Pancreatic Neoplasms
Conditions
Keywords
Beta-blocker, Propranolol, COX-2 inhibitor, Etodolac
Brief 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.
Interventions
A perioperative combined drug regimen
OTHERPlacebo
Placebo
Sponsors
Sheba Medical Center
Assaf-Harofeh Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to 80 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of cancer recurrence | 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 |
| Biomarkers in extracted tumor tissue samples | 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. |
| Biomarkers in blood samples | 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) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of patients with treatment related adverse events | 30 days following surgery | According to the Clavien-Dindo classification system (7 grades of events depicting the severity of the event) |
| Depression, Anxiety, Global distress | At baseline and at 30 days post-surgery | Assessed by changes on the brief symptom inventory 18 questionnaire (this questionnaire assess all three scales for depression, anxiety and global distress) |
| Fatigue | At baseline and at 30 days post-surgery | 4 items related to fatigue in the 36 item short-form survey questionnaire. |
Countries
Israel
Contacts
Primary ContactOded Zmora, MD
Outcome results
None listed