verbessert wurden, ebenso wenig wie die Lebensqualität. Nebenwirkungen traten in beiden Armenn vergleichbar oft und schwer auf, mit Ausnahme von Schluckstörungen, die im Zink-Arm deutlich öfter beschrieben wurden. Die Ergebnisse lassen darauf schließen, dass Zink keinen positiven Einfluss auf Geschmacksveränderungen während einer Radiotherapie nehmen kann. Die Autoren der Studie beschäftigten sich ausführlich mit der notwendigen Stichprobengröße für ihre Analysen und untersuchten eine große Anzahl an Patienten. Die Arme wurden zu Beginn auf ihre Vergleichbarkeit getestet, was eine Verzerrung der Ergebnisse unwahrscheinlicher werden lässt. Hauptkritikpunkt an dieser Studie ist der Ausfall der Patienten über die Zeit. Unklar bleibt dabei, wann und aus welchen Gründen die untersuchten Personen die Studie verließen, zudem sind die Rahmenbedingungen der Studie unzureichend beschrieben.

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	Multicentric
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	Head and neck cancer patients scheduled to receive ≥2,000 cGy of external beam radiotherapy to ≥30% of the oral cavity; ≥18 years of age; life expectancy of ≥3 months (as determined by the physician’s judgment); Eastern Cooperative performance score of 0, 1, or 2; be able to take oral medications reliably and be alert and competent; receiving amifostine and/or concomitant chemotherapy was allowed
Exclusion criteria	known mechanical obstruction of the alimentary tract; malabsorption, or intractable vomiting; previous surgery that had included ablation or removal of the olfactory component of taste; known intolerance to zinc sulfate; or untreated oral thrush; women who were pregnant, nursing, or of childbearing potential and unwilling to use contraception
N randomized	169
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	NI
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	weekly during radiotherapy; at 1, 2, 3, and 6 months after radiotherapy completion

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.	NI
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	NI
Specifications on cancer stages	NI
Comorbidities	NI
Current cancer therapies	Chemotherapy, Radiation therapy
Specifications on cancer therapies	planned radiation dose ≥6,000 vs. ≤6,000 cGy; n=71 with concomitant chemotherapy anticipated
Previous cancer therapies	NI
Gender	Mixed
Gender specifications	70% men
Age groups	Adults (18+)
Age groups specification	Median: 54 years, Range: 31-88 years

Arms

Drop-Out numbers and included patients for the analysis very unclear and inconsistent; Duration: start within 7 days of the initiation of radiotherapy and continue for another 4 weeks after radiotherapy completion

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	84
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	Drop-Out numbers and included patients for the analysis very unclear and inconsistent; In Analysis: 8 In Consort Diagram: 81 completed a questionnaire at baseline, 75 completed questionnaires during at least one follow-up visit, 36 completed the entire study
Drop-out reasons	27 patients declined further treatment, 6 dropped out from adverse events, 1 from disease progression, 3 other medical problems, 2 died on study, 8 dropped for other reasons
Intervention	Zinc sulfate
Dosage and regime	45 mg zinc sulfate orally 3 times daily after meals, Duration: start within 7 days of the initiation of radiotherapy and continue for another 4 weeks after radiotherapy completion
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	7% moderate or severe dysphagia and others but with our significant differences between the arms

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	85
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	Drop-Out numbers and included patients for the analysis very unclear and inconsistent; In Analysis: 2 In Consort Diagram: 83 completed a questionnaire at baseline, 83 completed questionnaires during at least one follow-up visit, 47 completed the entire study
Drop-out reasons	17 patients declined further treatment, 5 dropped out from adverse events, 2 from disease progression, 5 from other medical problems, 2 died on study, 7 dropped for other reasons
Intervention	Placebo
Dosage and regime	An identical-appearing placebo prescribed at the same frequency, Duration: start within 7 days of the initiation of radiotherapy and continue for another 4 weeks after radiotherapy completion
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	4% moderate or severe dysphagia and others but without significant differences between the arms

Outcomes

"Others" 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.

"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.

Dysgeusia

Outcome type As specificed by the authors	Primary
Outcome specification	Interval to taste alteration
Type of measurement	Self-developed measurement instrument
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 in the interval to taste alterations; the only factor that had a significant affect in influencing the outcome was the amount of oral mucosa in the radiation field (p = 0.004) + Zinc sulfate did not favorably affect most other clinical parameters either
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	?

Dysgeusia

Outcome type As specificed by the authors	Secondary
Outcome specification	Incidence of taste alteration
Type of measurement	Self-developed measurement instrument
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".	Not significant taste alterations during the first 2 months between the arms (p = 0.16)
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	?

Quality of life

Outcome type As specificed by the authors	Secondary
Outcome specification	NA
Type of measurement	LASA (Linear Analogue Self-Assessment)
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 significant differences
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	Secondary
Outcome specification	NA
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".	As many as 99% of zinc-treated patients maintained their weight in contrast to 92% of placebo-exposed patients (p = 0.04)
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	?

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