Reference ↗
Title	Vitamin E neuroprotection for cisplatin neuropathy
Topic	Vitamin E
Author	Pace, A, Giannarelli, D, Galie, E, Savarese, A, Carpano, S, Della Giulia, M, Pozzi, A, Silvani, A, Gaviani, P, Scaioli, V, Jandolo, B, Bove, L, Cognetti, F
Year	2010
Journal	Neurology
DOI	https://doi.org/10.1212/WNL.0b013e3181d5279e

Brief summary

This study investigated the effect of vitamin E on the occurrence of peripheral neuropathy (i.e. damage to multiple peripheral nerves, a common side effect associated with chemotherapy). The vitamin E arm took vitamin E daily for up to one month after chemotherapy and the control arm took a placebo instead. The results of this study are analogous to the findings of the study by Pace (2003). The authors reported significant differences in favor of the vitamin E arm both in the results of the electrophysiological measurements of one arm and one leg nerve and in the comparison of the patients' self-reported limitations. The polyneuropathy score determined by the authors, which includes several aspects of neuropathy and describes the severity of neuropathy, was also significantly lower in the vitamin E arm than in the control arm. There are numerous points of criticism of this study. In particular, the very high rate of over 60% of patients who dropped out during the course of the study and could not be included in the analysis makes a bias in the results very likely. Apart from this, incorrect use of the statistical methods cannot be ruled out.

In dieser Studie wurde der Effekt von Vitamin E auf das Auftreten von peripherer Neuropathie (d.h. der Schädigung mehrerer peripherer Nerven, eine häufige mit Chemotherapie assoziierte Nebenwirkung) untersucht. Der Vitamin E-Arm nahm während bis ein Monat nach der Chemotherapie täglich Vitamin E ein und der Kontrollarm stattdessen nur ein Placebo. Die Ergebnisse dieser Studie sind analog zu den Befunden der Studie von Pace (2003). Sowohl bei den Ergebnissen der elektrophysiologischen Messungen jeweils eines Arm- und eines Beinnervs, als auch beim Vergleich der selbstberichteten Einschränkungen der Patienten, berichteten die Autoren über bedeutsamen Unterschiede zugunsten des Vitamin E-Arms. Auch der von den Autoren ermittelten Polyneuropathie-Score, der mehrere Neuropathie-Aspekte einbezieht und die Neuropathie-Schwere beschreibt, fiel im Vitamin E Arm bedeutsam geringer aus als im Kontrollarm. An dieser Studie gibt es zahlreiche Kritikpunkte. Vor allem die sehr hohe Rate an Patienten von über 60%, die im Laufe der Studie ausgeschieden sind und nicht in die Auswertung einbezogen werden konnten, machen eine Verzerrung in den Ergebnissen sehr wahrscheinlich. Abgesehen davon kann eine fehlerhafte Verwendung der statistischen Methoden nicht ausgeschlossen werden.

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	Patients with solid malignancies and Karnofsky Performance Status 70–100
Exclusion criteria	Previous chemotherapeutic treatment or regimens including other neurotoxic drugs associated with cisplatin
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	Italy
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T0: Baseline T1: after 3. chemotherapy cycle T2: 1 month post-chemotherapy

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	Adrenal Cancer, Brain and Central Nervous System (CNS) Cancers - Glioblastoma, Carcinosarcoma, Genitourinary Cancers - Bladder Cancer, Gynecologic Cancers - Endometrial Cancer, Lung 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	NI
Specifications on cancer stages	NI
Comorbidities	NI
Current cancer therapies	Chemotherapy
Specifications on cancer therapies	Cisplatin-based chemotherapy, cisplatin was administered in combination regimens on the basis of the specific tumor site
Previous cancer therapies	NI
Gender	Mixed
Gender specifications	38.9% female
Age groups	Adults (18+)
Age groups specification	Median: 58.25; range: 28-74 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	37
Drop-out reasons	Received less than 300mg cumulative dose
Intervention	Vitamin E, alpha-tocopherol
Dosage and regime	400 mg daily, orally Start: before chemotherapy (Median: 3 days prior (Range: 1-8)) Duration: until 3 months post-chemotherapy
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	According to information 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	54
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	30
Drop-out reasons	Received less than 300mg cumulative dose
Intervention	Placebo
Dosage and regime	400 mg daily, orally Start: before chemotherapy (Median: 3 days prior (Range: 1-8)) Duration: until 3 months post-chemotherapy
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	According to information no side effects

Outcomes

Toxicity

Outcome type As specificed by the authors	Primary
Outcome specification	Neurotoxicity
Type of measurement	Electrophysiological evaluation, Neurologic examination, Reidel-Seiffer tuning fork, TNS (Total Neuropathy Score)
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".	Amplitude (µV): Mean (SD) N. suralis Intervention: prior to chemotherapy: 18.3 (9.9), 1 month after chemotherapy: 14.4 (7.1) Placebo: prior to chemotherapy: 23.8 (13.9), 1 month after chemotherapy: 18.3 (12.8) Intervention vs. Placebo: p < 0.05, sign. N. medianus Intervention: prior to chemotherapy: 11.4 (5.2), 1 month after chemotherapy: 11.5 (6.3) Placebo: prior to chemotherapy: 15.2 (9.0), 1 month after chemotherapy: 12.4 (8.3) Intervention vs. Placebo: p < 0.01, sign. Reflexes and distal paresthesia: Number of patients prior to chemotherapy: Intervention and Placebo: 0 1 month after chemotherapy: Intervention: 6/17, Placebo: 13/24 Neurotoxicity Score 1 month after chemotherapy (based on TNS system): Mean (SD) Intervention: 1.4 (1.5), Placebo: 4.1 (4.5); p < 0.01, sign. Number of patients with TNS Grade >3: Intervention: 1/17 (5.9%), Placebo: 10/24 (41.7%); p < 0.01, sign. RR = 0.14 (95% CI: 0.02, 1.00); p < 0.05, sign.
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	See Conflicts of Interest.
Conflicts of Interest	"Dr. Pace has received speaker honoraria from Schering-Plough Corp. and Italfarmaco. D. Giannarelli and Dr. Galie report no disclosures. Dr. Savarese has received funding for travel and speaker honoraria from Schering-Plough Corp. Dr. Carpano, Dr. Giulia, A. Pozzi, Dr. Silvani, Dr. Gaviani, and Dr. Scaioli report no disclosures. Dr. Jandolo serves on the editorial board of Neurobiologia and the editorial advisory board of Neurological Science. Dr. Bove reports no disclosures. Dr. Cognetti has served on scientific advisory boards of Bayer Schering Pharma, Wyeth, Roche, and Sanofi-Aventis; serves as a consultant for Abbott, Wyeth, and AstraZeneca; and receives research support from the Italian National Health System."

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:

Ethical approval obtained.

CONTRA:

Small sample size (less than calculated in power analysis, N < 80).
Very high dropout rate (A: 69%; B: 56%, main reason: Cisplatin dose < 300 mg/m²).
No intention-to-treat analysis.
Homogeneity of variance likely not met in some statistical analyses.
Poor reporting quality (e.g., no information on compliance).