Henning et al. (2015): Randomized Clinical Trial of Brewed Green and Black Tea in Men With Prostate Cancer Prior to Prostatectomy

Reference ↗
Title	Randomized Clinical Trial of Brewed Green and Black Tea in Men With Prostate Cancer Prior to Prostatectomy
Topic	Green tea (EGCG)
Author	Henning, SM, Wang, P, Said, JW, Huang, M, Grogan, T, Elashoff, D, Carpenter, CL, Heber, D, Aronson, WJ
Year	2015
Journal	The Prostate
DOI	https://doi.org/10.1002/pros.22943

Brief summary

In this study, 113 patients with prostate cancer were randomly assigned to one of three arms. One arm drank 6 cups of green tea (incl. 562mg EGCG) daily, the second arm 6 cups of black tea (incl. 28mg EGCG) and the third 6 cups of water as a control arm. The participants and study leaders knew whether they had drunk tea or water, as it was not possible to prevent this due to the flavour. The patients drank the tea until the prostate was surgically removed, after which the tissue was also examined. In addition to the collection of various laboratory parameters, the tea polyphenol uptake in the prostate tissue and urine was also analysed. Only the green tea arm showed a tea polyphenol uptake in the prostate tissue in 94% of the participants, which may be due to the continuous intake of green tea throughout the day (compared to one capsule per day). Tea polyphenols were also found in the morning urine of all participants in the green tea and black tea arm (but at a significantly lower level). No tea polyphenols were found in the urine samples from the control arm and in the urine samples from all three arms before the intervention. Furthermore, the PSA value was determined at the beginning of the study and after the intervention. This showed a small but significant decrease in serum PSA levels in the green tea arm compared to the black tea and water arms. There was no difference between the black tea arm and the control arm. Positive aspects include the control of treatment adherence and the given group comparability. It should be noted critically that only those study participants who completed the study were analysed, which does not necessarily correspond to reality. This can lead to a distortion of the results in favour of the intervention (e.g. with regard to the decrease in serum PSA levels in the green tea arm). In addition, it appears that not all study participants were analysed with regard to serum PSA levels, although more precise reasons for this are lacking.

In dieser Studie wurden 113 Patienten mit Prostatakrebs zufällig in eine von drei Armen eingeteilt. Der eine Arm trank täglich 6 Tassen Grünen Tee (inkl. 562mg EGCG), der zweite Arm 6 Tassen Schwarzen Tee (inkl. 28mg EGCG) und der dritte 6 Tassen Wasser als Kontrollarm. Die Teilnehmer und Studienleiter wussten, ob sie Tee oder Wasser getrunken haben, da es aufgrund des Geschmacks nicht möglich war, dies zu verhindern. Die Patienten tranken den Tee bis zur operativen Entfernung der Prostata, wonach auch das Gewebe untersucht wurde. Neben der Erhebung von verschiedenen Laborparametern wurde auch nach der Tee-Polyphenol Aufnahme im Prostatagewebe und Urin geschaut. Es zeigte sich nur in dem Grüntee-Arm eine Tee-Polyphenol Aufnahme im Prostatagewebe bei 94% der Teilnehmer, was ggf. auf die durchgängige Zufuhr des Grünen Tees über den gesamten Tag zurückzuführen ist (im Vergleich zu einer Kapsel pro Tag). Im Morgenurin fanden sich bei allen Teilnehmern im Grüntee- und Schwarztee-Arm (allerdings signifikant geringer) ebenfalls Tee-Polyphenole. In den Urinproben aus dem Kontrollarm und in den Urinproben aus allen drei Armen vor der Intervention fanden sich keine Tee-Polyphenole. Des Weiteren wurde der PSA-Wert zu Beginn der Studie und nach der Intervention bestimmt. Hierbei zeigte sich eine kleine, aber signifikante Abnahme des Serum-PSA-Wertes in dem Grüntee-Arm im Vergleich zum Kontrollarm (Wasser). Im Schwarztee-Arm gab es keinen Unterschied zum Kontrollarm. Positiv anzumerken sind unter anderem die Kontrolle der Therapieeinhaltung und die gegebene Gruppenvergleichbarkeit. Kritisch anzumerken ist, dass nur die Studienteilnehmer ausgewertet wurden, die die Studie auch beendet haben, was nicht zwangsläufig der Realität entspricht. Dies kann zu einer Verzerrung der Ergebnisse zugunsten der Intervention führen (bspw. in Hinblick auf die Abnahme des Serum-PSA-Wertes in dem Grüntee-Arm). Außerdem wurden anscheinend nicht alle Studienteilnehmer bezüglich des Serum-PSA-Wertes ausgewertet, wozu genauere Gründe jedoch fehlen.

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	Multicentric
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	No
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	3

Study characteristics

Inclusion criteria	40–70 years old; diagnosis of clinically localized prostate adenocarcinoma; were scheduled to undergo radical prostatectomy at least three weeks after study entry
Exclusion criteria	history of hepatitis, alcohol abuse and other significant medical or psychiatric condition ; took 5-alpha reductase inhibitors, antiandrogens, or luteinizing hormone-releasing hormone agonists
N randomized	113
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	Comparisons of baseline clinical and demographic variables between green tea arm, black tea arm and water arm was conducted using the ANOVA or Kruskal–Wallis tests for continuous variables and Fisher’s exact test or chisquare tests for categorical variables. If a statistically significant overall group effect was found, follow-up analysis was performed using pairwise t-tests or the Mann Whitney U tests to investigate which pairs of groups were significantly different.
Countries of data collection	United States
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T0: Baseline T1: green tea arm: after an average of 33 days black tea arm: after an average of 31 days water arm: after an average of 29 days

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.	Neo-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
Specifications on cancer stages	Stage II
Comorbidities	NI
Current cancer therapies	Diverse
Specifications on cancer therapies	NI
Previous cancer therapies	Diverse
Gender	Male
Gender specifications	100% male
Age groups	Adults (18+)
Age groups specification	Age in years, mean (SD) per arm: Green tea arm: 62.1 (6.9) Black tea arm: 61.4 (7.4) Water arm: 62.8 (6.2)

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	43
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	9
Drop-out reasons	Caffeine reactions (n=2); surgery postponed (n=2); unrelated death (n=1); tea volume too large (n=3), stomach distress (n=1)
Intervention	Green tea
Dosage and regime	6 cups of green tea (inclusive 562mg EGCG) daily until the operation (average duration = 33 days)
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.	33
Side effects / Interactions	According to the authors, there were no serious side effects associated with the intervention; no information on the recording of side effects

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	33
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	7
Drop-out reasons	Personal reasons (n=3); surgery cancelled (n=2); caffeine reactions (n=2)
Intervention	Black tea
Dosage and regime	6 cups of black tea (inclusive 28mg EGCG) daily until the operation (average duration = 31 days)
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.	31
Side effects / Interactions	According to the authors, there were no serious side effects associated with the intervention, no information on the recording of 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	37
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	4
Drop-out reasons	Personal reasons (n=3); surgery cancellation (n=1)
Intervention	Water
Dosage and regime	6 cups of water daily until the operation (average duration = 29 days)
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.	29
Side effects / Interactions	According to the authors, there were no serious side effects associated with the intervention, no information on the recording of side effects

Outcomes

"Others" is not in the list (AQoL-8D (Assessment of Quality of Life), ASAT (Auditory Sustained Attention Test), BIA (Bioelectrical impedance analysis), BPI-SF (Brief Pain Inventory - Short Form), CTCAE (Common Terminology Criteria of Adverse Events), ESAS (Edmonton Symptom Assessment Scale), FAACT (Functional Assessment of Anorexia-Cachexia Therapy), FACIT (Functional Assessment of Chronic Illness Therapy), FLIE (Functional Living Index for Emesis), Genitourinary atrophy self-assessment tool, ...) of allowed values for the "Type of measurement" property.

PSA level (Prostate-Specific Antigen)

Outcome type As specificed by the authors	Secondary
Outcome specification	Serum-PSA-Level evaluated by high performance liquid chromatography and ELISA analysis
Type of measurement	ELISA protocol (Enzyme-Linked Immunoabsorbent Assay)
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".	NI
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".	Decrease in serum PSA levels higher in the green tea arm compared to the water arm (p=0.04) PSA mean (SD) per arm Green tea arm (N=30): baseline= 9.6(5.2); after 33 days= 8.4(4.3) Water arm (N=30): baseline= 9.9(8.5); after 29 dayse= 10.0(9.0) No significant difference in changes between black tea arm and water arm (p>0.05)

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	?

Tea polyphenol uptake

Outcome type As specificed by the authors	Secondary
Outcome specification	Green tea and black tea polyphenol analysis in prostate tissue and urine: Three hundred milligrams of fresh frozen prostate tissue was homogenized and treated with 1,000 units of bglucuronidase and 40 units of sulfatase at 37 °C for 45 min. Solid phase extraction (SPE) was performed using preconditioned HLB cartridges and tea polyphenols quantified by HPLC-CoulArray electrochemical detection. The detection limit was 0.2 pmol/g tissue.
Type of measurement	Tissue testing
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".	NI
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".	Detection of tea polyphenols in prostate tissue in 32 of 34 men in the green tea arm , but not in the other arms. Detection of EGC, EC and methyl-EGC in early morning urine throughout the study in the green tea arm and at significantly lower concentrations in the black tea arm (p<0.01); no polyphenols in the water arm.

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	National Institutes of Health (NIH)
Conflicts of Interest	According to authors no conflict of interest

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

PRO:

• Ethics vote
• Group comparability is given
• Wash out and control of confounding factors: subjects were instructed to abstain from all teas and tea containing products (except the study tea) and not to consume any supplements or herbal therapies (i.e. lycopene, selenium, vitamin E, fish oil and saw palmetto).
• The polyphenon composition of the brewed tea (one sachet in 240 ml boiling water for 5 minutes) was determined by HPLC with electrochemical CoulArray detection.
• Power analysis
• Testing for normal distribution, consideration of the possibility of α-cumulation by multiple testing and adequate application of statistical methods
• Control of adherence to therapy (diary entries: Green tea-arm =95%, Black tea-arm=92%, Placebo-arm C= 93%)

CONTRA:

• Not blinded, but also rather difficult due to the different flavours of the teas
• Evaluation per-protocol (intention-to-treat would be better)
• Inconsistencies regarding arm size for PSA values (apparently not all analysed?, no information on missing data)
• High attrition
• Multiple endpoints, the overall false discovery rate was 10.8%