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
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 a large number of factors,
including the extent of tissue injury, technique of anesthesia and type of analgesia, blood
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 days or
weeks. The cellular immunity (macrophages, NK cells, cytotoxic T lymphocytes and dendritic
cells) undergo significant suppression, while the humoral immunity remains almost entirely
intact (1). These changes in cell mediated immunity may impact the systemic resistance to
infection as well as metastatic neoplastic processes. Specifically, NK cells have a pivotal
role in defense from neoplastic processes and leukemia. 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 the administration of
prostaglandins and catecholamines to rats suppresses NK cell activity in vivo, in
association with elevated susceptibility to cancer metastases and experimentally induces
In rats undergoing a laparotomy, peri-operative administration of β- adrenergic
blockers(propranolol or nadolol) together with COX-2 inhibitors (etodolac or indomethacin)
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): β- 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 of the other,
blockade of only one of these pathways will still 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 done in
rats directly supports this hypothesis (7).
Cells of the immune system express mostly β--2 adrenergic receptors, and to a lesser degree
- β--1 receptors as well (9, 10), so pharmacological blockade requires use of a no specific
blocker which can block both types of receptors. The β- antagonist propranolol (Deralin) was
chosen for this experiment since it is a no specific β- blocker, capable of blocking both
types of receptors, as well as the extensive clinical experience with this drug and the fact
that it is a relatively safe drug. The COX-2 inhibitor chosen is Etodlac (Etopan), which has
the advantage of being a selective COX-2 inhibitor which is synthesized during injury and
inflammation, with little effect on the COX-1 enzyme, which is associated with ongoing
maintenance of tissues.
Anesthetics and opiate analgesics also cause NK cell suppression. Research in animals and in
surgical patients have shown that morphine and fentanyl in analgesic or anesthetic doses
cause suppression of NK cell activity, and enhanced susceptibility to breast cancer
metastases in rats (11,12). Lower doses of opiates in patients have been reported to
decrease the immune suppression magnitude and duration (13). Therefore, peri-operative
interventions which decrease the use of opiates (or their endogenous secretion) may be
clinically important factors in cancer recurrence.
In addition to immune suppression, endogenous and exogenous opiates (endorphins morphine,
fentanyl) have been implicated as promoting metastatic spread and neoplastic proliferation
via other mechanisms:
- Catecholamines have been reported to increase VEGF secretion by human cancer cells, and
enhance tumor cell invasion (14-16).
- Morphine causes increased proliferation of human tumor cells and enhances tumor
- COX2 inhibitors enhance sensitivity of human tumor cells to induction of apoptosis, and
decrease capillary density in cancer tissue (18, 19).
Therefore, minimization of peri-operative opiate use and prevention or blockade of
prostaglandin and catecholamine effects may delay the metastatic process and the development
of existing micro-metastases.
A retrospective clinical study published in 2006 indirectly supports the proposed study: In
this study breast cancer patients were treated per-operatively with a COX inhibitor
(diclofenac) along with local blockade of the sympathetic and pain pathways (paravertebral
anesthesia). These treatments no doubt lowered the use of opiates during and after surgery.
Among patients thus treated a three fold decrease in recurrence rates was found three years
after surgery (21). Of note, this study quotes the previously mentioned study in rats (6,22)
and involves the same interventions.
AIM The aim of the proposed study is to examine whether peri-operative administration of
COX2 inhibitors with β- adrenergic blockers decreases the immune suppression around the time
of surgery, decreases stress hormone and pro-angiogenic factor secretion, and is associated
with a decrease in cancer recurrence rates.
The peri-operative variables which will be examined will include number and activity of NK
cells in the blood, levels of Th1 and Th2 cytokines, stress hormones and pro-angiogenic
factors, and Th1&2 cytokine production by leukocytes in response to in vitro stimulation. As
part of the clinical monitoring meticulous recording of type and doses of analgesics given
post operatively, as well as post operative pain assessment (NAS VAS). In addition to
these parameters, long term follow up will be conducted to determine long term effects of
the intervention on cancer recurrence during 5 years after surgery.
Peri-operative administration of COX inhibitors and β- adrenergic blockers Routine pre
medication before surgery generally includes anxiolytics such as benzodiazepines, drugs
routinely taken by the patient, and additional drugs for specific indications. Preventive
administration of β- blockers and COX inhibitors are recommended in the literature
pertaining to anesthesia and pain. Administration of β- blockers has been shown to stabilize
the cardio vascular system and decrease peri-operative ischemic events (23), while
preventive administration of COX inhibitors decreases post operative pain (5). Post
operative pain has significant immunological effects: it causes secretion of endogenous
opiates, and is often treated with synthetic opiates such as morphine. The opiates cause a
stress response, suppress immune functions and promote tumor growth and spread. Studies have
shown that administration of COX inhibitors together with morphine caused a decrease in
morphine requirements. Administration of COX inhibitors can help control pain by abrogation
of prostaglandin mediated pain pathways while at the same time decreasing opiate
requirements. An additional benefit of COX inhibitors is it's direct activity against tumor
cells by enhancing apoptosis and decreasing tumor blood supply as reported in a recently
published study (21). These studies indicate that peri-operative use of these drugs does not
have any detrimental effects, is not associated with increased complication - and in fact
may be beneficial.
Patients and Methods
Patients and treatments:
Immune system activity will be determined among 80 operated breast cancer patients, and 20
health women in the following groups:
- Treatment arm: 40 patients undergoing elective surgery for primary breast cancer will
be treated orally according to the following protocol:
- Propranolol (Deralin) - patients will receive a low dose of 40 mg/day (4X10mg)
starting two days before surgery (immediately following the first blood draw)
until the evening of surgery. The first dose will be given under supervision
(described later). On the morning of surgery, a single tablet of propranolol XL
80mg will be administered together with other pre-medication drugs, and will be
continued once daily for three days after surgery. Pulse and blood pressure will
be monitored during the first day of treatment, during the day of surgery and on
the following days until discharge from the hospital (usually on the day following
surgery). If pulse decreases to less than 50/min or blood pressure decreases to
under 100 systolic - the dose will be halved.
- Etodolac (Etopan) - patients will receive 600mg of etodolac XL twice a day
starting two days before and continuing through two days after surgery.
- Control arm: Fourty patients undergoing the same operations will be treated with
placebo drugs on the same schedule.
- Healthy controls: a third control arm will include 20 healthy age-matched women
presenting for routine breast exams and not undergoing surgery will undergo blood tests
Patients will be randomized to one of the two groups, and patient, physicians and laboratory
personnel will be blinded to the patient's assignment.
Dependent variables to be tested:
1. Cytotoxic activity of NK cells against K562 target cells.
2. Blood leukocyte levels of NK cells, NKT cells, lymphocytes, monocytes and granulocytes
as determined by FACS.
3. Serum levels of cytokines (Th1, Th2 and inflammatory): IFN-, IL-2, IL-12, IL-4, IL-10
IL-1 and IL-6.
4. In vitro cytokine secretion by leukocytes stimulated by HPA and LPS. (IFN- IL- 2,
IL-12, IL-4, IL-10 IL-1 and IL-6.)
5. Stress hormones and angiogenic factors: levels of cortisol and VEGF.
6. Doses of anesthetics and analgesics used during and after surgery.
7. Cancer recurrence during 5 years (including site of recurrence). In addition to the
aforementioned groups, another 190 patients will be recruited onto each group without
examining immunological parameters, and will be followed only for cancer recurrence.
- Women scheduled to undergo surgery for primary breast cancer.
- Ages 20-75.
- ASA 1-2.
- Patients with renal failure (creatinin >1.5)
- Significant heart failure (NYH ≥ 3)
- Patients with known liver failure (known cirrhosis, liver enzymes > 1.5 times normal)
- Patients with known allergies to one of the study drugs.
- Patients treated regularly with one of the study drugs
- Patients treated with digoxin.
- Peripheral vascular disease.
- Patients within 10 years of chemotherapy for any reason.
- Women with another malignancy other than breast cancer.
After obtaining Helsinki committee approval, eligible patients will receive explanations and
be invited to participate in the study. Women who consent will sign the approved informed
Anesthesia procedure will include:
Standard monitoring including automated blood pressure, ECG, O2 saturation, levels of
inhaled and exhaled gases Pre-medication: at anesthesiologists discretion Induction: at
anesthesiologist's discretion Maintenance: at anesthesiologist's discretion (an effort will
be made to minimize opiate use but without compromising on pain control).
Post operative pain management:
Patients will be given a choice of oral Paracetamol 1000 mg every 4 hours, oral Dipyrone
1000 mg every 4 hours, oral Tramadol solution 50 mg every 6 hours and combinations of the
above. If needed - 5 mg of oral percocet/oxycodone syrup every 6 hours may be added. For
patients who are unable to sustain oral intake, intravenous Tramal will be offered at a dose
of 50-100 mg every 6 hours and if needed - morphine 0.1 mg/kg every 4 hours. This protocol
is identical to the one currently used after this type of surgery.
Blood samples :
Blood samples will be obtained two days before surgery (prior to administration of study
drugs or placebo), on the morning of and the morning following surgery. Blood samples will
be drawn between 7:30 and 9:00 am, and will include 10 cc of peripheral blood, preferably
from the ante-cubital vein.
Blood will be collected in vacuum tubes containing 30 units of heparin without
preservatives, and will be transferred immediately to the neuro-immunology lab at Tel Aviv
University. Laboratory evaluation of the samples will begin within 3 hours of blood drawing.
The samples will be kept at room temperature.
The samples will be divided as follows:
NK cell activity testing - 2 ml FACS analysis of cells - 1 ml In vitro testing of cytokine
response to LPS - 2 ml Cytokine, cortisol and VEGF levels - 5 ml (to be performed in batches
at a later time - after separation of cells plasma will be kept at -80C).
Documentation and analysis of results:
Epidemiological data: identification (name, ID no), age, ethnic origin, background medical
conditions and drugs, smoking, menstrual status and date of last menstrual period, physical
activity, presence of infections or viral illnesses within last 2 weeks.
Data related to anesthesia and surgery:
Type and length of surgery, systemic administration of opioids during and after surgery
(type & dose).
Cancer related parameters: Tumor size, grade, histological type, lymph node status, adjuvant
Immunological parameters: as previously detailed is three blood samples from operated
patients and a single sample from the healthy controls.
Recurrence data: location, time since surgery and survival.
Statistical analysis will be done by ANOVA (between and within subjects) regarding the
variables. Determination of specific differences between groups will be based on the PLSD
test for planned comparisons, and the Scheffe test for unplanned comparisons. Chi square
tests will be used as well as Kaplan-Meier survival curves for non continuous or categorical
variables. In addition, Cox regressions will be calculated to evaluate the predictive
ability of treatments on cancer recurrence, taking other predicting factors into account.
Blood samples and immunological data will be collected for 40 patients in groups 1 & 2 and
20 healthy controls in group 3. In order to determine impact of treatment on recurrence
rates a total of 230 patients will be recruited in each group. Sample size was calculated to
provide an 805 power to detect a 30-50% decrease in cancer recurrence with an alpha of 0.05.
Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Prevention
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
Tanir M Allweis, MD
Hadassah Medical Organization
Israel: Ministry of Health
392-22.6.07 / 2358