Lyckholm et al. (2012): A randomized, placebo controlled trial of oral zinc for chemotherapy-related taste and smell disorders

Reference ↗
Title	A randomized, placebo controlled trial of oral zinc for chemotherapy-related taste and smell disorders
Topic	Zinc
Author	Lyckholm, L, Heddinger, SP, Parker, G, Coyne, PJ, Ramakrishnan, V, Smith, TJ, Henkin, RI
Year	2012
Journal	Journal of pain & palliative care pharmacotherapy
DOI	http://10.3109/15360288.2012.676618

Brief summary

The study investigated the relationship between zinc and changes in the sense of taste and smell in cancer patients during chemotherapy. In two randomly divided arms, 20 patients were given zinc and 21 a placebo over a period of three months. Over the course of the study, there was a tendency towards an improvement in the sense of smell and taste, although there were no significant differences between the arms or regarding the loss of these sensory stimuli. As a conclusion of the study, the authors therefore advise against treatment with zinc. However, as the study has several methodological shortcomings, such as the purely subjective measurement of the change in taste and smell, the high drop-out rate of participating patients during the course of the study and the complete lack of reporting of important statistical parameters, the results can only be viewed very critically and are not considered to be very trustworthy.

Die durchgeführte Studie beschäftigte sich mit dem Zusammenhang von Zink und Veränderungen im Geschmacks- bzw. Geruchssinn bei Krebspatienten während der Chemotherapie. In zwei zufällig aufgeteilten Armen bekamen über einen Zeitraum von drei Monaten hinweg 20 Patienten Zink und 21 ein Placebo. Im Verlauf der Studie zeigte sich eine Tendenz zur Verbesserung des Geruchs- und Geschmackssinns, wobei es keine bedeutsamen Unterschiede zwischen den Armen bzw. den Verlust dieser Sinnesreize betreffend gab. Als Fazit der Untersuchung raten die Autoren deshalb von einer Behandlung mit Zink ab. Da die Studie jedoch mehrere methodische Mängel aufweist, wie die rein subjektive Messung der Geschmacks- und Geruchsveränderung, der hohe Ausfall von teilnehmenden Patienten im Verlauf der Untersuchung und der völlige Verzicht auf die Berichterstattung wichtiger statistischer Parameter, können die Ergebnisse nur sehr kritisch betrachtet werden und gelten als wenig vertrauenswürdig.

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	≥18 years old, currently receiving, or had received, chemotherapy as part of their cancer treatment were asked if they have had any loss or change in their sense of taste or smell since starting chemotherapy: those answering “yes” were invited to participate in the study
Exclusion criteria	NI
N randomized	58
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	T0: prior to intervention T1-T3: at 1, 2, and 3 months after initiating zinc versus placebo

Characteristics of participants

26 patients used multiple vitamins at the same time

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	Breast Cancer, Colorectal Cancer - Colon Cancer, Gastrointestinal Cancers - Pancreatic Cancer, Genitourinary Cancers - Bladder Cancer, Gynecologic Cancers - Cervical Cancer, Hematologic Cancers - Leukemia (Acute Lymphocytic/Acute Myeloid/Chronic Lymphocytic/Chronic Myeloid), Hematologic Cancers - Lymphoma (Hodgkin and Non-Hodgkin), Lung Cancer, Prostate Cancer, Skin Cancer – Melanoma, Unspecified Sarcoma
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	14 patients were receiving or had received radiation therapy
Previous cancer therapies	NI
Gender	Mixed
Gender specifications	n=41 female
Age groups	Adults (18+)
Age groups specification	Mean: 53

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	29
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	Not arm specified: 15
Drop-out reasons	Death (non–study related) (n=4), cancer treatment discontinued (n=4), toxicity (diarrhea, abdominal pain, cramps, diaphoresis) (n=2), pill burden (n=2), family member asked the patient to withdraw consent (n=1), and no reason given (n=2)
Intervention	Zinc
Dosage and regime	Zinc dose was 220 mg orally twice daily (equivalent of 50 mg elemental zinc twice daily)
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.	84
Side effects / Interactions	Not arm specified: diarrhea, abdominal pain, cramps, diaphoresis

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	29
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	Not arm specified: 15
Drop-out reasons	Death (non–study related) (n=4), cancer treatment discontinued (n=4), toxicity (diarrhea, abdominal pain, cramps, diaphoresis) (n=2), pill burden (n=2), family member asked the patient to withdraw consent (n=1), and no reason given (n=2)
Intervention	Placebo
Dosage and regime	Capsules, containing lactose monohydrate powder and looked identical to the zinc capsules
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.	84
Side effects / Interactions	Not arm specified: diarrhea, abdominal pain, cramps, diaphoresis

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.

Taste alteration

Outcome type As specificed by the authors	Primary
Outcome specification	Change in taste and smell
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 statistically significant difference in loss of smell, distortion of smell, loss of taste, or distortion of taste; Taste and smell changes were highly correlated (p < .0001)
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	Yes
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	?