Azizi et al. (2015): Efficacy of Topical and Systemic Vitamin E in Preventing Chemotherapy-induced Oral Mucositis

Reference ↗
Title	Efficacy of Topical and Systemic Vitamin E in Preventing Chemotherapy-induced Oral Mucositis
Topic	Vitamin E
Author	Azizi, A, Alirezaei, S, Pedram, P, Mafi, AR
Year	2015
Journal	Reports of Radiotherapy and Oncology
DOI	https://doi.org/10.5812/rro.2(1)2015.796

Brief summary

This study investigated the efficacy of vitamin E in preventing oral mucositis (i.e. inflammation of the oral mucosa, a common side effect of chemotherapy) in patients with hematologic cancers such as leukemia and lymphoma. The patients were divided into three different arms, one of which coated the mouth twice daily with a vitamin E paste (arm A), one arm took a vitamin E tablet twice daily (arm B) and the control arm received a placebo paste (arm C). While there were no differences in the number of patients with severe mucositis after the first and second chemotherapy cycles, there were significantly fewer patients in arm A than in the other two arms after the third and fourth cycles. Comparable results were seen in the patients' self-assessment of pain. Here, too, the patients reported comparable pain in the first two cycles and in the other two cycles the pain in arm A was felt to be less than in the other two arms. There are numerous criticisms of this study. Among other things, only a very small sample with a high drop-out rate over the course of the study was examined. In addition, this study lacks numerous details, such as the values of the variables examined at the start of the study and other important demographic variables.

Diese Studie untersuchte die Wirksamkeit von Vitamin E bei der Vorbeugung von oraler Mukositis (d. h. Entzündung der Mundschleimhaut, eine häufige Nebenwirkung der Chemotherapie) bei Patienten mit hämatologischen Krebsarten wie Leukämie und Lymphomen. Die Patienten wurden in drei verschiedene Arme eingeteilt, von denen einer den Mund zweimal täglich mit einer Vitamin-E-Paste bestrich (Arm A), ein Arm nahm zweimal täglich eine Vitamin-E-Tablette ein (Arm B) und der Kontrollarm erhielt eine Placebopaste (Arm C). Während es nach dem ersten und zweiten Chemotherapiezyklus keine Unterschiede in der Zahl der Patienten mit schwerer Mukositis gab, waren es nach dem dritten und vierten Zyklus deutlich weniger Patienten in Arm A als in den beiden anderen Armen. Vergleichbare Ergebnisse ergaben sich bei der Selbsteinschätzung der Patienten bezüglich ihrer Schmerzen. Auch hier gaben die Patienten in den ersten beiden Zyklen vergleichbare Schmerzen an, in den beiden anderen Zyklen wurden die Schmerzen in Arm A als geringer empfunden als in den beiden anderen Armen. Es gibt zahlreiche Kritikpunkte an dieser Studie. Unter anderem wurde nur eine sehr kleine Stichprobe mit einer hohen Abbrecherquote im Verlauf der Studie untersucht. Außerdem fehlen in dieser Studie zahlreiche Details, wie z. B. die Werte der untersuchten Variablen zu Beginn der Studie und andere wichtige demografische Variablen.

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	Single
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	3

Study characteristics

Inclusion criteria	At least 18 years of age, diagnosis of a hematologic cancer (leukemia or lymphoma), and non-smoker and non-alcoholic.
Exclusion criteria	Patients who were supposed to receive head and neck radiotherapy as part of their treatment, patients who were taking anticoagulant therapy, as some studies have shown that vitamin E may increase the bleeding tendency.
N randomized	76
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: Baseline T1: after first cycle T2: after second cycle T3: after third cycle T4: after fourth cycle

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	Hematologic Cancers - Leukemia (Acute Lymphocytic/Acute Myeloid/Chronic Lymphocytic/Chronic Myeloid), Hematologic Cancers - Lymphoma (Hodgkin and Non-Hodgkin)
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	NA
Specifications on cancer stages	NA
Comorbidities	NI
Current cancer therapies	Chemotherapy
Specifications on cancer therapies	NI
Previous cancer therapies	NI
Gender	Mixed
Gender specifications	46% female
Age groups	Adults (18+)
Age groups specification	Mean (SD) = 30.72 (8.41) 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	26
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	7 (3 after third cycle, 4 after fourth cycle)
Drop-out reasons	Various reasons (death, severe mucositis, noncompliance, etc.)
Intervention	Vitamin E paste
Dosage and regime	1g; 2x daily Duration: day -2 chemotherapy until 20 days after the end of the chemotherapy cycle for 4 chemotherapy cycles
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	Intervention
Number of participants (arm) N randomized	24
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	8 (3 after third cycle, 5 after fourth cycle)
Drop-out reasons	Various reasons (death, severe mucositis, noncompliance, etc.)
Intervention	Vitamin E tablets
Dosage and regime	oral, 200mg, 2x daily Duration: day -2 chemotherapy until 20 days after the end of the chemotherapy cycle for 4 chemotherapy cycles
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	26
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	12 (4 after third cycle, 8 after fourth cycle)
Drop-out reasons	Various reasons (death, severe mucositis, noncompliance, etc.)
Intervention	Placebo paste
Dosage and regime	1g; 2x daily Duration: day -2 chemotherapy until 20 days after the end of the chemotherapy cycle for 4 chemotherapy cycles
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

Mucositis

Outcome type As specificed by the authors	Primary
Outcome specification	Oral mucositis
Type of measurement	WHO-Scale (World Health Organisation)
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".	Number in % with grade 3-4 After 1st cycle intervention arm (paste): 7.6, intervention arm (tablets): 8.3, placebo arm: 7.6; p = ns After 2nd cycle intervention arm (paste): 11.5, intervention arm (tablets): 12.5, placebo arm: 15.3; p = ns After 3rd cycle intervention arm (paste): 21.7, intervention arm (tablets): 33.3, placebo arm: 31.8; p = 0.01
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 in % with grade 3-4 After 4th cycle intervention arm (paste): 26.3, intervention arm (tablets): 43.7, placebo arm: 42.8; p = 0.01

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	?

Pain

Outcome type As specificed by the authors	Primary
Outcome specification	NA
Type of measurement	VAS (Visual Analogue 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".	Mean value After the 1st cycle Intervention arm (paste): 1.2, intervention arm (tablets): 1.3, placebo arm: 1; p = ns After 2nd cycle Intervention arm (paste): 2, intervention arm (tablets): 1.9, placebo arm: 2.2; p = ns After 3rd cycle Intervention arm (paste): 2.43, intervention arm (tablets): 3.8, placebo arm: 4.4; p = 0.05
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".	Mean value After 4th cycle Intervention arm (paste): 2.9, intervention arm (tablets): 4.33, placebo arm: 4.86; p = 0.001

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:

• Blinding of investigators.

CONTRA:

• Unclear randomization.
• No blinding of patients.
• Small sample size without power analysis.
• Very high dropout rate (after the fourth CTX cycle: Vitamin E paste: 27%, Vitamin E oral: 33%, Placebo: 46%).
• No information on compliance.
• Multiple testing without time-based models.
• Poor reporting quality (e.g., no information on cancer types or stages, no standard deviations or 95% confidence intervals, no baseline values of the variables studied).