Reference ↗
Title	A Prospective, Randomized, Double-Blind, Placebo-Controlled Trial of Retinol Palmitate (Vitamin A) for Symptomatic Chronic Radiation Proctopathy
Topic	Vitamin A (beta-carotene)
Author	Ehrenpreis, E, Jani, A, Levitsky, J, Ahn, J, Hong, J
Year	2005
Journal	Diseases of the Colon & Rectum
DOI	https://pubmed.ncbi.nlm.nih.gov/15690650/

Study Note

Brief summary

In this study, two garms of radiotherapy patients were compared regarding typical chronic symptoms following radiotherapy (rectal bleeding, pain, diarrhea, etc.). One arm received a common Vitamin A supplement for 90 days, while the other arm received only a placebo. According to this study, patients in the Vitamin A arm experienced a greater improvement in chronic symptoms after 90 days compared to those in the control arm. However, several criticisms must be raised about this study. Firstly, it involved a very small sample size (only 17 patients were examined in total across both arms). Additionally, the two arms differed in relevant characteristics at the beginning of the study. For example, the period between radiotherapy and the start of the study was, on average, longer in the Vitamin A arm than in the placebo group. Therefore, it cannot be ruled out that the results of this study are merely a random effect or that the results occurred because the arms differed from the outset.

In dieser Studie wurden zwei Gruppen von Radiotherapiepatienten hinsichtlich typischer chronische Beschwerden nach der Radiotherapie (rektales Bluten, Schmerzen, Durchfall etc.) miteinander verglichen. Die eine Gruppe bekam 90 Tage lang ein gängiges Vitamin A Präparat und die andere Gruppe nur ein Placebo. Laut dieser Studie haben Patienten in der Vitamin A-Gruppe nach 90 Tagen eine stärkere Verbesserung der chronischen Symptome als die in die Kontrollgruppe. An dieser Studie muss man einige Kritikpunkte aufführen. An erster Stelle war es eine sehr kleine Stichprobe (in beiden Gruppen wurden zusammen nur 17 Patienten untersucht). Zudem unterschieden sich die beiden Gruppen hinsichtlich relevanter Merkmale schon zu Beginn der Studie. Zum Beispiel war der Zeitraum zwischen Radiotherapie und Beginn der Studie in der Vitamin A Gruppe im Durchschnitt größer als in der Placebogruppe. Es kann also nicht ausgeschlossen werden, dass es sich bei den Ergebnissen dieser Studie nur um einen zufälligen Effekt handelt oder dass die Ergebnisse zustande kamen, weil sich die Gruppen schon zu Beginn unterschieden.

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	2

Study characteristics

Inclusion criteria	- Completed external beam radiation or seed implantation for a pelvic malignancy, including cancer of the prostate, cervix, or uterus at least six months before enrollment - At least two symptoms (diarrhea, rectal urgency, rectal pain, tenesmus, rectal bleeding, and fecal incontinence) with a severity score of 3 (moderate problem-cannot be ignored; no effect on daily activities) on at least a weekly basis
Exclusion criteria	- Hemoglobin level at the time of enrollment < 10 gm/dl or if patients had received two or more units of packed red blood cells as treatment for anemia - Patients with rectal ulcerations, strictures, or fistulization - Patients with clinicallysignificant liver disease
N randomized	19
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.	mITT Analysis
Specifications on analyses	- 2 patients did not take any doses of medicine and were therfore excluded from the analysis - Used tests: Fisher’s exact test and Mann-Whitney U test
Countries of data collection	United States
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T0: Baseline T1: 30 Tage T2: 60 tage T3: 90 Tage

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.	Adjuvant
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Anal Cancer, Colorectal Cancer, Gynecologic Cancers - Uterine Cancer, Prostate 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	NI
Specifications on cancer stages	NI
Comorbidities	NI
Current cancer therapies	?
Specifications on cancer therapies	Time since radiation therapy mean (range): 4.35 years (0.67-19)
Previous cancer therapies	Radiation therapy
Gender	Mixed
Gender specifications	15 male 2 female
Age groups	Adults (18+)
Age groups specification	Mean (range): 66 (50-87)

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	9
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	NI
Intervention	Vitamin A (Retinol palmitate)
Dosage and regime	10,000 IU orally 2 times a day
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.	90
Side effects / Interactions	No systematic indication, only one comment in discussion: "No change in liver enzyme testing has occurred in any patients receiving retinol palmitate"

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	8
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	NI
Intervention	Placebo
Dosage and regime	Placebo capsules orally 2 times a day
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.	90
Side effects / Interactions	NI

Outcomes

Toxicity

Outcome type As specificed by the authors	Primary
Outcome specification	Response rate = at least two fewer chronic radiation-induced proctopathy symptoms (diarrhea, urge to defecate, rectal pain, tenesmus, rectal bleeding, fecal incontinence)
Type of measurement	RPSAS (Radiation Proctopathy System Assessment 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".	Response rate after 90 days - intervention arm: 7/9 - placebo arm: 2/8 - p=0.057 Of the six patients who did not respond to placebo, five were enrolled in an open-label retinol palmitate treatment arm. All five of these met criteria for response to therapy.
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".	NI

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	?

Toxicity

Outcome type As specificed by the authors	Secondary
Outcome specification	Change in RPSAS-value
Type of measurement	RPSAS (Radiation Proctopathy System Assessment 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".	Change in means (SD) Baseline vs. after 90 days - intervention arm: 11 (5) - placebo arm: 2.5 (3.6) - p=0.013
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".	NI

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	Supported in part by a private grant from Arthur C. Nielsen, Jr.
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

Cross over results: Of the six patients who did not respond to placebo, five were enrolled in the open-label retinol palmitate treatment arm.

- 5/5 met criteria for response to therapy

- significant change in RPSAS-value (p<0.05)