Afonseca et al. (2013): Vitamin E for prevention of oxaliplatin-induced peripheral neuropathy: A pilot randomized clinical trial

Reference ↗
Title	Vitamin E for prevention of oxaliplatin-induced peripheral neuropathy: A pilot randomized clinical trial
Topic	Vitamin E
Author	Afonseca, SOd, Cruz, FM, Cubero, DDdlG, Lera, AT, Schindler, F, Okawara, M, Souza, LFd, Rodrigues, NP, Giglio, Ad
Year	2013
Journal	Sao Paulo Medical Journal
DOI	https://doi.org/10.1590/S1516-31802013000100006

Brief summary

In this study, the efficacy of vitamin E in preventing peripheral neuropathy (a common side effect associated with chemotherapy) during chemotherapy and in alleviating the general side effects associated with chemotherapy was investigated in colorectal and gastric cancer patients). No significant differences were found between the arm receiving vitamin E and the placebo arm in terms of both peripheral neuropathy and general side effects. However, it can be criticized that only a very small sample was examined and that important information was missing due to the poor quality of the report (e.g. in some cases the results could only be read from a graph).

In dieser Studie wurde bei Darm- und Magenkrebspatienten die Wirksamkeit von Vitamin E hinsichtlich der Prävention von peripherer Neuropathie (eine häufige mit Chemotherapie assoziierte Nebenwirkung) während der Chemotherapie und bezüglich der Linderung der allgemeinen Chemotherapie assoziierter Nebenwirkungen untersucht.). Sowohl hinsichtlich peripherer Neuropathie, als auch hinsichtlich der allgemeinen Nebenwirkungen fanden sich keine bedeutsamen Unterschiede zwischen der Gruppe die Vitamin E erhielt und der Placebo-Gruppe. Man kann jedoch kritisieren, dass nur eine sehr kleine Stichprobe untersucht wurde und dass durch die schlechte Berichtqualität wichtige Informationen fehlen (z.B. konnten man teilweise die Ergebnisse nur aus einer Grafik ablesen).

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	Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, diagnosed with colorectal or gastric cancer and scheduled to receive oxaliplatin-based regimens (fluouracil, leucovarine and oxaliplatin, FLOX; 5-FU/leucovarine plus axaliplatine, FOLFOX; epirubicin, oxaliplatin and capecitabine EOX; and capecitabine plus oxaliplatin, XELOX)
Exclusion criteria	previous history of peripheral neuropathy or with symptomatic peripheral neuropathy at entry into the study. We also excluded patients who had received other chemotherapy regimens (except 5-fluorouracil alone) and those currently receiving gabapentin, carbamazepine, amitriptyline, amifostine or multivitamins
N randomized	34
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.	ITT Analysis
Specifications on analyses	NA
Countries of data collection	Brazil
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	NI

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, Adjuvant
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Colorectal Cancer - Colon Cancer, Colorectal Cancer - Rectal Cancer, Gastrointestinal Cancers - Gastric (Stomach) 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	Early Stage, Advanced Stage
Specifications on cancer stages	NI
Comorbidities	Diabetes n=2, Alcohol consumption n=6
Current cancer therapies	Chemotherapy
Specifications on cancer therapies	Oxaliplatin-based chemotherapy + calcium and magnesium supplements before and after oxaliplatin infusions
Previous cancer therapies	Chemotherapy, No therapy
Gender	Mixed
Gender specifications	47.1% female
Age groups	Adults (18+)
Age groups specification	Mean value = 56.5 years; range: 29-76 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	18
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	0
Drop-out reasons	NA
Intervention	Vitamin E
Dosage and regime	From day 0 chemotherapy 400mg daily until end of 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	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	16
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	0
Drop-out reasons	NA
Intervention	Placebo
Dosage and regime	From day 0 chemotherapy daily until end of 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	NI

Outcomes

Peripheral neuropathy

Outcome type As specificed by the authors	Primary
Outcome specification	NA
Type of measurement	CTCAE (Common Terminology Criteria of Adverse Events)
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".	Time of onset of symptoms (graph only): p = 0.66
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: number of grade 1-2 intervention arm: 83%, placebo arm 68%; p = 0.45

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	?

Toxicity

Outcome type As specificed by the authors	NI
Outcome specification	NA
Type of measurement	CTCAE (Common Terminology Criteria of Adverse Events)
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 number (%): Diarrhea: intervention arm: 10 (55.6) (grade 1: n = 5, grade 2: n = 5); placebo arm: 4 (18.8) (grade 1: n = 3, grade 3: n = 1); p = 0.06; No differences with regard to nausea (p = 0.36), vomiting (p = 0.38), mucositis (p = 0.38), fatigue (p = 0.20), headache (p = 0.45), dizziness (p = 0.54), bleeding (p = 0.90)

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:

• Ethical approval obtained.
• Intention-to-treat analysis conducted.

CONTRA:

• Small sample size.
• Blinding lifted before data analysis.
• Overall 11% dropout with unclear group distribution.
• No information on compliance.
• Poor reporting quality (e.g., very brief methods and results sections, no information on Vitamin E administration and timing of endpoint collection, some data only available from graphics).