Reference ↗
Title	The use of vitamin E for the prevention of chemotherapy-induced peripheral neuropathy: results of a randomized phase 3 clinical trial
Topic	Vitamin E
Author	Kottschade, LA, Sloan, JA, Mazurczak, MA, Johnson, DB, Murphy, BP, Rowland, KM, Smith, DA, Berg, AR, Stella, PJ, Loprinzi, CL
Year	2011
Journal	Support Care Cancer
DOI	https://doi.org/10.1007/s00520-010-1018-3

Study Note

Brief summary

This study investigated the effectiveness of vitamin E in preventing chemotherapy-induced peripheral polyneuropathy. The vitamin E arm took vitamin E twice a day in parallel with chemotherapy until one month after chemotherapy, while the control arm received only a placebo instead. According to the authors, there were virtually no significant differences between the two arms. The only exception was the duration of symptoms of peripheral neuropathy. In the vitamin E arm, half of the patients (i.e. 48 patients) experienced a reduction in symptoms after 36 days; in the control arm, only 27 out of 93 patients experienced a reduction during the study period. A positive aspect of this study was the double blinding (i.e. patients and investigators did not know which arm patients were in). A negative aspect was the high drop-out rate of patients during the course of the study, although most of them were still included in the analyses.

In dieser Studie wurde die Wirksamkeit von Vitamin E hinsichtlich der Prävention chemotherapie-induzierter peripheren Polyneuropathie untersucht. Der Vitamin E-Arm nahm täglich parallel zur Chemotherapie bis einen Monat nach der Chemotherapie zweimal täglich Vitamin E ein, der Kontrollarm bekam stattdessen nur ein Placebo. Laut Autoren fanden sich so gut wie keine bedeutsamen Unterschiede zwischen den beiden Armen. Einzige Ausnahme war die Symptomdauer der peripheren Neuropathie. IM Vitamin E Arm sind bei der Hälfte der Patienten (d.h. bei 48 Patienten) die Symptome nach 36 Tagen zurückgegangen, im Kontrollarm konnten nur bei 27 von 93 Patienten während der Studiendauer ein Rückgang festgestellt werden. Positiv an dieser Studie waren die doppelte Verblindung (d.h. Patienten und Untersucher wussten nicht, in welchem Arm Patienten waren). Negativ war die hohe Ausfallrate der Patienten im Laufe der Studie, die meisten davon wurden jedoch trotzdem in die Analysen miteinbezogen.

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 who had all gross cancer removed (microscopic residual disease or residual margin involvement was allowed), scheduled to undergo curative-intent chemotherapy with either taxanes or platinum compounds, have a good performance status (ECOG 0-2), life expectancy ≥6 months, and not have preexisting peripheral neuropathy from any cause
Exclusion criteria	Prior exposure to neurotoxic, not have had any of the following conditions: coronary artery disease, congestive heart failure, diabetes (requiring pharmacologic intervention), head or neck cancers, or a history of a hemorrhagic stroke, pregnant or nursing women, concomitant use of anticoagulants, platelet aggregation inhibitors, opioids, anticonvulsants, tricyclic antidepressants, other neuropathic pain medication agents, or vitamin E, not have been receiving radiation
N randomized	207
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.	mITT Analysis
Specifications on analyses	Patients who received at least one dose of assigned therapy were defined as evaluable for the primary endpoint.
Countries of data collection	NI
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	Baseline, before each chemotherapy, 1 month and 6 months 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.	NI
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Breast Cancer, Lung Cancer, Other 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	Chemotherapy
Specifications on cancer therapies	Taxan (58%), Cisplatin (4%), Carboplatin (1%), Oxaliplatin (26%), Combination (11%)
Previous cancer therapies	NI
Gender	Mixed
Gender specifications	82% female
Age groups	Adults (18+)
Age groups specification	≤ 50 years: 39%, > 50 years: 61%

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	96
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	Before randomization n=7 During study n= 29
Drop-out reasons	Before randomization: n=4 cancelled, n=3 ineligible During study: n=11 refused further treatment, n=8 adverse events, n=2 alternate treatment, n=2 other medical problems, n=6 other reasons
Intervention	Vitamin E, DL-alpha-Tocopherol
Dosage and regime	oral, 300mg, 2x daily, Start: during days 1-4 of chemotherapy Duration: until 1 month 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	No side effects associated with vitamin E reported No sign. differences in patients with severe side effects: intervention arm: grade 3 n = 2 (thrombocytopenia; hypersensitivity, both most likely associated with CTX), placebo arm: grade 4 CNS hemorrhage

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	93
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	Before randomization n=11 During study n=33
Drop-out reasons	Before randomization: n=7 cancelled, n=4 ineligible During study: n=18 refused further treatment, n=3 adverse events, n=4 alternate treatment, n=4 other medical problems, n=3 other reasons, n=1 died on study
Intervention	Placebo
Dosage and regime	oral, 2x daily, Start: during days 1-4 of chemotherapy Duration: until 1 month 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	No side effects associated with placebo reported No sign. differences in patients with severe side effects: intervention arm: grade 3 n = 2 (thrombocytopenia; hypersensitivity, both most likely associated with CTX), placebo arm: grade 4 CNS hemorrhage

Outcomes

<ul><li>"Chemotherapy-induced peripheral neuropathy" is not in the list (Anorexia/Cachexia, Anxiety, Appetite, Cerebral oedema, Cognitive functioning, Cognitive impairment, Depression, Dermatitis, Distress, Dysgeusia, ...) of allowed values for the "Outcome name" property.</li> <li>"Symptom Experience Diary" 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.</li> <li>"Neuropathy Specific Question" 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.</li></ul>

Peripheral neuropathy

Outcome type As specificed by the authors	Primary
Outcome specification	Sensory Neuropathie
Type of measurement	CTCAE (Common Terminology Criteria of Adverse Events), Neuropathy specific question, Symptom experience diary (NCCTG)
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".	NA
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".	Overall: Numer in percentage (95% CI) intervention arm: 34 (25.0, 44.8) placebo arm: 29 (20.1, 39.4); p = 0.43, ns. No significant differences were found in subgroup analyses by gender, age, number of chemotherapy cycles, and types of chemotherapy (p > 0.05 for each). No significant differences in self-reported issues from neuropathic symptoms such as numbness, tingling, etc. (p = 0.11-0.88).

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	?

Peripheral neuropathy

Outcome type As specificed by the authors	Secondary
Outcome specification	Start of sensory neuropathy
Type of measurement	CTCAE (Common Terminology Criteria of Adverse Events), Neuropathy specific question, Symptom experience diary (NCCTG)
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".	NA
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".	Overall: Median in days (95% CI) intervention arm: 58 (43.0, 97.0); placebo arm: 69 (49.0, 105.0); p = 0.58, ns.

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	?

Peripheral neuropathy

Outcome type As specificed by the authors	Secondary
Outcome specification	Length of sensory neuropathy (Onset of symptoms to reduction of symptoms ≥ grade 1)
Type of measurement	CTCAE (Common Terminology Criteria of Adverse Events), Neuropathy specific question, Symptom experience diary (NCCTG)
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".	NA
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".	Overall: Median in days (95% CI) intervention arm: 36 (28.0, 44.0); placebo arm: could not be calculated as symptom reduction occurred in only 27 patients

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	"This study was conducted as a collaborative trial of the North Central Cancer Treatment Group and Mayo Clinic and was supported in part by Public Health Service grants CA-25224, CA-37404, CA-35113, and 124477."
Conflicts of Interest	According to authors none.

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, Double-blinded, Intention-to-treat analysis

CONTRA: Fewer patients than calculated in power analysis, High dropout rate during the study (immediately after randomization (A: Intervention, B: Pacebo): A: 7%, B: 11%; further dropout during the study, still part of ITT analysis: A: 35%, B: 42% due to treatment discontinuation (N = 29), side effects (N = 11), treatment change (N = 6), other medical problems (N = 6), death (N = 1), other reasons (N = 9)), Poor reporting quality (e.g., not all results reported as planned in the methods section, no information on compliance)