Perioperative Administration of COX 2 Inhibitors and Beta Blockers to Women Undergoing Breast Cancer Surgery
Status:
Unknown status
Trial end date:
2016-01-01
Target enrollment:
Participant gender:
Summary
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.
Phase:
N/A
Details
Lead Sponsor:
Kaplan Medical Center
Collaborators:
Rabin Medical Center Sheba Medical Center Tel Aviv University Tel-Aviv Sourasky Medical Center