Colorectal Neoplasms
Conditions
Keywords
Beta-blocker, Propranolol, COX-2 inhibitor, Etodolac
Brief summary
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
Interventions
A perioperative combined drug regimen
OTHERPlacebo
Placebo
Sponsors
Sheba Medical Center
Rabin Medical Center
Tel-Aviv Sourasky Medical Center
Rambam Health Care Campus
HaEmek Medical Center, Israel
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
1\. Patients planned for surgery for primary resection of colon or rectal cancer with curative intent. 2. Single colonic or rectal carcinoma, proven by full colonoscopy and tumor biopsy. 3. No evidence of metastatic disease prior to surgery. Minimal workup would include abdominal CT with IV contrast (or CT+liver US) and chest XR. 4. ASA score of 1-3 or ECOG Performance Status of 0 to 1 5. Signed informed consent form 6. Willing and able to comply with study procedures (physically and mentally) 7. Men and women from age 20 to age 80 \-
Exclusion criteria
1. Patients with metastatic disease, known prior to surgery 2. Patients in whom surgical resection is planned without curative intent 3. Patients with renal failure, measured by creatinine level \>1.5 4. Patients with significant heart failure (NYHA functional class 3 or higher) 5. Patients with significant liver failure (known cirrhosis, Bilirubin level\>2) 6. Patients currently suffering from asthma or Chronic Obstructive Pulmonary Disease (COPD) 7. Patients treated pharmacologically for diabetes mellitus (type 1/2), 8. Patients with peripheral vascular disease 9. Patients with known allergy to one or more of the study medications. 10. Patients with known allergy to any medication from the non-steroidal anti- inflammatory drug group or beta-blockers family 11. Patients treated chronically with any type of a beta-adrenergic blocker or a COX inhibitor 12. Patients with bradycardia or second or third degree AV block 13. Patients with a history of CVA/TIA 14. Patients with Printzmetal's angina 15. Patients with right sided heart failure owing to pulmonary hypertension 16. Patients with significant diagnosed cardiomegaly 17. Patients with (current) pheochromocytoma 18. Patients with chronic Digoxin treatment 19. Patients with active peptic disease 20. Pregnant women 21. Patients who participate in another interventional study 22. Patients with history or concomitant malignant disease of any type (except for the current colon/rectal cancer) 23. 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. 24. Patients who are treated with immunosuppressive medications 25. Patients with Immunodeficiency Disorders, or autoimmune disease treated by immunosuppressive medications. 26. Patients suffering from sick sinus syndrome
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 5-year disease-free-survival | 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 | 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 assessing pro- and anti-metastatic processes | 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 |
|---|---|---|
| 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) |
| 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) |
| 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