perioperative intervention to reduce metastatic processes in pancreatic cancer patients undergoing curative surgery

Conditions: Pancreatic Neoplasms

Summary: in israel, of the \~1000 patients diagnosed annually with pancreatic cancer (pc), approximately 250 (25 percent) will be eligible for curative surgery, of which 80 percent will succumb to post-surgical metastatic disease. a reduction in post-surgical metastatic disease will save dozens of patients in israel annually, and tens-of thousands-around the world. 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, our animal studies 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. we recently conducted two clinical trials 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, we propose to conduct a double-blind placebo-controlled two-arm phase ii clinical trial in 210 pancreatic cancer patients undergoing curative surgery in israel. a perioperative 35-day drug treatment will be initiated 5 days before surgery. primary outcomes will include (i) 1-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.


Eligibility criteria:
inclusion criteria: * newly diagnosed stage i or ii adenocarcinoma of the head, neck, or uncinated- process of the pancreas. * surgically resectable disease (r0 or r1) by spiral ct chest and abdomen scan, no distant metastases * eastern cooperative oncology group (ecog) performance status of 0 to 1 * signed informed consent form * willing and able to comply with study procedures * men and women from age 20 up to age 80 exclusion criteria: * patients with metastatic disease, known prior to surgery * patients with history or concomitant malignant disease of any type (except for the current pancreatic cancer * patients who were treated with chemotherapy in the last 10 years for any reason * patients in whom surgical resection is planned without curative intent * patients exhibiting levels carbohydrate antigen (ca) 19-9 above 500 * 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) * patients suffering from active asthma * patients with known allergy to any medication from the non-steroidal anti- inflammatory or beta-blockers drug group * patients treated chronically with any type of a beta-adrenergic blocker or a cyclooxygenase (cox) inhibitor * patients with bradycardia or second or third degree atrioventricular block (av) block * patients with a history of cerebrovascular accident (cva) or established diagnosed transient ischemic attack (tia) * patients with prinzmetal'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 * patients with peripheral vascular disease * pregnant woman * special population with impaired judgment * patients currently actively participating in any other clinical trial * contraindication for whipple procedure * patients suffering from sick sinus syndrome * patients with borderline resectable tumors, as defined by one of the following: * an infiltration \>180° of the portal vein * abutment of the tumor to the superior mesenteric artery * infiltration of the superior mesenteric artery or the celiac trunk

Keywords: beta-blocker propranolol cox-2 inhibitor etodolac