Nguyen et al. (2012): Randomized, Double-Blind, Placebo-Controlled Trial of Polyphenon E in Prostate Cancer Patients before Prostatectomy: Evaluation of Potential Chemopreventive Activities

Reference ↗
Title	Randomized, Double-Blind, Placebo-Controlled Trial of Polyphenon E in Prostate Cancer Patients before Prostatectomy: Evaluation of Potential Chemopreventive Activities
Topic	Green tea (EGCG)
Author	Nguyen, M, Ahmann, FR, Nagle, R, Hsu, CH, Tangrea, J, Parnes, H, Sokoloff, M, Gretzer, M, Chow, HHS
Year	2012
Journal	Cancer Prevention Research
DOI	https://doi.org/10.1158/1940-6207.CAPR-11-0306

Brief summary

In this study, 50 patients with prostate cancer were randomly assigned to one of two arms. One arm took four polyphenon E capsules (totalling 800mg EGCG) every morning, while the other arm received a matching placebo. Neither the participants nor the study leaders knew whether they were taking the capsule with or without the active ingredient. The patients took the capsule until their prostate was surgically removed. Afterwards, the prostate tissue was examined and various laboratory parameters were analysed. The active substance (intervention) was only detectable to a small extent in the prostate tissue. The PSA value was determined at the beginning of the study and after the intervention. This showed a greater decrease in the serum PSA value in the polyphenon E arm compared to the control arm, but this difference was not statistically significant. Overall, mainly mild to moderate side effects occurred (grade I and II according to CTCAE), with nausea being the most common side effect. The small sample size should be criticised. In addition, all patients were included in the evaluation of side effects, even if they did not complete the study. This can lead to an underestimation of side effects, but only one study participant per arm was excluded. Overall, the reporting leaves something to be desired.

In dieser Studie wurden 50 Patienten mit Prostatakrebs zufällig in einen von zwei Armen eingeteilt. Der eine Arm nahm täglich jeden Morgen vier Polyphenon E Kapseln (insgesamt 800mg EGCG) ein, der andere Arm bekam ein passendes Placebo. Weder die Teilnehmer noch die Studienleiter wussten, ob sie die Kapsel mit oder ohne Wirkstoff einnahmen. Die Patienten nahmen die Kapsel so lange ein bis ihre Prostata operativ entfernt wurde. Danach wurde unter anderem das Prostatagewebe untersucht und verschiedene Laborparamater ausgewertet. Der Wirkstoff (Intervention) war nur in geringem Ausmaß im Prostatagewebe nachweisbar. Der PSA-Wert wurde zu Beginn der Studie und nach der Intervention bestimmt. Hierbei zeigte sich eine stärkere Abnahme des Serum-PSA-Wertes im Polyphenon E Arm im Vergleich zum Kontrollarm, dieser Unterschied ist jedoch nicht statistisch signifikant. Insgesamt traten hauptsächlich gering bis mäßig starke Nebenwirkungen auf (Grad I und II nach CTCAE), worunter Übelkeit die häufigste Nebenwirkung darstellte. Kritisch anzumerken ist die kleine Stichprobengröße. Außerdem wurden alle Patienten in die Auswertung der Nebenwirkungen mit einbezogen, auch wenn sie die Studie gar nicht abgeschlossen haben. Dies kann zur Unterschätzung von Nebenwirkungen führen, allerdings ist nur jeweils ein Studienteilnehmer pro Arm ausgeschieden. Insgesamt lässt die Berichterstattung etwas zu wünschen übrig.

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	NI
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	Biopsy-proved prostate cancer; received no other therapy for their prostate cancer; current PSA less than 50 ng/mL; older than 18 years; no history of chemotherapy and/or radiation for any malignancy in the previous 5 years; good performance status; normal renal function (creatinine ≤ institutional upper limits of normal); normal hepatic function (total bilirubin, aspartate aminotransferase (AST; SGOT)/alanine aminotransferase (ALT; SGPT) ≤ institutional upper limits of normal)
Exclusion criteria	Drank tea regularly within 1 month of enrollment (more than 6 servings of hot tea or 12 servings of iced tea or equivalent combination per week); receiving other investigational agents; history of allergic reactions attributed to compounds of similar chemical to polyphenon E; uncontrolled intercurrent illness
N randomized	50
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, ITT Analysis
Specifications on analyses	Per-protocol evaluation of the endpoints; Intention-to-treat evaluation of side effects; 2-sided Wilcoxon rank-sum test: test whether the change in each of the endpoints differed by the intervention arm, because the distributions for some of the endpoints were not symmetrical; percentage of patients with positive or negative changes for each of the endpoints was compared between the intervention arm using a Fisher exact test of proportions at a 2-sided 0.05 level of significance; secondary analyses were not corrected for multiple comparisons, but the results were interpreted cautiously, given the multiple markers being explored.
Countries of data collection	United States
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T0: Baseline T1: after an average of 3 to 6 weeks until the operation

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	NI
Specifications on cancer stages	NI
Comorbidities	NI
Current cancer therapies	Surgery
Specifications on cancer therapies	Patients received no other therapy for their prostate cancer; no history of chemotherapy and/or radiation for any malignancy in the previous 5 years
Previous cancer therapies	No therapy
Gender	Male
Gender specifications	100% male
Age groups	Adults (18+)
Age groups specification	Median Age (SD) per arm: Polyphenon E arm: 63.4 (5.9) years, placebo arm: 61.3 (5.7) 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	25
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	Surgery cancelled + all participants: missing data for some of the endpoints due to the inability to collect some of the specimens or inadequate specimens for analysis; missing rate ranged from 2% (immunohistochemical tissue markers) to 23% (8-OHdG)
Intervention	Polyphenon E
Dosage and regime	4 polyphenon E oral capsules (200 mg EGCG per capsule = 800mg ECGC) each morning with food for 3 to 6 weeks until the day before surgery
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.	28
Side effects / Interactions	The NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 and diary were used for adverse event description and grading; side effects were all grade I or II; Summary of adverse events occurring in greater than 4% of subjects treated with polyphenon E or placebo, regardless of attribution Polyphenon E (N = 25), n (%) Nausea: 4 (16) Diarrhea: 2 (8) Headache: 1 (4)

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	25
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	Surgery cancelled + all participants: missing data for some of the endpoints due to the inability to collect some of the specimens or inadequate specimens for analysis; missing rate ranged from 2% (immunohistochemical tissue markers) to 23% (8-OHdG)
Intervention	Placebo
Dosage and regime	4 placebo oral capsules each morning with food for 3 to 6 weeks until the day before surgery
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.	28
Side effects / Interactions	The NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 and participant diary were used to for adverse event description and grading; side effects were all grade I or II; summary of adverse events occurring in greater than 4% of subjects treated with polyphenon E or placebo, regardless of attribution Placebo (N = 25), n (%) Nausea: 4 (16) Diarrhea: 5 (20) Headache: 2 (8) Fever: 3 (12) Body ache: 2 (8) Muscle ache: 2 (8)

Outcomes

PSA level (Prostate-Specific Antigen)

Outcome type As specificed by the authors	Secondary
Outcome specification	Determine the effect of polyphenon E intervention on serum prostate-specific antigen (PSA).
Type of measurement	Blood Test
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".	PSA values showed a greater decrease for those on polyphenon E than those on placebo but this did not reach statistical significance (p=0.26). Reduction of PSA in Polyphenon E arm = 14 (58.3), in Placbo arm = 8 (36.4), but no significant group difference (p=0.15).

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	Financial support for the study by the National Cancer Institute and the Arizona Cancer Centre
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	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:

• Ethics vote
• Wash out: Patients who drank tea regularly within one month of enrolment were excluded
• Control of treatment adherence (number of capsules and intake calendar)
• Testing of the normal distribution of the data and application of adequate tests

CONTRA:

• Overall small sample size (post-hoc power analysis performed and criteria not fulfilled)
• Intention-to-treat evaluation of side effects (underestimation of side effects, per-protocol would be better, but only 4% did not complete the study)
• Per-protocol evaluation of endpoints (intention-to-treat would be better)
• Unclear randomisation process
• No correction for multiple testing for comparison between arms for changes (but at least insight into this and cautious interpretation)
• No indication of the data collection site
• No explanation of blinding process