Villani et al. (2016): Vitamin E neuroprotection against cisplatin ototoxicity: Preliminary results from a randomized, placebo-controlled trial

Reference ↗
Title	Vitamin E neuroprotection against cisplatin ototoxicity: Preliminary results from a randomized, placebo-controlled trial
Topic	Vitamin E
Author	Villani, V, Zucchella, C, Cristalli, G, Galie, E, Bianco, F, Giannarelli, D, Carpano, S, Spriano, G, Pace, A
Year	2016
Journal	Head and Neck
DOI	https://doi.org/10.1002/hed.24396

Brief summary

In this study, two arms of cancer patients were examined, all of whom received chemotherapy. One arm took 400mg of vitamin E daily in addition to chemotherapy and the control arm took placebos instead. The study investigated the effectiveness of vitamin E in mitigating the side effects of chemotherapy on the inner ear, in particular the sensory cells of the hearing and balance organ, or the associated cranial nerves. In both the 2000 Hz and the 8000 Hz range, the hearing ability of the patients in the control arm was significantly worse, while there were no differences in the vitamin E arm. Otherwise, no significant differences were found. There are numerous criticisms of this study. In particular, the high drop-out rate of over 70% of patients in each arm over the course of the study makes a strong bias in the results very likely. Apart from this, it cannot be assumed beyond doubt that the arms were comparable at the beginning of the study (few demographic data, very small sample).

In dieser Studie wurden zwei Gruppen von Krebspatienten untersucht, die alle Chemotherapie erhielten. Ein Arm nahm zusätzlich zur Chemotherapie täglich 400mg Vitamin E ein und der Kontrollarm stattdessen Placebos. Untersucht wurde die Wirksamkeit von Vitamin E, die Nebenwirkung der Chemotherapie auf das Innenohr, insbesondere die Sinneszellen des Hör- und Gleichgewichtsorganes, oder den zugehörigen Hirnnerven abzumildern. Sowohl im 2000 Hz, als auch im 8000 Hz-Bereich wurde die Hörfähigkeit der Patienten im Kontrollarm bedeutsam schlechter, während sich im Vitamin E-Arm keine Unterschiede zeigten. Ansonsten fanden sich keine bedeutsamen Unterschiede. An diese Studie gibt es zahlreiche Kritikpunkte. Vor allem die hohe Ausfallrate im Laufe der Studie von über 70% der Patienten in jedem Arm macht eine starke Verzerrung der Ergebnisse sehr wahrscheinlich. Abgesehen davon kann nicht zweifellos von einer Vergleichbarkeit der Gruppen zu Beginn der Studie ausgegangen werden (wenige demographische Angaben, sehr geringe Stichprobe).

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	Patients with solid malignancies and good functional status (Karnofsky Performance Status 70–100) candidates to receive Cisplatin-chemotherapy
Exclusion criteria	Patients with Karnofsky Performance Status >2, previous exposure to neurotoxic therapies, and/or risk factors for neuropathy onset (diabetes mellitus, chronic alcoholism)
N randomized	108
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	NA
Countries of data collection	NI
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T0: Baseline T1: 1 month T2: 2 month T3: 3 month

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
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Solid Malignancies
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
Specifications on cancer therapies	Cisplatin-chemotherapy
Previous cancer therapies	NI
Gender	Mixed
Gender specifications	52.2% female
Age groups	Adults (18+)
Age groups specification	Mean (SD) = 59 (6) years

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	54
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	41
Drop-out reasons	Interrupted cisplatin early n=19 Suspended Vitamin E after 1 month n=2 Received less than 300mg/m2 dose of cisplatin or completed only one visit n=20
Intervention	Vitamin E
Dosage and regime	Oral, 400mg daily Start: after randomization prior to chemotherapy Duration: until 3 months post-CTX
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	NI

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	54
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	44
Drop-out reasons	Interrupted cisplatin early n=21 Received less than 300mg/m2 dose of cisplatin or completed only one visit n=23
Intervention	Placebo
Dosage and regime	Oral, 400mg daily Start: after randomization prior to chemotherapy Duration: until 3 months post-CTX
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	NI

Outcomes

Ototoxicity

Outcome type As specificed by the authors	Primary
Outcome specification	Audiograms 2000/4000/8000 Hz and evoked brainstem responses
Type of measurement	Audiogram
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".	Mean deterioration Baseline to 1 month (only p-values provided and imprecise graphic) 2000 Hz: Right ear: Intervention arm: p = ns Placebo arm: p = 0.05, sign. Left ear: Intervention arm: p = ns Placebo arm: p = 0.04, sign. 4000 Hz Right ear: Intervention arm: p = ns Placebo arm: p = n/a Left ear: Intervention arm: p = ns Placebo arm: p = n/a 8000 Hz: Right ear: Intervention arm: p = ns Placebo arm: p = 0.04, sign. Left ear: Intervention arm: p = ns Placebo arm: p = 0.03, sign. Evoked brainstem responses Intervention arm and Placebo arm: p = ns Follow-up 2 and 3 month was not possible due to high dropout (Intervention arm and Placebo arm: n = 8 each)
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".	NA

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

PRO:

• Double-blind design (patients/investigators).

CONTRA:

• Fewer patients than calculated in the power analysis (< 80 patients).
• Very high dropout rate (Intervention arm: 76%; Placebo arm: 81%; reasons: discontinuation or insufficient cisplatin; participation in only one assessment, planned follow-up assessments could not take place due to further dropout (Intervention arm and Placebo arm: n = 8 each)).
• No information on compliance.
• No proper statistical comparison between the groups due to small sample size.
• Poor reporting quality (e.g., no specific information on demographic variables such as cancer type, important numerical data missing, only imprecise graphics).
• Due to the lack of demographic variables and the small sample size, the comparability of the groups through randomization cannot be assured.