Crew et al. (2012): Phase IB Randomized, Double-Blinded, Placebo-Controlled, Dose Escalation Study of Polyphenon E in Women with Hormone Receptor–Negative Breast Cancer: Difference between revisions
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| Title | Phase IB Randomized, Double-Blinded, Placebo-Controlled, Dose Escalation Study of Polyphenon E in Women with Hormone Receptor–Negative Breast Cancer |
| Topic | Green tea (EGCG) |
| Author | Crew, KD, Brown, P, Greenlee, H, Bevers, TB, Arun, B, Hudis, C, McArthur, HL, Chang, J, Rimawi, M, Vornik, L, Cornelison, TL, Wang, A, Hibshoosh, H, Ahmed, A, Terry, MB, Santella, RM, Lippman, SM, Hershman, DL |
| Year | 2012 |
| Journal | Cancer Prevention Research |
| DOI | https://doi.org/10.1158/1940-6207.CAPR-12-0117 |
Study Note
Brief summary
In this dose-escalating study, some participants were initially given 400mg EGCG (in the form of polyphenon E capsules) twice a day. As soon as someone reported a severe side effect (grade II according to CTCAE), it was looked at again and calculated how likely it was that the next person would also experience such side effects. Depending on this, it was decided how many milligrams the next participant would receive. In this way, several participants were gradually included over a long period of time. A total of 40 female patients with a former hormone receptor-negative breast cancer were included. In the end, 16 participants received 400mg, 11 participants 600mg and 3 participants 800mg EGCG twice daily for 6 months (a total of 30 participants EGCG). The control arm with a total of 10 participants received a matching placebo. The ratio of 3:1 (EGCG:placebo) was determined in advance. At the end of the study, the maximum tolerated dose was determined in addition to the side effects. A total of 5 dose-limiting side effects were reported in the EGCG arms, on the basis of which dose level 2 (600mg EGCG twice daily) was defined as the maximum tolerated dose. On average, the participants had received 513mg EGCG. Statistically, there was no difference in the side effects compared to the placebo arm. However, the calculations used tend to underestimate differences. One participant who took EGCG and had a history of diverticulosis with hospitalisation developed severe rectal bleeding (grade III). The study leaders therefore decided to exclude women with a history of gastrointestinal haemorrhage in the future.
In dieser Dosis-eskalierenden-Studie wurde zunächst einigen Teilnehmerinnen 400mg EGCG (in Form von Polyphenon E-Kapseln) zweimal täglich verabreicht. Sobald jemand über eine starke Nebenwirkung (Grad II nach CTCAE) berichtet hat, wurde erneut geschaut und berechnet, wie wahrscheinlich es ist, dass auch der nächste solche Nebenwirkungen bekommt. Davon abhängig entschied sich, wie viel Milligramm die nächste Teilnehmerin erhält. Auf diese Art und Weise wurden stufenweise über einen langen Zeitraum mehrere Teilnehmerinnen eingeschlossen. Insgesamt wurden es 40 weibliche Patientinnen mit einem ehemaligen Hormon-Rezeptor-negativen Brustkrebs. Letztendlich erhielten 16 Teilnehmerinnen 400mg, 11 Teilnehmerinnen 600mg und 3 Teilnehmerinnen 800mg EGCG zweimal täglich für 6 Monate (insgesamt 30 Teilnehmer EGCG). Der Kontrollarm mit insgesamt 10 Teilnehmerinnen erhielt ein passendes Placebo. Das Verhältnis von 3:1 (EGCG:Placebo) wurde im Vorhinein festgelegt. Am Ende der Studie wurde neben den Nebenwirkungen auch die maximal tolerierte Dosis ermittelt. Insgesamt wurden 5 dosis-limitierende-Nebenwirkungen in den EGCG-Armen berichtet, aufgrund derer die Dosisstufe 2 (600mg EGCG zweimal täglich) als maximal tolerierte Dosis definiert wurde. Im Durchschnitt hatten die Teilnehmerinnen 513mg EGCG bekommen. Statistisch zeigte sich kein Unterschied in den Nebenwirkungen zur Placebogruppe. Allerdings tendieren die angewandten Berechnungen dazu, Unterschiede zu unterschätzen. Eine Teilnehmerin, die EGCG nahm und in der Vorgeschichte eine bestehende Divertikulose mit Krankenhausaufenthalt hatte, bekam eine starke Rektalblutung (Grad III). Von den Studienleitern wurde daher beschlossen, Frauen mit Magen-Darm-Blutung in der Vorgeschichte in Zukunft auszuschließen.
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 | 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 | 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 | 4 |
Study characteristics
| Inclusion criteria | Women; 21-65 years; history of histologically confirmed resected stage I–III ER negative and progesterone receptor (PR)-negative (defined as <10% ER and PR expression) breast carcinoma; without evidence of disease at trial entry; minimum of 6 months since completion of breast surgery, adjuvant chemotherapy (including trastuzumab), and radiation therapy; Eastern Cooperative Group performance status of 0 to 1; at least one intact breast (no radiation therapy, mastectomy, or breast implant); normal organ and marrow function, including total bilirubin and transaminases within normal institutional limits; Pre- and postmenopausal women: postmenopausal = absence of menses for more than 12 months, history of bilateral oophorectomy, or serum follicle-stimulating hormone (FSH) more than 20 mIU/mL |
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| Exclusion criteria | Bilateral breast cancer or metastatic disease; history of gastrointestinal bleeding; uncontrolled or significant comorbid illness; current use of hormone replacement therapy, tamoxifen, or raloxifene |
| N randomized | 40 |
| 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 | time-to-event continual reassessment method (TITE-CRM) |
| Countries of data collection | United States |
| LoE Level of evidence | 2b Oxford 2009 |
| Outcome timeline Data collection times | T0 = Baseline
T1 = after 6 month |
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. | NI |
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| Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included | Breast 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, Advanced Stage |
| Specifications on cancer stages | Stage I-III (non-metastasised) hormone receptor–negative breast cancer
Breast cancer stage at diagnosis: n(%) I: Poly E arm: 14(47) Placebo arm: 2(20) II Poly E arm: 9(30) Placebo arm: 6(60) III Poly E arm: 7(23) Placebo arm: 2(20) |
| Comorbidities | NI |
| Current cancer therapies | No therapy |
| Specifications on cancer therapies | Inclusion criteria: minimum of 6 months since completion of breast surgery, adjuvant chemotherapy (including trastuzumab), and radiation therapy
Breast cancer treatments: n(%) Chemotherapy: Poly E arm 29(97); Placebo arm 10(100) Trastuzumab: Poly E arm 5(17); Placebo arm 2(20) Radiation therapy: Poly E arm 23(77); Placebo arm 8(80) |
| Previous cancer therapies | Surgery, Chemotherapy, Radiation therapy |
| Gender | Female |
| Gender specifications | 100% female |
| Age groups | Adults (18+) |
| Age groups specification | Median age (range)
Poly E arm (all): 52 (36-64) Placebo arm: 53.5 (40-59) |
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 | 16 |
| 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 | Nonadherent (did not complete 6 months of study drug) (n = 1), but completed their 6-month study evaluations; lost to follow-up (n = 1); DLT (dose-limiting toxicity) (n = 1)
= completed follow-up n=14 |
| Intervention | Polyphenon E (Poly E) 400 |
| Dosage and regime | Oral green tea extract with 400mg EGCG twice daily for 6 month |
| 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. | 182 |
| Side effects / Interactions | Recording with CTCAE
Side effects in all Poly E arms: number of patients in n (%) Nausea: 8 (27) Diarrhoea: 3 (10) Constipation: 3 (10) Indigestion: 10 (33) Abdominal pain: 1 (3) Flatulence: 1 (3) Gastrointestinal haemorrhage: 1 (3) Weight gain: 1 (3) Palpitations: 1 (3) Elevated transaminases: 3 (10) Elevated alkaline phosphatase: 2 (7) Elevated lipase: 2 (7) Elevated uric acid: 1 (3) Proteinuria: 3 (10) Anaemia: 2 (7) Headache: 2 (7) Insomnia: 4 (13) Irregular menstruation: 1 (3) Hot flushes: 1 (3) |
| 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 | 11 |
| Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date | 5 |
| Drop-out reasons | Nonadherent (did not complete 6 months of study drug) (n = 2),but completed their 6-month study evaluations; DLT (dose-limiting toxicity) (n = 3), but completed their 6-month study evaluations
= completed follow-up n=11 |
| Intervention | Polyphenon E (Poly E) 600 |
| Dosage and regime | Oral green tea extract with 600mg EGCG twice daily for 6 month |
| 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. | 182 |
| Side effects / Interactions | Recording with CTCAE
Side effects in all Poly E arms: number of patients in n (%) Nausea: 8 (27) Diarrhoea: 3 (10) Constipation: 3 (10) Indigestion: 10 (33) Abdominal pain: 1 (3) Flatulence: 1 (3) Gastrointestinal haemorrhage: 1 (3) Weight gain: 1 (3) Palpitations: 1 (3) Elevated transaminases: 3 (10) Elevated alkaline phosphatase: 2 (7) Elevated lipase: 2 (7) Elevated uric acid: 1 (3) Proteinuria: 3 (10) Anaemia: 2 (7) Headache: 2 (7) Insomnia: 4 (13) Irregular menstruation: 1 (3) Hot flushes: 1 (3) |
| 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 | 3 |
| 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 | Lost to follow-up (n = 1); DLT (dose-limiting toxicity) (n = 1)
= Completed follow-up n=1 |
| Intervention | Polyphenon E (Poly E) 800 |
| Dosage and regime | Oral green tea extract with 800mg EGCG twice daily for 6 month |
| 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. | 182 |
| Side effects / Interactions | Recording with CTCAE
Side effects in all Poly E arms: number of patients in n (%) Nausea: 8 (27) Diarrhoea: 3 (10) Constipation: 3 (10) Indigestion: 10 (33) Abdominal pain: 1 (3) Flatulence: 1 (3) Gastrointestinal haemorrhage: 1 (3) Weight gain: 1 (3) Palpitations: 1 (3) Elevated transaminases: 3 (10) Elevated alkaline phosphatase: 2 (7) Elevated lipase: 2 (7) Elevated uric acid: 1 (3) Proteinuria: 3 (10) Anaemia: 2 (7) Headache: 2 (7) Insomnia: 4 (13) Irregular menstruation: 1 (3) Hot flushes: 1 (3) |
| 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 | 10 |
| 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 | Lost to follow-up (n = 2) |
| Intervention | NI |
| Dosage and regime | NI |
| 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. | 182 |
| Side effects / Interactions | Recording with CTCAE
Side effects in placebo arm: number of patients in n (%) Nausea: 2 (20) Diarrhoea: 2 (20) Indigestion: 2 (20) Abdominal pain: 2 (20) Flatulence: 1 (10) Palpitations: 1 (10) Shortness of breath: 1 (10) Cough: 1 (10) Elevated bilirubin: 1 (10) Elevated uric acid: 1 (10) Proteinuria: 1 (10) Headache: 2 (20) Confusion: 1 (10) Irregular menstruation: 1 (10) Flushing: 1 (10) Vaginal discomfort: 1 (10) |
Outcomes
Toxicity
| Outcome type As specificed by the authors | Primary |
|---|---|
| Outcome specification | Maximum tolerated dose (MTD):
Toxicity level of 25% of participants with toxicity ≥ grade II according to CTCAE |
| 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". | Per arm:
Rectal bleeding occurred in a woman with pre-existing diverticulosis and required hospitalization; after this serious adverse event, the protocol was amended to exclude women with a prior history of a gastrointestinal bleed. |
| 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". | The toxicities did not differ significantly by Poly E dose level or compared with placebo
All DLTs (dose-limiting toxicity) occurred in participants receiving active Poly E. The frequency of DLTs was 6.25% (1 of 16) for dose level 1, 27% (3 of 11) for dose level 2, and 33% (1 of 3) for dose level 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 | ? |
Funding and Conflicts of Interest
| Funding | NI |
|---|---|
| Conflicts of Interest | P. Brown (co-author) is a consultant/advisory board member of Susan G. Komen (Breast Cancer Organisation USA)
The Editor-in-Chief of Cancer Prevention Research is an author of the article. According to information no conflicts of interest of the other authors. |
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 | ? |