Perioperative Metformin Treatment for Colon Cancer, a Randomized Trial
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 48
- 试验地点
- 1
- 主要终点
- Expression of Ki67 on tumor samples
研究概览
简要总结
This is a double-blinded placebo controlled randomized trial examining the effect of metformin in non-diabetic patients with colon cancer on cell growth, immunological and metabolic changes. Patients are randomized to receive metformin 20 days before and 10 days after surgery. Tumor samples are examined for changes in level of cell growth and the composition of tumor cells in the tumor is examined. Blood samples are assessed for immunological markers and insulin resistance is measured. Cell proliferation, migration and adhesion are also examined in vitro by adding plasma obtained from the patients to colon cancer cell lines grown in culture.
详细描述
Background: Colorectal cancer (CRC) is the third most common cancer worldwide and more than 5000 patients are diagnosed each year in Denmark.
Metformin is the drug of choice for treatment of type 2 diabetes. Several studies indicate that the incidence of colorectal cancer is lower among metformin treated diabetic patients than other diabetic patients and survival after CRC is improved for this group as well.
Metformin lowers plasma glucose in diabetic patients, but studies suggest that metformin also inhibits cancer cell growth.
Tumor cell proliferation and apoptosis can be estimated by determining the expression levels of specific cell cycle related proteins such as Ki67 (proliferation) and cleaved caspase-3 (apoptosis) using immunohistochemistry.
The level of cell proliferation and apoptosis is important for tumor development, but growing evidence suggests that the microenvironment of the tumor and the patient's immune response play important roles as well. The immunoscore has been introduced as a prognostic marker for CRC. The immunoscore is determined by staining whole tumor slides for CD3 and CD8 positive lymphocytes using immunohistochemistry, followed by quantitative assessment and scoring of their densities. A high density is associated with better outcome than a low density. It is possible that metformin can influence the composition of immune cells as well.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients with adenocarcinoma of the colon planned for elective curative intended surgery at Slagelse hospital
- •Age of 18 or above
- •Must be able to understand and sign informed content
- •Sufficient amount of representative tumor material from the biopsies taken at the initial colonoscopy must be present
排除标准
- •Patients diagnosed with diabetes mellitus
- •Patients who are receiving or have received metformin or other oral antidiabetics
- •Impaired kidney function (eGFR < 60mL/min)
- •Severe liver disease (defined as transaminases above X 3 normal levels)
- •Participation in another pharmacological intervention trial
- •Predictable poor compliance (for instance not speaking fluent Danish, mentally impaired)
- •Presenting with metastatic disease
- •Patients undergoing neoadjuvant chemotherapy
- •Pregnancy or lactation (fertile women must have a negative serum or urine pregnancy test to participate)
- •Fertile women who do not use safe contraception during the study period.
- •Allergy to metformin or placebo
研究组 & 干预措施
metformin hydrochloride
metformin, encapsulated tablet, 500mg 3 times a day for 30 days.
干预措施: Metformin Hydrochloride (Drug)
placebo oral capsule
placebo, encapsulated tablet, 500mg 3 times a day for 30 days.
干预措施: Placebo oral capsule (Drug)
结局指标
主要结局
Expression of Ki67 on tumor samples
时间窗: colonoscopy (baseline) and at time of operation (after intervention)
The primary outcome is determination of the difference of the level of proliferation after the intervention (time of surgery) adjusted for the level seen at baseline (time of colonoscopy). This is done using immunohistochemical staining for Ki67 (a marker for proliferation) of biopsies from the tumor. The level of proliferation will be defined as the percentage of tumor nuclei showing Ki67 staining in a specific microscopic field counted at the invasive front.
次要结局
- cell growth in vitro - proliferation(At baseline, postoperative day 1 and 10.)
- immunological changes in bloodsamples(At baseline, day of operation and postoperative day 1, 2 and 10.)
- insulin resistance(At the day of surgery and postoperative day 1 and 2.)
- immunoscore(time of operation (after the tumor is removed))
- Expression of cleaved Caspase-3 on tumor samples(colonoscopy (baseline) and at time of operation (after intervention))
- blood glucose level(4 times a day on postoperative day 1 and 2)
- cell growth in vitro - invasion(At baseline, postoperative day 1 and 10.)
- Quality of recovery(At baseline, postoperative day 1, 2, 10 and 30.)
- cell growth in vitro - adhesion(At baseline, postoperative day 1 and 10.)
- microbiota(At baseline and the day before surgery)