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 ↗ | |
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| 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 |
Study Note
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 |
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| 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 |
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| 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:
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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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 | |
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| 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 |
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| 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 |
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| Conflicts of Interest | According to authors no conflict of interest |
Further points for assessing the study
Sample
| Power analysis performed | ? |
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| - 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 | |
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| - 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 | |
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| 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) | ? |
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| 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.