Margalit et al. (2012): Beta-carotene Antioxidant Use During Radiation Therapy and Prostate Cancer Outcome in the Physicians’ Health Study

Reference ↗
Title	Beta-carotene Antioxidant Use During Radiation Therapy and Prostate Cancer Outcome in the Physicians’ Health Study
Topic	Vitamin A (beta-carotene)
Author	Margalit, DN, Kasperzyk, JL, Martin, NE, Sesso, HD, Gaziano, JM, Ma, J, Stampfer, MJ, Mucci, LA
Year	2012
Journal	International journal of radiation oncology, biology, physics
DOI	https://doi.org/10.1016/j.ijrobp.2011.05.032

Brief summary

This study investigated whether the administration of beta-carotene (i.e. a precursor of vitamin A) in addition to radiotherapy shortens the survival time or causes metastases to appear earlier. There were no differences between patients who received radiotherapy and beta-carotene and those who received only a placebo in addition to radiotherapy. It also made no difference which form of radiotherapy the patients received. In a comparison sample in which surgical tumor removal was performed instead of radiotherapy, significantly more deaths and metastases occurred in the beta-carotene group. However, this difference disappeared when age and cancer stage were taken into account in the calculations. One advantage of this study is the large sample size and the double blinding (investigators and patients do not know which group they are in). However, there are some points of criticism. It cannot be ruled out that the two groups already differed at the beginning of the study and, as the sample was taken from a large data set, only the variables that were recorded in this data set could be reported and taken into account.

In dieser Studie wurde untersucht, ob eine Betacarotin-Gabe (d.h. eine Vorstufe von Vitamin A) zusätzlich zur Radiotherapie die Überlebenszeit verkürzt oder früher Metastasen auftreten. Es zeigten sich keine Unterschiede zwischen Patienten, die Radiotherapie und Betacarotin erhielten und denen, die zusätzlich zur Radiotherapie nur ein Placebo bekamen. Es machte auch keinen Unterschied, welche Radiotherapie-Form die Patienten erhielten. In einer Vergleichsstichprobe, bei denen statt der Radiotherapie eine operative Tumorentfernung durchgeführt wurde, traten in der Betacarotin-Gruppe bedeutsam mehr Todesfälle und Metastasen auf. Dieser Unterschied verschwand jedoch, wenn man in den Berechnungen unter anderem Alter und Krebsstadium mitberücksichtigte. Ein Vorteil dieser Studie ist die große Stichprobe und die doppelte Verblindung (Untersucher und Patienten wissen nicht, in welcher Gruppe sie sind). Es gibt jedoch einige Kritikpunkte. Es kann nicht ausgeschlossen werden, dass sich die beiden Gruppen schon zu Beginn der Studie unterschieden und da die Stichprobe aus einem großen Datensatz entnommen wurde, konnten nur die Variablen berichtet und berücksichtigt werden, die in diesem Datensatz erfasst wurden.

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

Sub-sample of the Physicians' Health Study dataset, Period of data collection: 1982-2003

Inclusion criteria	Men, 40 to 84 years old at baseline (1982), who were free from diagnosed cancer at enrollment
Exclusion criteria	Participants who had undergone prostatectomy prior to radiation therapy or who had metastatic disease at the time of radiation therapy
N randomized	383
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.	ITT Analysis
Specifications on analyses	- Kaplan-Meier method to estimate survival probabilities and the Mantel-Haenszel log-rank test to compare groups - Cox proportional hazards regression to estimate crude and adjusted hazard ratios (HR) and 95% confidence intervals (CI)
Countries of data collection	United States
LoE Level of evidence	1b Oxford 2009
Outcome timeline Data collection times	T0: Baseline T1: Follow-up, median (range): 10.5 years (0.3-27.2)

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	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	Early Stage, Advanced Stage
Specifications on cancer stages	Cancer stage per group: - intervention: 163x T1-T2, 15x T3, 5x T4 or N1, 8x missing - placebo: 169x T1-T2, 13x T3, 6x T4 or N1, 4x missing
Comorbidities	NI
Current cancer therapies	Radiation therapy
Specifications on cancer therapies	Radiation type per group: - intervention: 129x external beam radiation, 39x brachytherapy, 21x both, 2x unknown or missing - placebo: 133x external beam radiation, 40x brachytherapy, 16x both, 3x unknown or missing
Previous cancer therapies	NI
Gender	Male
Gender specifications	NI
Age groups	Adults (18+)
Age groups specification	Age at diagnosis (years) in median (IQR) - intervention group: 73 (68, 76) - placebo group: 73 (69, 76) Age at treatment (years) in median (IQR) - intervention group: 73 (68, 76) - placebo group: 73 (69, 76)

Arms

NI regarding specific duration in days, mean (range) follow-up: 10.5 years (0.3-27.2)

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	192
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	NI
Drop-out reasons	NI
Intervention	Radiotherapy + beta-carotene
Dosage and regime	Beta-carotene 50mg orally every 2nd day, start at the time of radiation therapy, mean (range) follow-up: 10.5 years (0.3-27.2)
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	191
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	NI
Drop-out reasons	NI
Intervention	Radiotherapy + placebo
Dosage and regime	Placebo orally every 2nd day, start at the time of radiation therapy, mean (range) follow-up: 10.5 years (0.3-27.2) + "6% of participants in the placebo group reported taking supplemental beta-carotene or vitamin A"
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, Placebo
Number of participants (arm) N randomized	690
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	NI
Drop-out reasons	NI
Intervention	Prostatectomy with and without beta-carotene (other sample of the Physicians' Health Study dataset)
Dosage and regime	NI
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

Mortality rate

Outcome type As specificed by the authors	Primary
Outcome specification	Time from radiation therapy initiation to lethal prostate cancer (death from prostate cancer or participant-reported bone metastases among living participants)
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".	Overall No significant difference between the intervention and placebo group (p = 0.24), even taking into account the kind of radiotherapy (external beam radiation vs. brachytherapy, p = 0.52) and other control variables (age at treatment, Gleason score, PSA concentration, and clinical stage) Number of lethal cases in patients receiving prostatectomy with vs. without beta-carotene: 35 vs. 17 (p = 0.03; p = 0.15 when considering control variables)

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	Study funded by National Institutes of Health, study drugs provided in part by BASF Corporation (Florham Park, NJ), Wyeth Pharmaceuticals (Madison, NJ), and DSM Nutritional Products, Inc. (formerly Roche Vitamins) (Parsippany, NJ); and the Prostate Cancer Foundation (LAM)
Conflicts of Interest	Howard D. Sesso has received research funding from the National Institutes of Health, the American Heart Association, the American Cancer Society, the California Strawberry Commission and the Tomato Products Wellness Council, Roche Vitamins, Inc (now DSM Pharmaceuticals) and Cambridge Theranostics, Ltd for the last 5 years; Consultant to Iovate Health Sciences USA, Inc.

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	?