View source for Pace et al. (2010): Vitamin E neuroprotection for cisplatin neuropathy

{{Reference
|Reference=Publication: Vitamin E neuroprotection for cisplatin neuropathy
}}

=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=

{{Study Design (RCT)
|Perspective=Prospective
|Centralized=Multicentric
|Blinding=Double
|Is randomized=Yes
|Cross-over=No
|Number of arms=2
}}
=Study characteristics=

{{RCT study general properties
|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 Analysis
|Specifications on analyses=NA
|Countries of data collection=Italy
|LoE=2b Oxford 2009
|Outcome timeline=T0: Baseline
T1: after 3. chemotherapy cycle
T2: 1 month post-chemotherapy
}}
=Characteristics of participants=

{{Characteristics of participants
|Setting=Curative
|Types of cancer=Adrenal Cancer, Brain and Central Nervous System (CNS) Cancers - Glioblastoma, Carcinosarcoma, Genitourinary Cancers - Bladder Cancer, Gynecologic Cancers - Endometrial Cancer, Lung Cancer
|Stage cancer=NI
|Cancer stage specification=NI
|Comorbidity=NI
|Current cancer therapy=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
|Arm type=Intervention
|Number of participants (arm)=54
|Drop-out=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=-999
|Side Effects / Interactions=According to information no side effects
|Order number=1
|Arm topic=Vitamin E
}}
{{Arm
|Arm type=Placebo
|Number of participants (arm)=54
|Drop-out=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=-999
|Side Effects / Interactions=According to information no side effects
|Order number=1
|Arm topic=Vitamin E
}}
{{Arm Overview}}
=Outcomes=

{{Outcome
|Outcome type=Primary
|Outcome name=Toxicity
|Outcome specification=Neurotoxicity
|Type of measurement=Electrophysiological evaluation, Neurologic examination, Reidel-Seiffer tuning fork, TNS (Total Neuropathy Score)
|Results during intervention=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=NA
|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=?
|Order number=1
|Outcome topic=Vitamin E
}}
{{Outcome Overview}}
=Funding and Conflicts of Interest=

{{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=

{{Further points for assessing the study
|power analysis performed=?
|Sample size corresponds to power analysis=?
|Reasons given for samples being too small according to power analysis=?
|Samples sufficiently large=?
|Ethnicity mentioned=?
|Other explanations for an effect besides the investigated intervention=?
|Possibility of attention effects=?
|Possibility of placebo effects=?
|Other reasons=?
|Correct use of parametric and non-parametric tests=?
|Correction for multiple testing=?
|Measurement of compliance=?
|Consistent reporting in numbers=?
|Comprehensive and coherent reporting=?
|Cross-over=?
|sufficient washout period=?
|Tested for carry-over effects=?
|Were sequence effects tested=?
|Effect sizes reported=?
|Were side effects systematically recorded=?
|Side effects taken into account in the interpretation of the results=?
|Ethics / CoI / Funding=?
|Blinding reliable=?
|Check whether blinding was successful=?
|reasons given for samples being too small according to power analysis=?
|Testing for normal distribution=?
|Correct application of statistical tests=?
|mono- or multicentric=?
}}
{{Additional Notes
|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).
}}