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

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.

Sex

Female

Minimum age

20 Years

Maximum age

70 Years

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

• DERIVEDSakis N, Sorski L, Asraf E, Ricon-Becker I, Shaashua L, Haldar R, Shvalbo BB, Shabat-Simon M, Gutman M, Nissan A, Nachmany I, Kent I, Pery R, Pencovich N, Shussman N, Wasserberg N, Reshef A, Quint E, Lishtzinsky YY, Kashtan H, Shabtai M, Brenner B, Sharon E, Allweis T, Shahar N, Eckerling A, Sandbank E, Zmora O, Ben-Eliyahu S. Favorable safety outcomes of a perioperative propranolol and etodolac regimen in cancer patients in four randomized controlled trials. Front Pharmacol. 2026 Apr 20;17:1823113. doi: 10.3389/fphar.2026.1823113. eCollection 2026. PMID 42088573