Study Note
Brief summary
This study investigated the efficacy of, among other things, vitamin E in alleviating radiotherapy-associated fibrosis (i.e. abnormal proliferation of connective tissue in human and animal tissues and organs) in breast cancer patients. Over a period of six months, four different study arms were investigated, of which one arm received a combination of vitamin E and pentoxifylline in addition to radiotherapy, one arm received pentoxifylline and a placebo, one arm received only vitamin E and a placebo and the control arm received two placebos instead. Since the vitamin E/placebo arm showed comparable values to the control arm and less favorable values to the combination of vitamin E and pentoxifylline in terms of both surface reduction and volume reduction of fibrosis, it can be concluded that vitamin E alone has no effect on radiotherapy-associated fibrosis. Positive aspects of this study were the double blinding and the low dropout. Negative was the small sample size (especially selected statistical methods). In addition, further biases cannot be excluded due to the poor report quality (e.g. no information on pairwise group comparisons).
Diese Studie untersuchte die Wirksamkeit von unter anderem Vitamin E, Radiotherapie assoziierte Fibrose (d.h. krankhafte Vermehrung des Bindegewebes in menschlichen und tierischen Geweben und Organen) bei Brustkrebspatientinnen zu lindern. In einem Zeitraum von sechs Monaten wurden vier verschiedenen Studienarme untersucht, von denen ein Arm zusätzlich zur Radiotherapie eine Kombination aus Vitamin E und Pentoxifyllin, ein Arm Pentoxifyllin und ein Placebo, ein Arm nur Vitamin E und ein Placebo und der Kontrollarm stattdessen zwei Placebos erhielt. Da, sowohl bezüglich der Oberflächenreduktion, als auch der Volumenreduktion der Fibrose der Vitamin E/Placebo-Arm vergleichbare Werte wie der Kontrollarm und ungünstigere Werte wie die Kombination aus Vitamin E und Pentoxifyllin zeigte, kann geschlussfolgert werden, dass Vitamin E allein keinen Effekt auf die Radiotherapie assoziierte Fibrose hat. Positiv an dieser Studie waren die doppelte Verblindung und der geringe Dropout. Negativ war die kleine Stichprobe (vor allem gewählten statistischen Methoden). Zusätzlich dazu können weitere Verzerrungen wegen der schlechten Berichtqualität nicht ausgeschlossen werden (z.B. keine Angaben zu paarweisen Gruppenvergleichen).
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
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| Is randomized
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Yes
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| Cross-over Participants alternate between different treatment groups or conditions over a specified period, allowing each participant to serve as their own control
|
No
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| Number of arms
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4
|
Study characteristics
| Inclusion criteria
|
Women who had had radiotherapy for breast cancer and exhibited clinically measurable radiation induced fibrosis that had occurred more than 6 months after radiotherapy completion, without evidence of recurrent or evolutionary cancer or skin pathology
|
| Exclusion criteria
|
NI
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| N randomized
|
24
|
| 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
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| Countries of data collection
|
France
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| LoE Level of evidence
|
2b Oxford 2009
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| Outcome timeline Data collection times
|
T0: before randomization
T1: after 3 months
T2: after 6 months
|
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.
|
No therapy setting
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| Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included
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Breast 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
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NA
|
| Specifications on cancer stages
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Survivors
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| Comorbidities
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Radiotherapy induced fibrosis
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| Current cancer therapies
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No therapy
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| Specifications on cancer therapies
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NA
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| Previous cancer therapies
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Radiation therapy
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| Gender
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Female
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| Gender specifications
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100% female
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| Age groups
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Adults (18+)
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| Age groups specification
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Mean (SD) = 57 (8) years
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Arms
| Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment
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Intervention
|
| Number of participants (arm) N randomized
|
6
|
| Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date
|
1
|
| Drop-out reasons
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Withdrawn (intercurrent disease)
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| Intervention
|
Pentoxifyllin + Vitamin E
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| Dosage and regime
|
oral, 800 mg daily Pentoxifyllin (2x 400 mg) + 1000 U daily Vitamin E (2x 500 U)
Start: +7 (± 4) years post-RTX
Duration: 6 months
|
| 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.
|
182
|
| Side effects / Interactions
|
Discomfort (including hot flushes, nausea, asthenia, headaches, dizziness) in n=2
|
| Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment
|
Placebo, Active control
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| Number of participants (arm) N randomized
|
6
|
| Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date
|
1
|
| Drop-out reasons
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Withdrawn (changed mind before study)
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| Intervention
|
Pentoxyllin + Placebo
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| Dosage and regime
|
oral, 800 mg daily Pentoxifyllin (2x 400 mg) + 2x placebo
Start: +7 (± 4) years post-RTX
Duration: 6 months
|
| 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.
|
182
|
| Side effects / Interactions
|
Discomfort (including hot flushes, nausea, asthenia, headaches, dizziness) in n=4
|
| Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment
|
Intervention, Placebo
|
| Number of participants (arm) N randomized
|
6
|
| 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 + Placebo
|
| Dosage and regime
|
oral, 2x Placebo + 1000 U daily Vitamin E (2x 500 U)
Start: +7 (± 4) years post-RTX
Duration: 6 months
|
| 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.
|
182
|
| Side effects / Interactions
|
Discomfort (including hot flushes, nausea, asthenia, headaches, dizziness) in n=0
|
| 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
|
6
|
| 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
|
Placebos
|
| Dosage and regime
|
oral, 4x Placebo
Start: +7 (± 4) years post-RTX
Duration: 6 months
|
| 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.
|
182
|
| Side effects / Interactions
|
Discomfort (including hot flushes, nausea, asthenia, headaches, dizziness) in n=4
|
Outcomes
Fibrosis
| Outcome type As specificed by the authors
|
Primary
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| Outcome specification
|
Surface reduction of fibrosis (after 6 months)
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| Type of measurement
|
Observation
|
| 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".
|
After 6 month, reduction in % (SD) in each case:
Pentoxyfillin + vitamin E: 60.2 (10.7), pentoxyfillin + placebo: 39.1 (37.4), vitamin E + placebo: 40.0 (32.0); placebos: 42.6 (17.4)
ANOVA: ns., trend of a signif. interaction with vitamin E
|
| 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
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| Bias due to missing outcome data
|
?
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| Bias in measurement of the outcome
|
?
|
| Bias in selection of the reported result
|
?
|
| Other sources of bias
|
?
|
| Overall RoB judgment
|
?
|
Fibrosis
| Outcome type As specificed by the authors
|
Secondary
|
| Outcome specification
|
Surface reduction of fibrosis (after 3 months)
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| Type of measurement
|
Observation
|
| 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".
|
After 3 month, reduction in % (SD) in each case:
Pentoxyfillin + vitamin E: 34.7 (20.6), pentoxyfillin + placebo: 18.9 (18.3), vitamin E + placebo: 25.8 (21.8); placebos: 29.2 (10.3)
|
| 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
|
?
|
Fibrosis
| Outcome type As specificed by the authors
|
Secondary
|
| Outcome specification
|
Volume reduction
|
| Type of measurement
|
AQoL-8D (Assessment of Quality of Life), Ultrasonography
|
| 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".
|
After 3 month, reduction in % (SD) in each case:
Pentoxyfillin + vitamin E: 45.1 (22.4), pentoxyfillin + placebo: 18.9 (18.3), vitamin E + placebo: 34.8 (23.8); placebos: 36.2 (13.5)
|
| 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".
|
After 6 month, reduction in % (SD) in each case:
Pentoxyfillin + vitamin E: 73.0 (7.2), pentoxyfillin + placebo: 48.6 (35.9), vitamin E + placebo: 52.8 (29.4); placebos: 50.8 (23.9)
|
| 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
|
?
|
Objective signs and subjective symptoms
| Outcome type As specificed by the authors
|
Secondary
|
| Outcome specification
|
Subjective Objective Medical management and Analytic evaluation of injury (SOMA)-Score: T1und T2
|
| Type of measurement
|
SOMA (Subjective Objective Medical management and Analytic evaluation of injury)
|
| 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".
|
After 3 month, reduction in % (SD) in each case:
Pentoxyfillin + vitamin E: 20.2 (10.6), pentoxyfillin + placebo: 10.5 (11.5), vitamin E + placebo: 15.2 (16.1); placebos: 24.7 (13.1)
|
| 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".
|
After 6 month, reduction in % (SD) in each case:
Pentoxyfillin + vitamin E: 39.1 (12.1), pentoxyfillin + placebo: 32.4 (20.8), vitamin E + placebo: 37.1 (15.5); placebos: 32.9 (18.5)
|
| 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
|
?
|
Fibrosis
| Outcome type As specificed by the authors
|
Secondary
|
| Outcome specification
|
Individual development of fibrosis
|
| Type of measurement
|
AQoL-8D (Assessment of Quality of Life), Observation, Ultrasonography
|
| 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".
|
Individual reduction in surface fibrosis in % per month:
Pentoxyfillin + vitamin E: 10.1 (1.6), pentoxyfillin + placebo: 6.5 (6.2), vitamin E + placebo: 6.7 (0.3); placebos: 7.1 (2.9)
Individual volume reduction in % per month:
Pentoxyfillin + vitamin E: 12.8 (2.0), pentoxyfillin + placebo: 8.1 (6.0), vitamin E + placebo: 8.8 (4.9); placebos: 8.5 (4.0)
|
| 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
|
?
|
Additional Notes
