Emami et al. (2014): Double-blinded, randomized, placebo-controlled study to evaluate the effectiveness of green tea in preventing acute gastrointestinal complications due to radiotherapy

Reference ↗
Title	Double-blinded, randomized, placebo-controlled study to evaluate the effectiveness of green tea in preventing acute gastrointestinal complications due to radiotherapy
Topic	Green tea (EGCG)
Author	Emami, H, Nikoobin, F, Roayaei, M, Ziya, HR
Year	2014
Journal	Journal of Research in Medical Sciences: The official journal of Isfahan University of Medical Sciences
DOI	http://PMC4116577

Brief summary

In this study, 42 patients receiving standardised abdominal or pelvic radiotherapy were randomly assigned to one of two arms. One arm received a 450mg green tea tablet and the other arm received a placebo tablet, each once daily for 5 weeks. Neither the participants nor the study leaders knew whether they were receiving the tablet with green tea or without the active ingredient. The frequency and severity of diarrhoea and vomiting was recorded in a diary from the first day of the second week to the end of the fifth week. There were arm differences in the frequency of diarrhoea, but a reduction in (radiation-induced) diarrhoea due to green tea could not be statistically proven. There were no differences between the two arms in the reduction of vomiting. Furthermore, the green tea tablet was well tolerated. Overall, the reporting in the study is inadequate and there are some contradictions. The interpretation of the results by the authors is also flawed and misleading and leaves much to be desired.

In dieser Studie wurden 42 Patienten, die eine standardisierte Bauch- oder Beckenbestrahlung erhielten, zufällig in eine von zwei Armen eingeteilt. Der eine Arm erhielt eine Tablette mit 450mg Grünen Tee, der andere Arm eine Placebo-Tablette, jeweils einmal täglich für 5 Wochen. Weder die Teilnehmer noch die Studienleiter wussten, ob sie die Tablette mit grünem Tee oder ohne Wirkstoff bekommen. Die Häufigkeit und Schwere von Durchfall und Erbrechen wurde mittels Tagebuchführung vom ersten Tag der zweiten Woche bis zum Ende der fünften Woche ermittelt. Es zeigten sich Armunterschiede bezüglich der Häufigkeit von Durchfall, eine Reduktion des (Bestrahlung-induzierten) Durchfalls durch Grünen Tee konnte statistisch aber nicht nachgewiesen werden. Bei der Reduktion von Erbrechen zeigten sich keine Unterschiede zwischen beiden Armen. Des Weiteren war die Grüner-Tee-Tablette gut verträglich. Insgesamt ist die Berichterstattung in der Studie mangelhaft und es ergeben sich einige Widersprüche. Auch die Interpretation der Ergebnisse durch die Autoren ist fehlerhaft und missverständlich und lässt 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	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 receiving standardized abdomen and pelvic irradiation 5000 cGy (1000 cGy weekly) for prostate, uterus, cervix, bladder, rectum and colon
Exclusion criteria	Patients with past history of irradiation; diarrhea before the beginning of pelvic irradiation, taking another drug for treatment of diarrhea during the study, unwilling to participate in the study at any time
N randomized	42
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	Two-sample t-tests: comparison of continuous variables Pearson’s Chi-square tests: comparison of categorical variables Mann–Whitney U-test: comparison of the grade of diarrhea and vomiting between two groups Nonparametric analysis (Friedman): comparison of the score of diarrhea and vomiting during 4 weeks
Countries of data collection	Iran
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T0: Baseline T1: Diarrhea and vomiting scaling weekly for 4 weeks (2nd-5th) daily diary (number, consistency of stools, occurrence of symptoms such as nausea, vomiting and gastrointestinal cramps) from day 1 of the 2nd week to the end of the 5th week

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	Colorectal Cancer - Colon Cancer, Colorectal Cancer - Rectal Cancer, Genitourinary Cancers - Bladder Cancer, Gynecologic Cancers - Cervical 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	Radiation therapy
Specifications on cancer therapies	Patients receiving standardized abdomen and pelvic irradiation 5000 cGy (1000 cGy weekly) Cancer treatments: per arm n(%) Radiotherapy + chemotherapy: green tea arm 8(38.1); Placebo arm 7(33.3) Radiotherapy + surgery: green tea arm 16(76.2); Placebo arm 16(76.2)
Previous cancer therapies	Surgery, Chemotherapy, Radiation therapy
Gender	Mixed
Gender specifications	Male n(%) per arm: Green tea arm: 9 (42.9), placebo arm: 14 (66.7) Female n(%) per arm: Green tea arm: 12 (57.1), placebo arm: 7 (33.3)
Age groups	Adults (18+)
Age groups specification	Mean age (SD) per arm: Green tea arm: 65.7 (9.3) years, placebo arm: 58.7 (13.6) 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	21
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	0
Drop-out reasons	NA
Intervention	Green tea
Dosage and regime	One green tea tablet (450 mg Camgreen) daily for 5 weeks during radiation
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.	35
Side effects / Interactions	According to reporting, no side effects/ interactions.

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	21
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	0
Drop-out reasons	NA
Intervention	Placebo
Dosage and regime	One placebo tablet daily for 5 weeks during radiation
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.	35
Side effects / Interactions	According to reporting, no side effects/ interactions.

Outcomes

Diarrhoe

Outcome type As specificed by the authors	Primary
Outcome specification	severity: CTCAE normal = 0 or 1 mild = 2 or 3 severe = 4 Frequency: Diary entries All participants recorded daily in a diary (number, consistency of stools, occurrence of symptoms such as nausea, vomiting and gastrointestinal cramps) from day 1 of the 2nd week to the end of the 5th week
Type of measurement	CTCAE (Common Terminology Criteria of Adverse Events)
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".	2nd week: No significant difference in incidence of diarrhoe between the arms (p=0.4) 3rd-5th week: Significantly lower incidence of diarrhoea in green tea arm compared to placebo arm Green tea vs. placebo: Week 3: 14 (66.7%) vs. 9 (42.9%) p=0.04 Week 4: 16 (76.2%) vs. 7 (33.3%) p=0.002 Week 5: 17 (81.0%) vs. 8 (38.1%) p=0.002
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".	Using Friedman analysis, the score of diarrhea did not significantly increase throughout 4 weeks in patients receiving green tea (p<0.3)

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	?

Vomiting

Outcome type As specificed by the authors	Primary
Outcome specification	Severity: FLIE mild = ≤6; moderate = 7-12; severe = 13-15 Frequency: Diary entries All participants recorded daily in a diary (number, consistency of stools, occurrence of symptoms such as nausea, vomiting and gastrointestinal cramps) from day 1 of the 2nd week to the end of the 5th week
Type of measurement	FLIE (Functional Living Index for Emesis)
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".	There was no significant difference in vomiting (frequency of grade) between green tea arm and placebo arm during 2nd-5th week (p=0.4-0.7).
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".	Friedman analysis indicated that there was no significant increase in vomiting in both arms during irradiation period.

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 was funded by the Chancellor of Research at Isfahan University of Medical Sciences.
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
• Comparability of the groups is given
• Power analysis was performed and criteria are fulfilled
• Exclusion for use of other anti-diarrhoeal medication

CONTRA:

• Small sample size
• No test for normal distribution
• No detailed information on randomisation process
• Hardly any demographic variables (type of cancer, stage, first diagnosis, medication, comorbidities, previous experience with etc. missing) availible
• Information in text only ‘p<’, not very meaningful and inconsistent with information from table (cf. age, group comparisons)
• Unclear to which comparison the p-value in the table belongs, or what was compared (occurrence of vomiting or non-occurrence?)
• Insufficient description of the results in the text
• Statement in the text that vomiting and diarrhoea occurred more frequently on average over the 4 weeks in the placebo arm. This is not statistically substantiated and is therefore misleading reporting.
• Discussion states that the intervention reduces diarrhoea, but there is no statistical evidence for this. The text only states that Friedman's analysis could not find any increase. Correct would be: decrease compared to the control arm.
• The results section reports the frequency of vomiting and diarrhoea during the 1st week, but the measurement did not officially start until the 2nd week - misleading timing.
• Very brief reporting, with few details and inconsistencies. Statistical results not comprehensible and interpretation of results by authors incorrect and misleading.