Perioperative Use of a β-adrenergic Blocker, Propranolol, and a COX2 Inhibitor, Etodolac, in Patients Undergoing Resection With Curative Intent for Primary Colon and Rectal Cancer: Effect on Tumor Recurrence and Survival
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 200
- 试验地点
- 6
- 主要终点
- Biomarkers in blood samples assessing pro- and anti-metastatic processes
研究概览
简要总结
The short perioperative period (days to weeks around surgery) is characterized by stress-inflammatory responses, including catecholamines (CAs, e.g., adrenaline) and prostaglandins (PGs, e.g., prostaglandin-E2) release, and induce deleterious pro-metastatic effects. Animal studies implicated excess perioperative release of CAs and PGs in facilitating cancer progression by affecting the malignant tissue, its local environment, and anti-metastatic immune functions. Congruently, animal studies conducted by the investigators indicate that combined use of the beta-adrenergic blocker, propranolol, and the prostaglandins inhibitor, etodolac - but neither drug separately - efficiently prevented post-operative metastatic development. Two recently conducted clinical trials, conducted by the investigators, in three medical centers in Israel, recruiting breast (n=38) and colorectal (n=34) cancer patients, assessing the safety and short-term efficacy of perioperative propranolol and etodolac treatment. Drugs were well tolerated, without severe adverse events. Importantly, molecular/biological analyses of the excised primary tumor indicated that drug treatment caused promising anti-metastatic transformations, as well as improvements in immune and inflammatory indices. These included (i) decreased tumor cell capacity to migrate, (ii) reduced pro-metastatic capacity of the malignant tissue, and (iii) improvement in immune infiltrating into the tumor (Paper published in Clinical Cancer Research, 2017). Herein, the investigators propose to conduct a double-blind placebo-controlled two-arm Phase II clinical trial in 200 colorectal cancer patients undergoing curative surgery in Israel. A perioperative 20-day drug treatment will be initiated 5 days before surgery. Primary outcomes will include (i) 3-year disease-free-survival (DFS), and 5-year overall survival (OS); and (ii) biological markers in blood samples, and in the excised tumor tissue. Secondary outcomes will include safety indices and psychological measures of depression, anxiety, distress, and fatigue
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 20 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients planned for surgery for primary resection of colon or rectal cancer with curative intent.
- •Single colonic or rectal carcinoma, proven by full colonoscopy and tumor biopsy.
- •No evidence of metastatic disease prior to surgery. Minimal workup would include abdominal CT with IV contrast (or CT+liver US) and chest XR.
- •ASA score of 1-3 or ECOG Performance Status of 0 to 1
- •Signed informed consent form
- •Willing and able to comply with study procedures (physically and mentally)
- •Men and women from age 20 to age 80
排除标准
- •Patients with metastatic disease, known prior to surgery
- •Patients in whom surgical resection is planned without curative intent
- •Patients with renal failure, measured by creatinine level >1.5
- •Patients with significant heart failure (NYHA functional class 3 or higher)
- •Patients with significant liver failure (known cirrhosis, Bilirubin level>2)
- •Patients currently suffering from asthma or Chronic Obstructive Pulmonary Disease (COPD)
- •Patients treated pharmacologically for diabetes mellitus (type 1/2),
- •Patients with peripheral vascular disease
- •Patients with known allergy to one or more of the study medications.
- •Patients with known allergy to any medication from the non-steroidal anti- inflammatory drug group or beta-blockers family
- •Patients treated chronically with any type of a beta-adrenergic blocker or a COX inhibitor
- •Patients with bradycardia or second or third degree AV block
- •Patients with a history of CVA/TIA
- •Patients with Printzmetal's angina
- •Patients with right sided heart failure owing to pulmonary hypertension
- •Patients with significant diagnosed cardiomegaly
- •Patients with (current) pheochromocytoma
- •Patients with chronic Digoxin treatment
- •Patients with active peptic disease
- •Pregnant women
- •Patients who participate in another interventional study
- •Patients with history or concomitant malignant disease of any type (except for the current colon/rectal cancer)
- •Patients who were treated with chemotherapy in the last 10 years for any reason besides neo-adjuvant therapy for rectal cancer within the last six months.
- •Patients who are treated with immunosuppressive medications
- •Patients with Immunodeficiency Disorders, or autoimmune disease treated by immunosuppressive medications.
- •Patients suffering from sick sinus syndrome
研究组 & 干预措施
Propranolol and etodolac
Both study medications will be given orally for an intervention phase of 20 days as follows. Etodolac:400mg PO bid for the entire intervention period, Propranolol (slow release): 20 mg PO b.i.d. for 5 preoperative days; 80 mg PO b.i.d. on the day of surgery; 40 mg PO b.i.d. for the first post-operative week and 20 mg PO b.i.d. for the second post-operative week.
干预措施: Propranolol and etodolac (Drug)
Placebo
Same schedule as in the active comparator arm
干预措施: Placebo (Other)
结局指标
主要结局
Biomarkers in blood samples assessing pro- and anti-metastatic processes
时间窗: An average of one year following surgery
Cytokine levels in blood samples (interleukin-6, interleukin-10, C-reactive protein, interferon-gamma, and vascular endothelial growth factor and additional exploratory analysis of other cytokines)
5-year disease-free-survival
时间窗: From the date of surgery until malignant disease is identified, assessed up to 60 months post-surgery]
Data regrading post-surgical recurrence will be recorded at 1,3,6,12,18,24,36,48, and 60 following surgery. Primary outcome 1 will be rate of recurrence/disease at 60 months.
Biomarkers in extracted tumor tissue samples assessing pro- and anti-metastatic processes
时间窗: An average of one year following surgery
Epithelial-to-mesenchymal-transition ( EMT) status and natural-killer cell, macrophage, T-cell, and B-cell infiltration levels into tumor tissue (as assessed by messenger RNA profiling of tissue samples
次要结局
- Depression, Anxiety, Global distress(At baseline and at 30 days post-surgery)
- Number of patients with treatment related adverse events(30 days following surgery)
- Fatigue(At baseline and at 30 days post-surgery)