Argyriou et al. (2006): Preventing Paclitaxel-Induced Peripheral neuropathy: A Phase 2 Trial of Vitamin E Supplementation

Reference ↗
Title	Preventing Paclitaxel-Induced Peripheral neuropathy: A Phase 2 Trial of Vitamin E Supplementation
Topic	Vitamin E
Author	Argyriou, AA, Chroni, E, Koutras, A, Iconomou, G, Papapetropoulos, S, Polychronopoulos, P, Kalofonos, HP
Year	2006
Journal	Journal of Pain and Symptom Management
DOI	https://doi.org/10.1016/j.jpainsymman.2006.03.013

Study Note

Same study design, but different sample as Argyriou et al. (2006): A randomized controlled trial evaluating the efficacy and safety of vitamin E supplementation for protection against cisplatin-induced peripheral neuropathy: final results.

Brief summary

In this study, the effectiveness of vitamin E in preventing peripheral neuropathy (a common side effect associated with chemotherapy) during chemotherapy was investigated in various cancer patients. In the arm of patients who took vitamin E twice daily in addition to chemotherapy, there were significantly fewer cases of peripheral polyneuropathy than in the control arm who received chemotherapy alone. In addition, according to the authors of the study, peripheral polyneuropathy was on average less severe in the vitamin E arm than in the control arm. Points of criticism of this study were the small sample size, the lack of blinding and further possible biases of the study cannot be ruled out due to the poor report quality.

In dieser Studie wurde bei verschiedenen Krebspatienten die Wirksamkeit von Vitamin E hinsichtlich der Prävention peripherer Neuropathie (eine häufige mit Chemotherapie assoziierte Nebenwirkung) während der Chemotherapie untersucht. In der Gruppe von Patienten, die zusätzlich zur Chemotherapie zweimal täglich Vitamin E einnahmen tauchen bedeutsam weniger Fälle von peripherer Polyneuropathie auf, als in der Kontrollgruppe, die lediglich Chemotherapie erhielten. Zudem war die periphere Polyneuropathie laut Autoren der Studie in der Vitamin E-Gruppe im Durchschnitt weniger schwer ausgeprägt als in der Kontrollgruppe. Kritikpunkte dieser Studie waren die kleine Stichprobe, die fehlende Verblindung und weitere mögliche Verzerrungen der Studie wegen der schlechten Berichtqualität nicht ausgeschlossen werden können.

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	No
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	Adult patients with a confirmed diagnosis of solid or nonmyeloid malignancy scheduled to receive six courses of paclitaxel-based chemotherapy regimen were enrolled if they had satisfactory liver and renal function, a life expectancy of at least 9 months, and a WHO performance score of 0–1.
Exclusion criteria	History of peripheral neuropathy (i.e., hereditary, paraneoplastic, or associated with nutritional agents) and a history of systemic diseases (i.e., diabetes mellitus, SLE, HIV, alcohol abuse); excluded if they were not chemotherapy-naïve or if clinical or electrophysiological evidence of peripheral neuropathy was disclosed at baseline
N randomized	37
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, ITT Analysis
Specifications on analyses	Separate intention-to-treat (ITT) and all those who completed the study (PP) analysis for primary endpoint, secondary endpoints only PP analysis
Countries of data collection	NI
LoE Level of evidence	1b Oxford 2009
Outcome timeline Data collection times	T0: Baseline T1 or T2: after 3rd or 6th chemotherapy cycle T3: 3 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.	Curative
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Breast Cancer, Gynecologic Cancers - Ovarian Cancer, Lung Cancer - Non-Small Cell 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	Early Stage, Advanced Stage
Specifications on cancer stages	All stages included.
Comorbidities	NI
Current cancer therapies	Chemotherapy
Specifications on cancer therapies	Paclitaxel-based chemotherapy
Previous cancer therapies	NI
Gender	Mixed
Gender specifications	62.2% female
Age groups	Adults (18+)
Age groups specification	Age Mean (SD) = 57.0 (9.9) (ITT population)

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	2
Drop-out reasons	Disease progression n=1, patient decision n=1
Intervention	Vitamin E, synthetic DL-α-Tocopherylacetat
Dosage and regime	oral, 300mg, 2x daily Duration: during chemotherapy until 3 months afterwards
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	Number of side effects (ITT): Intervention arm: 16/18 (88.8%); control arm: 18/19 (94.7%); p = 0.96 (mainly nausea, vomiting and hair loss, no side effects associated with vitamin E, no deaths caused by vitamin E.

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Passive control
Number of participants (arm) N randomized	19
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	3
Drop-out reasons	Death n=1, Disease progression n=2
Intervention	Usual Care
Dosage and regime	NA
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	NA

Outcomes

Functionality

Outcome type As specificed by the authors	Secondary
Outcome specification	NA
Type of measurement	FGS (Hughes' Functional Grading Scale)
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".	Number of patients ITT: not reported PP: intervention arm: A: grade 0: 13/16; grade 1: 2/16, grade 2: 1/16; control arm: grade 0: 6/16; grade 1: 5/16, grade 2: 4/16; grade 4: 1/16

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	Primary
Outcome specification	Chemotherapy-induced peripheral neuropathy; Outcome rated with PN Score: Gradations mild (1-11), moderate (12- 23) and severe (>24), summarized from the three measurement types
Type of measurement	Electrophysiological evaluation, NDS (Neurological Disability Score), NSS (Neurological Symptom 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".	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".	Number with PIPN ITT: intervention arm: 5/18 (27.8%); control arm: 13/19 (68.4%); p = 0.032 PP: intervention arm: 3/16 (18.7%); 10/16 (62.5%); p = 0.03; RR = 0.3 (95% CI: 0.1, 0.9) PIPN score. Mean (SD): ITT: not reported PP: intervention arm: 2.25 (5.1) (range: 0-15), control arm: 11 (11.63; range: 0-32); p = 0.01 Neurolog. Data (number of patients) intervention arm: mainly numbness/paresthesia limited to fingers/toes (n = 1), stocking-and-glove distribution (n = 2), ankle hyporeflexia ( n = 2) control arm: mainly numbness/paresthesia limited to fingers/toes (n = 3), or extended to knees/elbows ( n = 3), stocking-and-glove distribution (n = 4) Neurophysiolog. Data In each case sign. Difference in amplitude sensor. Action potential: N. ulnaris (p = 0.014), peroneus superfic. (p = 0.003); sural nerve (p = 0.008) Otherwise no sign. differences

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.

CONTRA:

• No blinding of investigators/patients.
• Moderate dropout (11% & 16%).
• Small sample size without power analysis.
• Separate intention-to-treat (ITT) and per-protocol (PP) analyses, but most endpoints reported only for PP.
• Poor reporting quality (e.g., partially missing information on the ITT population, no information on cancer stage, no data on the progression of PIPN during the study).