Revision as of 09:41, 4 July 2024

Reference ↗
Title	A randomized, controlled clinical trial to evaluate the effects of zinc sulfate on cancer patients with taste alterations caused by head and neck irradiation
Topic	Zinc
Author	Ripamonti, C, Zecca, E, Brunelli, C, Fulfaro, F, Villa, S, Balzarini, A, Bombardieri, E, De Conno, F
Year	1998
Journal	Cancer
DOI	https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/(SICI)1097-0142(19980515)82:10<1938::AID-CNCR18>3.0.CO;2-U

Study Note

Brief summary

In this study, the authors investigated the effects of zinc on changes in perception (i.e. recognizing a taste difference compared to water) and specific recognition of the tastes sour, salty, sweet and bitter. difference compared to water) and the specific recognition of the tastes sour, salty, sweet and bitter. Nine out of 18 patients with head and neck carcinoma were given a zinc preparation and the other nine a placebo. It was then investigated to what extent the arms differed in their perception of taste during radiotherapy and one month after the end of radiotherapy. All patients showed a change in taste during the therapy. occurrence of changes in taste. However, during radiotherapy, the placebo arm deteriorated more than the zinc arm and the zinc arm recovered within one month. arm recovered from the changes more quickly than the placebo arm within one month of treatment. With regard to the flavors, significant differences in perception and recognition were observed in the zinc arm, which is why this this study could be used to recommend the use of zinc. The study carried out a complex statistical analysis that was adapted to the size of the sample. However, both the process of arm allocation and the study design do not allow for the inclusion of baseline values, in terms of ensuring the comparability of the arms and usable baseline data at the beginning of the study leaves much to be desired.

In dieser Studie untersuchten die Autoren die Auswirkungen von Zink auf Veränderungen der Wahrnehmung (d.h. Erkennung eines geschmacklichen Unterschieds im Vergleich zu Wasser) und der spezifischen Erkennung der Geschmacksrichtungen sauer, salzig, süß und bitter. Neun von 18 Patienten mit Kopf-Hals Karzinom erhielten hierfür ein Zinkpräparat und die anderen neun ein Placebo. Es wurde dann untersucht, inwiefern sich die Arme in ihrer Geschmackswahrnehmung während der Radiotherapie und einen Monat nach deren Beenden unterschieden. Alle Patienten zeigten während der Therapie ein Auftreten von Geschmacksveränderungen. Während der Radiotherapie verschlechterte sich der Placebo-Arm jedoch stärker, als der Zink-Arm und der Zink-Arm erholte sich innerhalb eines Monats nach der Behandlung schneller von den Veränderungen als der Arm mit Placebo. In Hinblick auf die Geschmacksrichtungen konnte man im Zink-Arm bzgl. einzelner bedeutsame Unterschiede in der Wahrnehmung und Erkennung feststellen, weswegen man anhand dieser Studie zur Einnahme von Zink raten könnte. Die Studie führt eine aufwendige und für die Größe der Stichprobe angepasste statistische Analyse durch in diese sogar Ausgangswerte eingeschlossen werden, allerdings lässt sowohl der Vorgang der Armzuordnung als auch der Studienaufbau, im Sinne der Sicherstellung der Vergleichbarkeit der Arme und verwertbaren Ausgangsdaten zu Beginn der Studie zu wünschen übrig.

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	External beam radiotherapy treatment for head and neck cancer for the first time
Exclusion criteria	Demolitive surgery of the tongue, palate, or oropharynx; the presence of oral lesions, such as stomatitis, ulcers, necrosis, or candidiasis; complete or full upper dentures; elimination of the olfactory component of taste after laryngectomy; concomitant administration of chemotherapy and or any other kind of drug affecting taste; lesions of cranial nerves V, VII, IX, or X; damage to the nervous system after surgery or cerebral lesions; metabolic alterations or disorders; endocrine or neurologic diseases known to influence taste and/or smell sensitivity; local disease in the nose or ears; and lack of cooperation on the part of patients
N randomized	18
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	Italy
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T0: prior to radiotherapy, weekly intervals during radiotherapy Follow-Up: 1 month 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.	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	Radiation therapy
Specifications on cancer therapies	External beam radiotherapy: LINAC or Cobalt-10, total mean radiation dose (SD): 62.3 (9.13), radiotherapy duration (wks) (SD): 7.38 (1.28); daily fractions of 180– 200 cGy lasting from 5 to 9 weeks, for a total dose of 45-70 Gy, the radiation fields were the same for all patients, and the tongue was always included
Previous cancer therapies	Chemotherapy
Gender	Mixed
Gender specifications	n=14 male (78%), n=4 female (22%)
Age groups	Adults (18+)
Age groups specification	Mean (SD): 57.9 (12.81)

Arms

Duration: from the onset of subjective perception of taste alterations (hypogeusia or dysgeusia) and continuing through radiotherapy until 1 month after radiotherapy termination

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	9
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: 1
Drop-out reasons	Stopped receiving radiotherapy at the 4th week due to acute oral cavity toxicity (assessment at 1 month after ERT termination was not made)
Intervention	Zinc sulfate
Dosage and regime	5-mg zinc sulfate tablets 3 times daily after meals, Duration: from the onset of subjective perception of taste alterations (hypogeusia or dysgeusia) and continuing through radiotherapy until 1 month after radiotherapy termination
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	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	9
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: 1
Drop-out reasons	Stopped receiving radiotherapy at the 4th week due to acute oral cavity toxicity (assessment at 1 month after ERT termination was not made)
Intervention	Placebo
Dosage and regime	Placebo tablets 3 times daily after meals, Duration: from the onset of subjective perception of taste alterations (hypogeusia or dysgeusia) and continuing through radiotherapy until 1 month after radiotherapy termination
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	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.

Taste alteration

Outcome type As specificed by the authors	NI
Outcome specification	Taste acuity (detection and recognition) for four taste qualities (salty, sweet, sour, and bitter)
Type of measurement	Three-stimulus drop technique (by Henkin)
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".	T0: before receiving radiotherapy, 15 patients (88.9%) had already experienced a reduction in taste acuity in at least 1 of the detection or recognition thresholds for at least 1 of the 4 taste qualities, whereas 66.7% of the patients had 4 taste qualities compromised (in both detection and recognition thresholds), the moment of subjective worsening of taste acuity reported by the patient to be the moment to start zinc sulfate or placebo treatment: after 1 week of radiotherapy, 55% of the placebo arm versus 11% of the intervention had already begun their respective prescribed treatment, 2nd week: taste alteration awareness rose to 77% for the placebo arm and 66% for the intervention arm, 4th week: taste alteration awareness rose to 100% for both groups; During radiotherapy, the worsening of taste acuity in the placebo arm was greater than in the intervention 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".	1 month after radiotherapy: patients in the intervention arm had quicker recovery of taste acuity than the those in the placebo arm (with the exception of the NaCl detection threshold), up to total recovery of taste acuity with respect to basal time and the NaCl recognition threshold, and even an improvement in the HCl recognition threshold

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".	No statistically significant difference in weight loss between the two arms at the end of radiotherapy
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 statistically significant difference in weight loss between the two arms 1 month after radiotherapy

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	Supported in part by Italian Research Council Grant No. ACRO 96.00692.PF39 and Italian As- sociation for Cancer Research Grant No. AIRC 198512
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