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
试验速览
- 阶段
- 不适用
- 发起方
- 入组人数
- 32
- 试验地点
- 3
- 主要终点
- 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
研究概览
简要总结
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.
详细描述
Scientific Background Anesthesia and surgery are stressful situations which cause neuro-endocrine, metabolic and neurological responses. Cancer surgery may cause a decrease in anti-angiogenic factors, and enable dissemination of tumor cells through manipulation of the tumor and it blood vessels, as well as local and systemic secretion of growth hormones, and immune suppression. The magnitude of the response depends on many factors, including the extent of tissue injury, technique of anesthesia and type of analgesia, transfusions, temperature changes, psychological stress and genetic factors (1-3). The tissue damage starts a cascade of local and systemic processes which include secretion of hormones and cytokines (1).
Post operatively, suppression of several immune functions occurs, and may last for weeks. The cellular immunity undergoes suppression, while the humoral immunity remains almost entirely intact (1). These changes in cell mediated immunity may impact systemic resistance to infection as well as metastatic processes. Specifically, NK cells have a pivotal role in defense from neoplastic processes. Studies have shown that high levels of activity of NK cells are associated with long term survival (1). Therefore, understanding of the processes which cause post-operative immune suppression, and prevention of such suppression, are of clinical significance.
Several substances which are secreted after surgery are thought to contribute to immune suppression in general and NK cell dysfunction in particular. These include prostaglandins, catecholamines, steroids and endorphins, have all been shown to suppress several immunological functions in vitro (1). Animal studies have shown that administration of prostaglandins and catecholamines to rats suppresses NK cell activity in vivo, in association with elevated susceptibility to metastases 4-6).
In rats undergoing a laparotomy, peri-operative administration of beta- adrenergic blockers together with COX-2 inhibitors significantly abrogated the NK cell suppression as well as the enhanced susceptibility to metastases after surgery (4,7).
The mechanism of effect of prostaglandins and catecholamines on NK cells has been elucidated (1): beta- adrenergic receptors and prostanoid receptors on the cell membrane cause elevated levels of intra-cellular cAMP when activated by their ligand, which in turn interferes with the NK cell cytotoxic activity against cancer cells or viral pathogens. Since the elevated intra-cellular levels of cAMP is caused by each type of receptor independently, blockade of only one of these pathways will enable an increase in intracellular cAMP levels via the other pathway, and have no effect of the suppression of cytotoxic activity. Therefore, simultaneous blockade of both pathways may be more effective. Research in rats directly supports this hypothesis (7).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Double (Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 20 Years 至 70 Years（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 是
入选标准
- •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.
排除标准
- •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
研究组 & 干预措施
1
Peri-operative etodolac and propranolol as described in protocol
干预措施: Propranolol, etodolac (Drug)
结局指标
主要结局
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
时间窗: 5 years
次要结局
未报告次要终点
研究者
Tanir M Allweis, MD
Director, Sarah Markowitz Breast Health Center
Kaplan Medical Center