Pace et al. (2003): Neuroprotective Effect of Vitamin E Supplementation in Patient Treated With Cisplatin Chemotherapy

Reference ↗
Title	Neuroprotective Effect of Vitamin E Supplementation in Patient Treated With Cisplatin Chemotherapy
Topic	Vitamin E
Author	Pace, A, Savarese, A, Picardo, M, Maresca, V, Pacetti, U, Del Monte, G, Biroccio, A, Leonetti, C, Jandolo, B, Cognetti, F, Bove, L
Year	2003
Journal	Journal of Clinical Oncology
DOI	https://doi.org/10.1200/JCO.2003.05.139

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 authors reported significant differences in favor of the vitamin E arm both in the results of the electrophysiological measurements of one arm nerve and one leg nerve, as well as 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 40% 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. In addition, placebo effects cannot be ruled out due to the lack of blinding (i.e. patients and investigators knew which arm they were in).

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. 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 40%, die im Laufe der Studie ausgeschieden sind und nicht in die Auswertung einbezogen werden konnten, machen eine Verzerrung in den Ergebnissen sehr wahrscheinlich. Zudem können aufgrund der fehlenden Verblindung (d.h. Patienten und Untersucher wussten, in welchen Arm sie waren) Placebo-Effekte 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	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	Patients with solid malignancies and a Karnofsky Performance Status between 70 to 100
Exclusion criteria	Previous chemotherapeutic treatment or regimens including other neurotoxic drugs associated with cisplatin
N randomized	47
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	NI
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T0: prior to chemotherapy T1: after 3. chemotherapy-cycle T2: 1 month after 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	Gastrointestinal Cancers - Gastric (Stomach) Cancer, Gastrointestinal Cancers - Esophageal Cancer, Genitourinary Cancers - Testicular Cancer, Gynecologic Cancers - Ovarian Cancer, Head and Neck Cancers - Nasopharyngeal Cancer, Lung Cancer, Uretheral Cancer"Uretheral Cancer" is not in the list (Breast Cancer, Colorectal Cancer, Prostate Cancer, NI, Lung Cancer, Skin Cancer, Gastrointestinal Cancers, Gynecologic Cancers, Hematologic Cancers, Head and Neck Cancers, ...) of allowed values for the "Types of cancer" property., Ethmoid Cancer"Ethmoid Cancer" is not in the list (Breast Cancer, Colorectal Cancer, Prostate Cancer, NI, Lung Cancer, Skin Cancer, Gastrointestinal Cancers, Gynecologic Cancers, Hematologic Cancers, Head and Neck Cancers, ...) of allowed values for the "Types of cancer" property., Tongue Cancer"Tongue Cancer" is not in the list (Breast Cancer, Colorectal Cancer, Prostate Cancer, NI, Lung Cancer, Skin Cancer, Gastrointestinal Cancers, Gynecologic Cancers, Hematologic Cancers, Head and Neck Cancers, ...) of allowed values for the "Types of cancer" property.
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 based on the specific tumor site as follows: Lung and urethral cancer:cisplatin 75 mg/m² on day 1 and gemcitabine 1,000 mg/m² on day 1 and day 8 every 3 weeks; ovarian cancer: cisplatin 75 mg/m² and endoxan 600 mg/m² on day 1 every 3 weeks; head and neck cancer: cisplatin 100 mg/m² on day 1 and fluorouracil 1,000 mg/m² on day 1 to 4 every 3 to 4 weeks; ethmoidal cancer: cisplatin 25 mg/m² and etoposide 80 mg/m² on day 1 to 3 every 3 weeks; gastric cancer: PELF regimen (cisplatin 40 mg/m² and epirubicin 30 mg/m² on days 1 and 5 plus fluorouracil 300 mg/m² and folinic acid 100 mg/m² on days 1 to 4 every 3 weeks); testicular cancer: PEB regimen (cisplatin 20 mg/m² and etoposide 100 mg/m² on days 1 to 5 plus bleomycin 30 mg on days 2, 9, and 16 every 3 weeks)
Previous cancer therapies	NI
Gender	Mixed
Gender specifications	25.9% female
Age groups	Adults (18+)
Age groups specification	Median: 57.5; 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	13
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	Reported n=2 Not seperated by group n=18
Drop-out reasons	Reported n=2 suspended Vitamin E supplementation after 1 month, Not seperated by arm: interrupted treatment after two or three cycles because of disease progression n=18
Intervention	Vitamin E, alpha-tocopherol
Dosage and regime	300 mg daily, orally Start: before chemotherapy (Median: 4 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	Passive control
Number of participants (arm) N randomized	14
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	Not seperated by group n=18
Drop-out reasons	Not seperated by arm: interrupted treatment after two or three cycles because of disease progression n=18
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

<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> <!--br--><li>"Neurologic Examination" 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	NA
Type of measurement	Electrophysiological evaluation, Neurologic examination, 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".	Electrophysiological Measurement: Mean (SD): N. suralis Amplitude (µV): Intervention: prior to chemotherapy: 15.5 (6.3), 1 month after chemotherapy: 13.7 (5.5) Control: prior to chemotherapy: 14.5 (8.5), 1 month after chemotherapy: 13.6 (9.2) Intervention vs. Control: ns. Sensory Conduction Velocity (m/sec): Intervention: prior to chemotherapy: 51.2 (4.1), 1 month after chemotherapy: 49.6 (5.1) Control: prior to chemotherapy: 49.5 (5.1), 1 month after chemotherapy: 45 (5.9) Intervention vs. Control: p < 0.01, sign. N. medianus Amplitude (µV): Intervention: prior to chemotherapy: 15.1 (5.2), 1 month after chemotherapy: 12 (5.1) Control: prior to chemotherapy: 15 (9.2), 1 month after chemotherapy: 8.7 (5.3) Intervention vs. Control: p < 0.01, sign. Impairment Reflexes and Distal Paresthesia: Number of Patients Prior to chemotherapy: Intervention and Control: 0 1 month after chemotherapy: Intervention: 4/13, Control: 12/14 Neurotoxicity Score 1 month after chemotherapy (based on neuropathic signs/symptoms and electrophysiological changes): Mean (SD) Intervention: 2.1 (2.1), Control: 4.7 (2.9); p < 0.01, 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	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	?