Hejazi et al. (2016): Effect of Curcumin Supplementation During Radiotherapy on Oxidative Status of Patients with Prostate Cancer: A Double Blinded, Randomized, Placebo-Controlled Study

Reference ↗
Title	Effect of Curcumin Supplementation During Radiotherapy on Oxidative Status of Patients with Prostate Cancer: A Double Blinded, Randomized, Placebo-Controlled Study
Topic	Curcumin
Author	Hejazi, J, Rastmanesh, R, Taleban, F-A, Molana, SH, Hejazi, E, Ehtejab, G, Hara, N
Year	2016
Journal	Nutrition and Cancer
DOI	https://doi.org/10.1080/01635581.2016.1115527

Study Note

One study in two publications. Further endpoints are reported in Hejazi et al. (2013): A pilot clinical trial of radioprotective effects of curcumin supplementation in patients with prostate cancer.

Brief summary

Prostate cancer patients were examined in this study. One half took curcumin capsules three times a day during radiotherapy and the other half took placebo capsules instead. In the first study of Hejazi et al. (2013): A pilot clinical trial of radioprotective effects of curcumin supplementation in patients with prostate cancer, the quality of life of the patients was examined. The curcumin arm reported fewer urinary-related symptoms that limited quality of life. No differences were found with regard to bladder-related and treatment-related symptoms or sexual activity. In the second study of Hejazi et al. (2016): Effect of Curcumin Supplementation During Radiotherapy on Oxidative Status of Patients with Prostate Cancer: A Double Blinded, Randomized, Placebo-Controlled Study, there were no significant differences between the arms in the development of prostate specific antigen (PSA; an important marker in prostate cancer) in the blood over the course of the study. Positive aspects of these studies were the double blinding (patients/investigators do not know which arm they belong to), the low drop-out rate and that the majority of patients took the curcumin/placebo as prescribed. Overall, however, it was a very small sample and the two arms differed slightly even at the beginning of the study. In addition, other endpoints were reported than described in the study protocol.

In dieser Studie Prostatakarzinompatienten untersucht. Eine Hälfte nahm während der Radiotherapie drei Mal täglich Curcumin-Kapseln ein und die andere Hälfte stattdessen Placebo-Kapseln. In der ersten Studie von Hejazi et al. (2013): A pilot clinical trial of radioprotective effects of curcumin supplementation in patients with prostate cancer wurde die Lebensqualität der Patienten betrachtet. Die Curcumin-Gruppe berichtete weniger harnbezogenen Symptome, die die Lebensqualität einschränkten. Keine Unterschiede fanden sich hinsichtlich blasenbezogenen und behandlungsbezogenen Symptome sowie hinsichtlich der sexuellen Aktivität. In der zweiten Studie von Hejazi et al. (2016): Effect of Curcumin Supplementation During Radiotherapy on Oxidative Status of Patients with Prostate Cancer: A Double Blinded, Randomized, Placebo-Controlled Study zeigten sich zwischen den Gruppen keine bedeutsamen Unterschiede hinsichtlich der Entwicklung des Prostataspezifisches Antigens (PSA; ein wichtiger Marker beim Prostatakrebs) im Blut über die Studie hinweg. Positiv an diesen Studien war die doppelte Verblindung (Patienten/Untersucher wissen nicht, welcher Gruppe sie angehören), die geringe Ausfallrate und dass die Mehrheit der Patienten das Curcumin/Placebo eingenommen hat, wie vorgegeben. Insgesamt war es jedoch nur eine sehr kleine Stichprobe und beiden Gruppen haben sich schon zu Beginn der Studie leicht unterschieden. Zudem wurden andere Endpunkte berichtet, als im Studienprotokoll beschrieben.

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	Patients referred to local curative radiotherapy with external beam radiotherapy (EBRT), in combination with hormone ablation; Adenocarcinoma of the prostate must be histologically confirmed on biopsy; life expectancy greater than 5 years; no metastatic disease detected during physical examination, standard radiography, bone scan, and magnetic resonance spectroscopy (MRS); no prior hormone therapy, radiotherapy or systemic treatment for prostate cancer and no other malignancy
Exclusion criteria	Clinical stage T3 or T4, Gleason score ≥ 8, serum PSA ≥ 20 ng/mL, other prior surgery for prostate cancer, concurrent participation in another clinical trial which would require approval upon entry to this trial, gastrointestinal disorders such as inflammatory bowel disease, reflux and peptic ulcers and any adverse reaction to curcumin
N randomized	45
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	Iran
LoE Level of evidence	1b Oxford 2009
Outcome timeline Data collection times	T0: week -1 radiotherapy T1: 3 months after radiotherapy (20 weeks after T0)

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	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
Specifications on cancer stages	T1-2, M0
Comorbidities	NI
Current cancer therapies	Hormone therapy, Radiation therapy
Specifications on cancer therapies	External beam radiotherapy (EBRT), in combination with hormone ablation
Previous cancer therapies	NI
Gender	Male
Gender specifications	100% male
Age groups	Adults (18+)
Age groups specification	Mean (SD): 70.74 (8.21) 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	22
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	2
Drop-out reasons	Withdrew during intervention
Intervention	Curcumin
Dosage and regime	BCM95, Biocurcumin (each capsule contained 440mg curcuminoids (347mg curcumin, 84mg desmethoxycurcumin, and 9mg bisdesmethoxycurcumin) and essential oil of turmeric 38mg) Orally, 2 capsules 3 times a day Start: week -1 radiotherapy Duration: until the end of radiotherapy, approx. 9 weeks in total
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	According to information no side effects

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	23
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	3
Drop-out reasons	Withdrew during intervention
Intervention	Placebo
Dosage and regime	Orally, 2 capsules 3 times a day (each capsule contained 500mg roasted rice flour) Start: week -1 radiotherapy Duration: until the end of radiotherapy, approx. 9 weeks in total
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	According to information no side effect

Outcomes

PFS (Progression-Free Survival)

Outcome type As specificed by the authors	NI
Outcome specification	During 1 year
Type of measurement	Blood Test, 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".	PSA level (ng/ml) within 3 months: Mean change (SD): Intervention arm 0.12 ( 0.16), placebo arm: 0.13 (0.06); p = 0.78 No information on PFS within one year

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	some concerns
Bias due to deviation from intended intervention (assignment to intervention)	low risk
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	some concerns
Bias in measurement of the outcome	some concerns
Bias in selection of the reported result	high risk
Other sources of bias	NA
Overall RoB judgment	high risk

Funding and Conflicts of Interest

Funding	"This study was funded by grants from National Nutrition and Food Technology Research Institute, Iran National Science Foundation, and research deputy of Shahid Beheshti University of Medical Sciences."
Conflicts of Interest	"This study was part of PhD dissertation by the first author and was supported by the research grants from National Nutrition and Food Technology Research Institute, Iran National Science Foundation, and research deputy of Shahid Beheshti University of Medical Sciences. We gratefully acknowledge Arjuna Natural Extracts Ltd for providing the curcumin capsules and placebos."

Further points for assessing the study

Sample

Power analysis performed	No
- Sample size corresponds to power analysis	NA
- Reasons for insufficient sample size based on power analysis	Pilot Trial
If no power analysis performed: at least moderate sample size (n >= 30 per arm)	No
Ethnicity mentioned	No

Alternative Explanation

Other explanations for an effect besides the investigated intervention	No
- Possibility of attention effects	NA
- Possibility of placebo effects	NA
- Other reasons	NA

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	NA
Measurement of compliance	Yes
Consistent reporting in numbers (figures, flowchart, abstract, results)	Yes
Comprehensive and coherent reporting	No
Cross-over	No
- Sufficient washout period	NA
- Tested for carry-over effects	NA
- Tested for sequence effects	NA

Interpretation of results

Effect sizes reported (clinical vs. statistical significance)	No
Side effects systematically recorded	Yes
Side effects considered in result interpretation	NA
Ethics votum	Yes

Additional Notes

PRO:

• Ethics approval obtained
• Double-blinding
• High compliance
• Acceptable dropout (10% & 15%)
• Intention-to-treat analysis conducted
• No baseline differences in Quality of Life

CONTRA:

• Small sample size
• No power analysis calculated
• Baseline differences between arms (total antioxidant capacity; p = 0.045)
• Different endpoints calculated than described in the study protocol; primary endpoints were Progression free survival and PSA after one year, but the studies only reported Quality of life and PSA value after three months
• Poor reporting quality