Perioperative Administration of COX 2 Inhibitors and Beta Blockers to Women Undergoing Breast Cancer Surgery

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by Kaplan Medical Center
Sponsor:
Collaborators:
Tel Aviv University
Tel-Aviv Sourasky Medical Center
Sheba Medical Center
Rabin Medical Center
Information provided by (Responsible Party):
Tanir M Allweis, MD, Kaplan Medical Center
ClinicalTrials.gov Identifier:
NCT00502684
First received: July 17, 2007
Last updated: June 29, 2014
Last verified: June 2014
  Purpose

Surgery for breast cancer has a major role in enhancing long term survival and cure, but several physiological aspects associated with surgery are implicated as enhancing tumor spread and formation of distant metastases. These include: an increase in pro-angiogenic factors, direct spread of tumor cells, accumulation of grown factors, immune suppression and direct effects of anesthetics and opiate pain relievers on cancer cells. Some of these pro-metastatic mechanism may be blocked by the interventions proposed in this study, namely by administration of beta-adrenergic blockers and COX2 inhibitors around the time of surgery.

Studies have shown that surgery increases levels of catecholamines and prostaglandins, which in turn may promote the release of pro-angiogenic factors such as VEGF, and enhance vascularization of micro metastases.

Opiates given for pain relief during and after surgery have been reported to enhance tumor cell division and cause immune suppression.

The immune system is significantly suppressed during surgery. This suppression has been shown to affect the systemic resistance to infection as well as neoplastic metastatic processes.

Several studies have shown that increased levels of catecholamines and prostaglandins add to the immune suppression.

Studies in rats found that peri-operative administration of the beta beta-blocker propranolol together with the COX2 inhibitor etodolac significantly reduced the suppression of NK cell activity as well as the risk for distant metastases.

A recent retrospective clinical study found that among breast cancer patients treated with a combination of regional anesthesia and a COX inhibitor the recurrence rated were significantly less than among patients undergoing surgery without these two interventions.

The purpose of the proposed prospective trial is to examine if peri-operative administration of the combination of a beta-blocker together with a COX2 inhibitor will prevent suppression of cellular immunity, decrease VEGF levels, and decrease cancer recurrence rates.

In the proposed study breast cancer patients will be treated with a combination of a beta-blocker and COX2 inhibitor (or placebo) before, during and after surgery. (A control group of healthy women will serve as untreated controls). The variables which will be examined are: number and activity of NK cells, levels of Th1 and Th2 cytokines, serum stress hormones and angiogenic factors, and the ability of leukocytes to produce Th1 and Th2 cytokines as a result of in vitro stimulation.

In addition to these immediate parameters, long term follow up will be conducted in order to determine the effect of the intervention on long term cancer recurrence over five years.

Statistical analysis will be done using t-tests, ANOVA, and multivariate regressions, with regard to the known risk factors for recurrence such as tumor grade, lymph node involvement etc. Sample size for immunological parameters will be 40 patients in each group and 20 healthy women. Sample size for estimates of cancer recurrence at five years of follow up wiil be 460 women (230 in each group). This sample size provides a power of 80% to detect a 50% reduction in cancer recurrence at an α of 0.05.


Condition Intervention
Primary Operable Breast Cancer
Drug: Propranolol, etodolac

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Perioperative Administration of COX 2 Inhibitors and Beta Blockers in Women Undergoing Breast Cancer Surgery: an Intervention to Decrease Immune Suppression, Metastatic Potential and Cancer Recurrence

Resource links provided by NLM:


Further study details as provided by Kaplan Medical Center:

Primary Outcome Measures:
  • No. & cytotoxic activity of NK cells, levels of NKT cells, lymphocytes, monocytes and granulocytes; cytokine levels; In vitro cytokine secretion; levels of cortisol and VEGF. Cancer recurrence in 5 years [ Time Frame: 5 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 32
Study Start Date: June 2014
Estimated Study Completion Date: January 2016
Estimated Primary Completion Date: January 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
Peri-operative etodolac and propranolol as described in protocol
Drug: Propranolol, etodolac
propranolol 10 mg X 4 /day, starting on day -3 pre-op, for 6 days, till POD 2 Etodolac 400 mg X2/day, starting on day -3 pre-op, for 6 days, till POD 2
Placebo Comparator: 2
peri-operative placebo as described in protocol

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   20 Years to 70 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Women that are scheduled to undergo surgery of a single, stage I-III, invasive ductal or lobular carcinoma tumor with curative intent
  • No evidence of metastatic disease prior to surgery. Minimal workup would include chest XR, abdominal ultrasound and bone scan.
  • Age between 20 and 70 year old.
  • ASA score of 1-2
  • The patient is able to understand the study objectives and procedures, able to comply with the protocol, and is capable to sign an informed consent.

Exclusion Criteria:

  • Patients with metastatic disease, known prior to surgery.
  • Patients in whom surgical resection is planned without curative intent.
  • Patients who have undergone neoadjuvant treatment.
  • 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 suffering from asthma
  • 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.
  • Patients with diabetes mellitus (type 1 or 2).
  • Patients treated chronically with one or more of the study medications
  • Patients treated chronically with any type of Beta adrenergic blocker.
  • Patients treated chronically with any type of COX inhibitor.
  • Patients with second or third degree AV block.
  • Patients with sinus bradycardia (patients with heart rate of less than 50).
  • Patients with sick sinus syndrome.
  • Patients with current atrial fibrillation/flutter.
  • Patients with Printzmetal's angina
  • Patients with hypertension
  • Patients with right sided heart failure owing to pulmonary hypertension.
  • Patients with significant cardiomegaly
  • Patients with (current) pheochromocytoma
  • Patients with chronic Digoxin treatment
  • Patients with active peptic disease
  • Patients with peripheral vascular disease
  • Patients with history or concomitant malignant disease of any type other than breast cancer.
  • Patients who were treated with chemotherapy in the last 10 years for any reason besides neo-adjuvant therapy for breast cancer within the last six months.
  • Pregnant woman.
  • Patients currently participating in any other clinical trial
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00502684

Contacts
Contact: Tanir M Allweis, MD +972-8-9441693 taniral@clalit.org.il
Contact: Shamgar Ben-Eliyahu, Prof +972-3-6407266 shamgar@post.tau.ac.il

Locations
Israel
Rabin Medical Center Recruiting
Petah Tikva, Israel, 49100
Contact: Eran Sharon, MD    +972-3-9376213    erans@clalit.org.il   
Contact: Irit Glik    +972-3-9376717    IritGlik@clalit.org.il   
Principal Investigator: Eran Sharon, MD         
Sheba Medical Center Recruiting
Ramat Gan, Israel, 52621
Contact: Moshe Shabtai, MD    972-3-5302247    Moshe.Shabtai@sheba.health.gov.il   
Contact: Maytal Shabat-Simon, PhD    972-50-2624233    maytal.shabat@gmail.com   
Principal Investigator: Moshe Shabtai, MD         
Kaplan Medical Center Recruiting
Rehovot, Israel, 76100
Contact: Tanir M Allweis, MD    +972-50-7874268    taniral@clalit.org.il   
Contact: Maytal Shabat-Simon, PhD    972-50-2624233    maytal.shabat@gmail.com   
Principal Investigator: Tanir M Allweis, MD         
Sponsors and Collaborators
Kaplan Medical Center
Tel Aviv University
Tel-Aviv Sourasky Medical Center
Sheba Medical Center
Rabin Medical Center
Investigators
Principal Investigator: Tanir M Allweis, MD Kaplan Medical Center
Study Director: Shamgar Ben-Eliyahu, PhD Tel Aviv University, Neuroimmunology Research Unit
Principal Investigator: Moshe Shabtai, MD Sheba Medical Center
Principal Investigator: Eran Sharon, MD Rabin Medical Center
  More Information

No publications provided

Responsible Party: Tanir M Allweis, MD, Director, Sarah Markowitz Breast Health Center, Kaplan Medical Center
ClinicalTrials.gov Identifier: NCT00502684     History of Changes
Other Study ID Numbers: 392-22.6.07 / 2358 HMO-CTIL
Study First Received: July 17, 2007
Last Updated: June 29, 2014
Health Authority: Israel: Ministry of Health

Keywords provided by Kaplan Medical Center:
breast cancer
surgery
immune suppression
beta blockers
COX2 inhibitors

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Adrenergic beta-Antagonists
Propranolol
Etodolac
Cyclooxygenase 2 Inhibitors
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Anti-Arrhythmia Agents
Cardiovascular Agents
Therapeutic Uses
Antihypertensive Agents
Vasodilator Agents
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Anti-Inflammatory Agents
Central Nervous System Agents
Antirheumatic Agents

ClinicalTrials.gov processed this record on July 26, 2014