Perioperative Administration of COX 2 Inhibitors and Beta Blockers to Women Undergoing Breast Cancer Surgery
Recruitment status was: Recruiting
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.
|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|
- 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 ]
|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)|
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
Please refer to this study by its ClinicalTrials.gov identifier: NCT00502684
|Rabin Medical Center|
|Petah Tikva, Israel, 49100|
|Sheba Medical Center|
|Ramat Gan, Israel, 52621|
|Kaplan Medical Center|
|Rehovot, Israel, 76100|
|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|