Delanian et al. (2003): Randomized, placebo-controlled trial of combined pentoxifylline and tocopherol for regression of superficial radiation-induced fibrosis

Reference ↗
Title	Randomized, placebo-controlled trial of combined pentoxifylline and tocopherol for regression of superficial radiation-induced fibrosis
Topic	Vitamin E
Author	Delanian, S, Porcher, R, Balla-Mekias, S, Lefaix, J-L
Year	2003
Journal	Journal of clinical Oncology
DOI	https://doi.org/10.1200/JCO.2003.06.064

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
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	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
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
Countries of data collection	France
LoE Level of evidence	2b Oxford 2009
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
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	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	NA
Specifications on cancer stages	Survivors
Comorbidities	Radiotherapy induced fibrosis
Current cancer therapies	No therapy
Specifications on cancer therapies	NA
Previous cancer therapies	Radiation therapy
Gender	Female
Gender specifications	100% female
Age groups	Adults (18+)
Age groups specification	Mean (SD) = 57 (8) 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	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	Withdrawn (intercurrent disease)
Intervention	Pentoxifyllin + Vitamin E
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
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	Withdrawn (changed mind before study)
Intervention	Pentoxyllin + Placebo
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
Outcome specification	Surface reduction of fibrosis (after 6 months)
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
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	Surface reduction of fibrosis (after 3 months)
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	NI
- Reasons for insufficient sample size based on power analysis	NI
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	NI
- 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	NI
Correction for multiple testing	?
Measurement of compliance	?
Consistent reporting in numbers (figures, flowchart, abstract, results)	?
Comprehensive and coherent reporting	?
Cross-over	NI
- 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.
• Double-blinded.
• Low dropout (N = 2).

CONTRA:

• Very small sample size (though sufficient according to power analysis).
• Baseline group differences not ruled out.
• Placebo arm tends to have lower values (e.g., in terms of surface area and volume; not significant, but this could be due to the small sample size).
• No information on compliance.
• No information on whether assumptions for ANOVA are met (with such a small sample size).
• Poor reporting quality (e.g., no information on pairwise group comparisons).