Regional Anesthesia and Breast Cancer Recurrence
Phase: PHASE3
Conditions: Breast Neoplasms
Sponsor: The Cleveland Clinic

 
Version 88 
11/14/2019 
Regional Anesthesia and Breast Cancer Recurrence  
Daniel I. Sessler, M.D. and Colleagues  
Department of OUTCOMES RESEARCH 
 
The Cleveland Clinic 
9500 Euclid Ave 
Cleveland, OH 44195  
Tel: 216-444-4900 
Fax: 216-444-61353 
Email: DS@OR.org 
Web: www.OR.org 
  
Abstract  
Surgery is the primary and most effective treatment of breast cancer, but residual disease in the form of 
scattered micrometastases and tumor cells are usually unavoidable. Whether minimal residual disease results 
in clinical metastases is a function of host defense and tumor survival and growth. At least three perioperative 
factors shift the balance toward progression of minimal residual disease: (1) Surgery per se depresses cell-
mediated immunity, reduces concentrations of tumor-related anti-angiogenic factors (e.g., angiostatin and 
endostatin), increases concentrations of pro-angiogenic factors such as VEGF, and releases growth factors 
that promote local and distant growth of malignant tissue. (2) Anesthesia impairs numerous immune functions, 
including those of neutrophils, macrophages, dendritic cells, T-cell, and natural killer cells. (3) Opioid 
analgesics inhibit both cellular and humoral immune function in humans, increase angiogenesis, and promote 
breast tumor growth in rodents. However, regional analgesia attenuates or prevents each of these adverse 
effects by largely preventing the neuroendocrine surgical stress response, eliminating or reducing the need for 
general anesthesia, and minimizing opioid requirement. Animal studies indicate that regional anesthesia and 
optimum postoperative analgesia independently reduce the metastatic burden in animals inoculated with 
breast adenocarcinoma cells following surgery. Preliminary data in cancer patients are also consistent: 
paravertebral analgesia for breast cancer surgery reduced risk of recurrence or metastasis approximately four-
fold (95% CI of estimated hazard ratio is 0.71 - 0.06) during a 2.5 to 4-year follow-up period compared to opioid 
analgesia. Similar results were observed with epidural analgesia for prostate surgery. We will thus test the 
hypothesis that recurrence after breast cancer surgery is lower in patients randomized to regional anesthesia & 
analgesia with propofol sedation than to sevoflurane general anesthesia and opioid analgesia. In a Phase III, 
multi-center trial, Stage 1-3 patients having mastectomies will be randomly assigned to paravertebral or 
thoracic epidural anesthesia/analgesia, or to general anesthesia and morphine analgesia. Confirming our 
hypothesis will indicate that a small modification to anesthetic management, one that can be implemented with 
little risk or cost, will reduce the risk of cancer recurrence — a complication that is often ultimately lethal.       

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Personnel  
Key Personnel 
Name 
Organization 
Role on Project 
Daniel I. Sessler, M.D. 
CCLCM-CWRU*  
Principal investigator 
Andrea Kurz, M.D. 
Cleveland Clinic Main  
Site director 
Sabry Ayad, M.D. 
CCF Regional Hospitals 
Site director 
Donal Buggy, M.D. 
Mater Misericordia Hospital 
Site director 
Edith Fleischmann, M.D. 
University of Vienna 
Site director 
Hazel Pei, M.D. 
PUMCH 
Site director 
John Tey & Ern Yu 
Tan Tock Seng 
Site directors 
Tanja A. Meyer-Treschan 
University of Düsseldorf 
Site director 
Edward Mascha, Ph.D. 
CCLCM-CWRU 
Principal statistician 
*Cleveland Clinic Lerner College of Medicine, Case Western Reserve University. 

Regional analgesia and breast cancer recurrence 
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A. Specific Aims 
“It may seem strange that a man of science should believe a thing of this kind — an idle tale for the ignorant and 
superstitious, you will say — but I do believe it. And if you would know why, listen:” (W.H.C. Pynchon) 
Breast cancer is the most common cancer in women and the second leading cause of cancer death. 
Treatment hinges on effective surgical removal of the primary tumor, but recurrence occurs in a significant 
portion of patients. Even with the best technique, tumor surgery is usually associated with release of 
tumor cells into the lymphatic and blood streams and a large fraction of patients already harbor 
micrometastases and scattered tumor cells at the time of surgery.1-3  
Whether this minimal residual disease results in clinical metastases depends largely on the balance 
between anti-metastatic immune activity and the tumor’s ability to seed, proliferate, and attract new blood 
vessels.4-6 In practice, the immune system and other host defenses frequently fail to neutralize minimal 
residual disease; consequently, local recurrence and metastatic disease remains common after breast cancer 
surgery. At least three perioperative factors shift the balance toward progression of minimal residual disease: 
• 
The first is surgery per se, which releases tumor cells into circulation,1-3 depresses cell-mediated 
immunity including cytotoxic T-cell and natural killer (NK) cell functions,7-10 reduces circulating 
concentrations of tumor-related anti-angiogenic factors (e.g., angiostatin and endostatin),11-14 increases 
concentrations of pro-angiogenic factors such as VEGF,15,16 and releases growth factors that promote 
local and distant growth of malignant tissue.5  
• 
The second factor is that anesthesia, per se, which impairs neutrophil, macrophage, dendritic-cell, T-
cell, and NK-cell immune functions.17-20  
• 
The third is opioids, which are given to control surgical pain. Opioids inhibit both cellular and humoral 
immune function in humans.17,21,22 Furthermore, morphine is pro-angiogenic and promotes breast tumor 
growth in rodents.23 Consequently, non-opioid analgesia helps preserve natural killer cell function in 
animals and humans and reduces metastatic spread of cancer in rodents.8  
Regional anesthesia (intra-operative blockade of nociception) and analgesia (postoperative pain relief) 
attenuate or prevent each of these adverse effects. For example, regional anesthesia largely prevents the 
neuroendocrine stress response to surgery by blocking afferent neural transmission from reaching the central 
nervous system and activating the stress response, and by blocking descending efferent activation of the 
sympathetic nervous system.24-26 As might thus be expected, surgical stress is attenuated better by regional 
than by general anesthesia. Consequently, NK-cell function is better preserved and metastatic load to the 
lungs is reduced in a rat model of breast cancer metastasis.7  
When regional and general anesthesia are combined, the amount of general anesthetic required is 
much reduced — as is, presumably, immune suppression. Furthermore, regional analgesia provides superb 
pain relief, essentially obviating the need for postoperative opioids, and the consequent adverse effects on 
immune function and of tumor growth.17,22,26 Regional analgesia also reduces release of endogenous opioids.27 
Available data thus suggest that regional anesthesia and analgesia help preserve effective defenses 
against tumor progression by attenuating the surgical stress response, by reducing general anesthesia 
requirements, and by sparing postoperative opioids. Animal studies are consistent with this theory, showing 
that regional anesthesia and optimum postoperative analgesia independently reduce the metastatic burden in 
animals inoculated with breast adenocarcinoma cells.7,9 Our preliminary data in cancer patients are also 
consistent with this theory: paravertebral anesthesia and analgesia for breast cancer surgery was associated 
with an approximately four-fold reduced risk of recurrence or metastasis during a 2.5 to 4-year follow-up period 
(95% CI of estimated hazard ratio is 0.71 - 0.06).  
We propose a Phase III, multi-center study of patients having mastectomies for breast cancer. Patients 
will be randomly assigned to 1) paravertebral or thoracic epidural anesthesia/analgesia28-31 or 2) general 
anesthesia combined with postoperative patient-controlled morphine analgesia. Specifically, we will test the 
primary hypothesis that the recurrence of local and metastatic cancer after primary breast cancer surgery is 
reduced when patients receive intraoperative and postoperative regional anesthesia and analgesia rather than 
general anesthesia and opioid analgesia.   

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The significance of our proposed study is that it addresses a major women’s health problem (cancer 
recurrence) and suggests an intervention that is safe, inexpensive, and easy to implement.32 The solution we 
propose is innovative in challenging the current practice of using mostly general anesthesia and opioid 
analgesia for cancer surgery. Our approach will be to conduct a large, multi-center randomized trial that will 
provide “gold-standard” evidence to support or refute our hypothesis.   
B. Background and Significance 
There are 211,000 new cases of invasive breast cancer diagnosed each year in the United States, and 
the disease causes approximately 40,000 deaths annually. One woman in eight develops breast cancer, and 
breast cancer is the most common type of cancer and the second most common cause of cancer death in 
women.33 Treatment hinges on effective surgical removal of the primary tumor. Failure of effective treatment is 
marked by local recurrence or metastatic disease — with either often being an ultimately lethal event.  
In this section, we will start by reviewing the basic physiology of tumor metastasis, including recent 
information about the importance of angiogenic factors for tumor development and promotion of angiogenesis 
by surgery. We will then discuss the role of the immune system in controlling minimal residual disease after the 
removal of the primary tumor, the immunosuppressive effects of surgery per se, the immunosuppressive 
effects of general anesthetics and opioids, the promotion of tumor-induced angiogenic factors by opioids, and 
finally the mechanisms by which regional anesthesia and analgesia might ameliorate each of these metastasis-
enhancing effects.  
Tumor Recurrence and Metastasis: Angiogenesis and Cell-mediated Immunity 
Tumor cells are able to spread from a primary neoplasm and colonize other organs, a phenomenon 
named metastasis. Tumor metastasis is the most common cause of death in cancer patients.34 Malignant cells 
are probably released nearly continuously from most solid tumors in humans. This highly selective and 
sequential process involves tumor cell invasion of the surrounding tissue, evasion of host defense, penetration 
into the lymphatic system or blood stream, circulation, arrest in organs, adherence to vessel wall, 
extravasation, and proliferation at secondary sites where, after vascularization, the cancer cells can form life 
threatening tumors. Only tumor cells that can succeed in all these steps have the capacity to metastasize. The 
molecular mechanisms enabling this sequence of events are still being uncovered;38 however, tumor 
angiogenesis is known to be a critical component of metastasis. Primary tumors that are highly vascularized 
provide increased contact between tumor cells and the circulation; consequently, barrier function is reduced 
because tumor angiogenesis results in immature, highly permeable blood vessels that facilitate transmigration 
of tumor cells into the circulation.37 
Judah Folkman’s group has demonstrated that angiogenesis inhibitors released into the circulation by 
or in consequence of the primary tumor can inhibit metastatic growth, and that removal of the primary tumor 
enables vascularization and growth of pre-existing micrometastases.39,40 More recently, a mechanism has 
been established whereby hematopoietic progenitors localize to tumor-specific premetastatic sites where they 
create a microenvironment conductive to future incoming tumor cells.38 
The suggestion that protecting cell-mediated immunity from postoperative suppression may reduce 
long-term recurrence rates critically hinges on the assumption that cell-mediated immunity can control minimal 
residual disease after the removal of the primary tumor. Although animal studies have repeatedly supported 
this suggestion, these studies were justifiably criticized for not simulating the natural course of primary tumor 
development and the metastatic process in humans.41,42 Clearly, in patients presenting with a primary tumor, 
the immune system has failed to control the major bulk of the malignant tissue.  
Nonetheless, several lines of evidence in humans suggest that cell-mediated immunity limits the 
metastatic process and that the removal of the primary tumor presents cell-mediated immunity with an 
opportunity to eliminate or control minimal residual disease. For example, NK activity and the response of 
mixed lymphocytes toward autologous malignant cells predict long-term survival in humans better than stage 
and grade of tumors.43,44 Additionally, even though most cancer patients harbor minimal residual disease after 
surgery, only a portion of them subsequently develop metastases.45 Lastly, various surgical procedures shown 
to improve or worsen postoperative levels of cell-mediated immunity affect recurrence rates. We have recently 
reviewed in detail the evidence from human and animal studies supporting a critical role for cell-mediated 
immunity in controlling metastasis following the removal of a primary tumor.5 

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Cancer Surgery Facilitates Metastases: A Decisive Period for Intervention 
Surgical removal of the primary breast tumors remains a major modality of cancer therapy, eliminating 
the main pool of metastasizing cells. Chemotherapy, endocrine therapy, and radiotherapy all have significant 
roles, but surgical removal of the tumor usually offers the best prospect for an improved prognosis.46 Surgical 
treatment of a primary tumor rarely removes all malignant foci, especially pre-existing scattered 
micrometastases. It does, though, remove the major tumor bulk of metastasizing cells, providing host defenses 
an opportunity to eradicate residual disease. However, several mechanisms exist by which surgery per se 
might accelerate the metastatic process: 
• 
Tumor cells are released into the circulation by the unavoidable physical manipulation of the tumor or 
its vascularization in humans.1,47,48 Surgery facilitates metastasis by suppressing tumor-directed 
immunity,49,50 impairing the detection and destruction of circulating tumor cells, and upsetting the 
balance between proliferation and tumoricidal activity within established metastases51; 
• 
Removal of the tumor decreases the concentration of anti-angiogenic factors such as angiostatin and 
endostatin,11,14,39,40 which are metabolites or degradation products released from the host extracellular 
matrix in response to damage by tumor invasion. 
• 
Stress hormones released postoperatively, including catecholamines, promote release of pro-
angiogenic factors such as VEGF15,16; 
• 
Growth factors, which are released by injured tissue to facilitate healing, also promote local and distant 
growth of malignant tissue.52,53  
 
 
 
Fig.1. Multiple factors associated with cancer 
surgery simultaneously increase the risk of 
metastasis. The perioperative period represents 
a decisive period and an opportunity to eliminate 
or control minimal residual disease. 
These five risk factors occur simultaneously during and immediately after surgery, consequently 
activating dormant micrometastases and establishing new metastases. During and immediately after surgery 
is a decisive period during which interventions that promote effective host defense may be especially 
beneficial (Fig. 1). As developed below, anesthetic and analgesic techniques have a significant impact on 
these processes, providing an opportunity to reduce the risk of metastases. 
Surgical Stress is Immunosuppressive 
The inflammatory and neuroendocrine responses to surgical tissue injury eventually lead to 
compromised immunocompetence in both humans and animals.54 After major surgery, there is a sharp 
increase in plasma concentrations of acute inflammatory cytokines (IL-6 and IL-8), prostaglandins (PG-E2), 
and stress hormones (catecholamines, corticosteroids); and a decrease in Th1 cytokines. These alterations 
profoundly suppress cell-mediated immunity in animals and humans.5,55-58 Cytokine balance, circulating 
effector cell numbers, and ex-vivo effector cell function are all altered in animals and humans.18,59 A relevant 
example is natural killer (NK) cell activity.  

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Fig. 2. Time course of the effects of surgery on NK activity in blood (A) and spleen 
(B) (both in lytic units) and on MADB106 lung tumor retention (C), an index of the 
metastatic process. Rats served as controls (Cont) or underwent surgery at either 5, 
12 or 24 hr, or 7 days before blood and spleen were taken, or at either 5 or 24 hr, or 
7 days before MADB106 tumor cells were inoculated for the assessment of 24-hr 
lung tumor retention (rats were not inoculated with the tumor at 12 hr after surgery 
because the 24-hr period starting at this point is covered by the 5- and 24-hr groups). 
Significant suppression of blood and splenic NK activity was evident up to 24 hr post-
surgery but not at 7 days. Correspondingly, a significant increase in tumor retention 
was evident if tumor cells were injected up to 24 hr post-surgery but not at 7 days. 
Error bars represent SEM. *Significant difference from the respective control group. 
From Ben-Eliyahu, S., et al. Evidence that stress and surgical interventions promote 
tumor development by suppressing natural killer cell activity. Int J Cancer 80:880-8, 
2002.  
NK-cells are a subpopulation of lymphoid cells that spontaneously recognize and kill a variety of tumor 
cells in vitro and in vivo60 and are known to play a determinant role in controlling tumor development — and 
especially the metastatic process.61 Suppression of NK-cell activity occurs within hours of surgery, lasts 
for few days, and is proportional to the invasiveness of the surgery.18,62 Tissue damage, inflammation, 
pain, anesthetic and analgesic compounds, and psychological stress all contribute to NK-cell suppression and 
the tumor-promoting effects of surgery (Fig. 2).63-66 Major surgery in humans and in animals also suppresses 
other important aspects of innate immunity including cytotoxic T lymphocytes (CTLs), macrophages, and 
dendritic cells.67-69 
In addition to the surgery per se, several factors associated with surgery impair perioperative immune 
competence. Among these are hemorrhage,70 which causes immunosuppression correlated with the volume of 
lost blood,5 and allogenic blood transfusion, which reduces NK activity71 and increases cancer recurrence in 
humans after operations designed to be curative.72 Hypothermia suppresses lymphocyte proliferation, 
macrophage phagocytosis, and NK activity, and also exacerbates the immunosuppressive effects of surgery.5 
However, hypothermia per se does not increase the recurrence of colon cancer.73 Highly relevant to breast 
cancer surgery is the fact that estrogens modulate stress-induced immunosuppression.51,74 Pain suppresses 
NK-cell function and promotes tumor metastasis,75 and the opioid antagonist naltrexone prevents the 
immunosuppressive effects of surgery.76 Stress — including stressors far less intense than surgery — also 
impairs NK-cell function, an effect that is prevented by adrenergic blockers.77,78 
General Anesthetics are Immunosuppressive and Tumor-promoting 
Ketamine, thiopental, and halothane each have been shown to suppress NK-cell activity and promote 
metastasis in an animal model (Fig. 3).79 Other volatile anesthetics also impair NK-cell function18 by as much 
as 90%.19 Halothane and isoflurane comparably reduce neutrophil motility80 and sevoflurane impairs T 
lymphocytes.81 While the immune effects of other volatile anesthetics differ somwhat,82,83 most — including the 
newer agents sevoflurane and desflurane — appear to substantially inhibit various immune functions. It is likely 
that anesthetic-induced impairment of NK-cell activity is most pronounced in the context of the stress response 
to surgery.84  
Nitrous oxide depresses chemotactic migration by monocytes, apparently by interfering with 
microtubules.85 There is also in vitro evidence indicating that exposure to nitrous oxide inactivates vitamin B12 
and as a result methionine synthase.86 Methionine synthase is the enzyme responsible for both conversion of 
homocysteine to methionine and methyltetrahydrofolate to tetrahydrofolate. Both are critical pathways for 
thymidine formation; thymidine is essential in DNA formation. Even after brief periods of nitrous oxide 

Regional analgesia and breast cancer recurrence 
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administration, DNA synthesis remains abnormal until the fourth postoperative day and does not return to 
normal until the sixth day.87 This restricts formation of new cells, including the immune cells critical for fighting 
tumors. Inhibition of methionine synthase may explain the link between nitrous oxide exposure and 
spontaneous abortion.88 By the same mechanism, nitrous oxide might impair proliferation of cancer cells. 
There is currently no evidence that nitrous oxide is better or worse than volatile anesthetics in terms of 
promoting metastases.  
 
Fig. 3. Rats were anesthetized for 1 hour with halothane (2-3%) or infusion of ketamine (74 mg kg-1 hr-1), propofol (83.3 mg kg-1 hr-1), 
or thiopental (92.5 mg kg-1 hr-1). Activity of NK-cells was assessed 3.5 h after induction of anesthesia. A parallel group of animals was 
simultaneously inoculated I.V. with radiolabeled MADB106 breast tumor cells, and lung tumor retention (LTR) assessed at 24 h. Mean 
± S.E.M; * indicates a significant difference from control. (Left) Percent specific killing per ml blood to different effectors: target (ET) 
ratios (NK:YAC-1). Ketamine, halothane, and thiopental, but not propofol, significantly suppressed NK activity. (Right) Percent of LTR 
of radiolabeled MADB106 tumor cells. Ketamine, halothane, and thiopental, but not propofol treated rats had significantly higher LTR 
compared to controls.79 
Propofol, ketamine, and midazolam markedly increase the release of inflammatory cytokines in human 
cells.57,58 Propofol impairs neutrophil phagocytosis and killing of bacteria in humans,89 and propofol and 
thiopental comparably impair neutrophil polarization.90 Propofol also decreased pokeweed mitogen-induced 
lymphocytic responses in one study,91 but had no effect in another.56 The effects of propofol and isoflurane 
were compared with respect to a variety of immune responses including total leukocytes, percentages of 
lymphocyte subpopulations (CD3, CD4, CD8, CD20, CD16), and monocytes (CD14). Additionally, 
phytohemagglutinin-, concanavalin A- and pokeweed mitogen-induced and unstimulated lymphocyte 
proliferative responses, polyclonal immunoglobulin synthesis, and serum cortisol concentrations were 
explored. The immune response to ophthalmic surgery was basically similar in both anesthetic groups.92  
In contrast, propofol appears to have no effect or possibly even protects against metastases (as also 
seen in Fig. 3, Right): clinically relevant concentrations of propofol (1-5 µ/ml) decrease the invasion ability of 
human cancer cells in vitro. In HeLa cells treated with propofol, focal adhesion and the formation of actin stress 
fibers were inhibited while propofol had little effect on the invasion ability of the HeLa cells with active Rho A. 
Furthermore, continuous propofol administration either had no effect on metastasis of a breast cancer cell line 
in rats79 or inhibited pulmonary metastasis of murine osteosarcoma cells in mice.93 In contrast, halothane, 
ketamine, and thiopental all increase metastases in similar studies.79 
Opioids and Metastasis 
The metastatic process is selective for cancer cells that succeed in all steps of the process detailed 
previously.36 Any factor facilitating one or more of these steps will presumably augment the probability of 
metastasis. Considerable evidence suggests that opioids facilitate metastasis both via suppression of critical 
anti-tumor immune functions and by mechanisms independent of immune suppression.  
Acute and chronic administration of exogenous opioids inhibits components of the cellular and humoral 
immune function such as antibody production, NK-cell activity, cytokine secretion, lymphocyte proliferative 
responses to mitogens, and phagocytic activity.94,95 The immunosuppressive effects of morphine are best 
studied;22,96 however, other opioids, including fentanyl21,97 and subtype-specific opioid receptor agonists 
0
0.5
1
1.5
2
2.5
3
3.5
4
Control
Propofol
Thiopental
Halothane
Ketamine
*
*
*

Regional analgesia and breast cancer recurrence 
Sessler, et al. 
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(Fig. 4),98 produce comparable immune suppression in most studies.68 Inhibition appears to be dose-
dependent.21 
 
 
Fig. 4. Rats were injected with fentanyl (0.15 mg/kg). One hour later, specific killing was assessed at different Effector:Target ratios 
(NK:YAC-1). Fentanyl significantly suppressed NK cytotoxicity compared with control values (left). A parallel group of rats were 
injected IV with radiolabeled MADB106 tumor cells at the same time; fentanyl significantly increased tumor retention (by 5.8-fold) 
compared to controls (right).97 
Opioids are now known to modulate immune response by a combination of central and peripheral 
mechanisms.99 Endogenous and exogenous opioids bind three major types of receptors: the mu-, delta-, and 
kappa-opioid receptors that have been identified not only in peripheral sensory neurons and the CNS, but also 
in cells of the immune system such as PMNs, macrophages, T-lymphocytes, splenocytes, and macrophage-
like and T-cell-like cell lines.95 Opioids also alter the macrophage protein expression profile100 and impair 
macrophage function including chemotaxis and phagocytosis. And finally, opioids reduce B-cell proliferation 
and antibody production.101 In contrast, a number of studies have failed to find a direct effect of morphine on 
NK-cell activity in vitro,101 suggesting CNS-mediated effects. 
Signals of central origin may be relayed through 1) the hypothalamic-pituitary-adrenal axis resulting in 
the production of glucocorticoids, which are immunosuppressive, and 2) the sympathetic nervous system 
eliciting the release of biologic amines into lymphoid organs, which, in turn, also reduce immuno-
competence.102 Rahim et al. thus proposed that the HPA axis is involved in the immunosuppression by chronic 
opioid exposure, while the sympathetic nervous system mediates the immunosuppression induced by acute 
opioid administration.103 
The extent to which opioid-induced immune suppression is central or peripheral in origin remains 
unclear.99 Certainly, central opioid receptors can cause immune suppression.104 For example, Hernandez 
found that systemic injection of a morphine analog that does not cross the blood-brain barrier did not impair 
immune responses, whereas small doses injected centrally did.105 Similarly, injection of opioids into the 
periaqueductal gray matter suppressed NK-cell activity, whereas injection in other areas did not. However, 
intracerebral injections are quite different from spinal or epidural injections: Hamra compared equi-analgesic 
doses of subcutaneous and intrathecal morphine, and found that only the subcutaneous dose impaired cell-
mediated immunity;106 It is thus unlikely that the tiny opioid doses that are sometimes used clinically in 
conjunction with local anesthetics for spinal or epidural blocks produce substantial immune inhibition.  
Opioids Upregulate Nitric Oxide Production and Angiogenesis 
In vitro exposure of human leukocytes to morphine upregulates constitutive endothelial and neuronal 
nitric oxide synthases.100 Furthermore, human endothelial cells express opioid receptor(s) and respond to 
opiates by increasing intracellular calcium concentration and nitric oxide (NO) production.107,108 Morphine-
induced increases in NO induce vasodilation in aortic rings ex vivo. NO also mediates increased vascular 
permeability, which could both increase release of cancer cells into the circulation before tumor excision and, 
subsequently, increase extravasation of circulating tumor cells and the formation of new metastases. 
Nitric oxide also regulates endothelial cell proliferation, migration, and protease release — all of which 
are important for angiogenesis. Endothelial NO synthase (eNOS) plays a central role in endothelial cell 
migration and angiogenesis.109 Morphine increases angiogenesis as evidenced by enhanced endothelial cell 
proliferation and tube formation in vitro, and increases in vivo blood-vessel formation in a matrigel plug assay 
and in breast-tumor xenographs.23 And although one study showed reduced angiogenesis in the chicken 
0
1
2
3
4
% Tumor Retention
Control
Fentanyl

Regional analgesia and breast cancer recurrence 
Sessler, et al. 
9 
chorioallantoic assay in the presence of morphine,110 more recent work suggests that morphine and other 
opioids improve wound healing via an angiogenesis mechanism.111  
Vascular Endothelial Growth Factor (VEGF) plays a key role in angiogenesis, prompting researchers to 
investigate whether surgery and/or surgery-related factors could affect the circulating concentrations of VEGF. 
In cultured endothelial cells, morphine inhibits the hypoxia-induced expression of VEGF,112 but the effect of 
morphine on normoxic endothelial cells was not tested. In a recent study, patients having surgery for breast 
cancer under general anesthesia were given either paravertebral or opioid analgesia and tested for serum 
VEGF concentrations perioperatively; concentrations in the two groups were similar.26 However, circulating 
VEGF receptor levels were not measured in that study. This is a critical limitation since circulating soluble 
forms of VEGF receptors act as negative regulators of angiogenesis because they bind to VEGF and form 
inactive complexes.113-115 Concentrations of VEGF detected in serum, therefore, do not directly reflect the 
activity of this growth factor. For example, in breast-cancer patients the concentrations of VEGF are higher and 
the concentration of soluble VEGF-receptor-1 lower than in healthy controls; statistical significance of the 
difference between control and patients was therefore increased considerably when the results were 
expressed as the ratio of VEGF-receptor to VEGF rather than VEGF concentration per se.116 More recent 
evidence indicates that opioids promote VEGF-induced angiogenesis, an effect that is nearly completely 
blocked by opioid antagonists.117   
Regional Anesthesia Blocks Surgical Stress and Reduces Both General Anesthetic and Opioid 
Requirements 
The severity of perioperative immunosuppression has prompted researchers and clinicians to suggest 
various strategies aimed at reducing consequences that are likely to be particularly deleterious in cancer 
surgery. These strategies include minimally invasive surgery to reduce tissue damage,118 pharmacological and 
immunological interventions targeting the neuroendocrine and cytokine responses that mediate immune 
suppression,119 development of novel synthetic opioids that retain analgesic properties but lack 
immunosuppressive effects,120 and use of peripheral opioid antagonists that may prevent the peripheral 
immunosuppressive effects of opioids while retaining their central analgesic properties.99,121 Another major 
strategy to attenuate the multifactorial immunosuppressive and tumor-promoting effects of cancer resection is 
the use of regional anesthesia and analgesia. 
Inflammatory markers and immune function are similar with general and regional anesthesia in non-
surgical volunteers who do not have concomitant tissue injury.122,123 However, regional anesthesia markedly 
attenuates the neuroendocrine response to surgery, as evidenced by smaller perioperative concentrations of 
stress-induced plasma catecholamines and cortisol in patients receiving regional anesthesia compared to 
those given general anesthesia.26,124 These alterations were expected to reduce postoperative immune 
suppression, as were indeed reported. For example, intraoperative neutrophil function is better preserved 
during spinal anesthesia than during either halothane or isoflurane anesthesia in rabbits.80 Similarly, NK and 
Th1 cell activity is better preserved when epidural anesthesia is used compared with general anesthesia in 
humans.125-128  
The consequences of these clinical observations have been evaluated in an animal model.7 Rats were 
subjected to halothane anesthesia alone, with systemic morphine, or with spinal block. They underwent 
laparotomy or were left undisturbed, and were inoculated with metastatic adenocarcinoma cells to mimic the 
cancer cell shedding that occurs during curative resection. Laparotomy under halothane anesthesia alone 
increased lung retention of tumor cells up to 17-fold. The addition of spinal blockade reduced this effect by 
70%. A similar pattern was observed when studying the actual development of metastasis (Fig. 5). Findings 
were nearly identical in a more recent study in mice.129 There is thus compelling small-animal evidence that 
regional analgesia reduces metastasis of experimental cancer. 

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Fig. 5. The effect of surgery on the number of pulmonary 
metastases (mean + SEM). In rats undergoing general 
(halothane) anesthesia (G.A.), surgery significantly increased 
the number of pulmonary metastases compared to the non-
operated control group. Adding spinal block (G.A. + spinal 
block) abolished this increase. Asterisk denotes statistically 
significant differences. Reproduced from data presented in: Bar-
Yosef.7 
 
 
In addition to attenuating the stress response, regional analgesia obviates the need for postoperative 
opioids by producing profound analgesia.32 In patients receiving regional analgesia versus intravenous 
morphine to alleviate postoperative pain, the neuroendocrine response is attenuated and the NK-cell activity 
preserved.125,130 Regional analgesia also reduces release of endogenous opioids.27 Consistent with this theory 
is evidence that melanoma recurrence rates in patients are 40% higher with general anesthesia than with local 
anesthesia, even after multivariate compensation for other prognostic factors.131  
Regional Anesthesia and Chronic Pain 
Chronic postsurgical pain is defined as pain developing after a surgical procedure that lasts at least 
three months for which other causes (i.e., malignancy or chronic infection) have been excluded.132  Chronic 
postsurgical pain reportedly occurs in 31-49% of patients after breast surgery.133 Other studies suggest that the 
incidence of chronic pain after thoracotomy may be as high as 50% one year after surgery.134  Some level of 
residual pain is reported for up to several months after the procedure in about half of patients undergoing lower 
abdominal surgery.135-137 Approximately 25% of patients report pain 1 yr after sternotomy138,139 or 
herniorrhapy.138,140   
The causes of chronic postoperative pain remain obscure. However, excellent acute analgesia may 
protective. Patients report that acute postoperative analgesia is best with nerve blocks.141-149  For example, 
Najarian et. al. report retrospective results in 289 patients undergoing breast cancer surgery in which some 
received regional anesthesia (paraverterbral block) while others had general anesthesia. Patients given 
regional anesthesia had less early post-operative pain, along with less nausea and vomiting.28 Furthermore, a 
meta-analysis of 1,404 abstracts and 100 full studies showed that regional analgesia provides better 
postoperative analgesia than systemic analgesia, regardless of analgesic agent, location of catheter 
placement, and type and time of pain assessment.150     
Consistent with the importance of good acute analgesia, a number of studies in thoracotomy patients 
have shown that regional anesthesia decreases the incidence and intensity of chronic pain.151,152  For example, 
a study by Kairaluoma, et.al. reported that regional anesthesia [preincisional paravertebral block (PVB)] 
provides better immediate postoperative analgesia after breast cancer surgery than opioids.32 In the same 60 
patients, the prevalence and severity of pain  at 6-months and 1-year was reduced in those given regional 
anesthesia.153  Iohom, et.al. similarly report that among 29 patients who had breast surgery, 80% of the 
patients given systemic analgesia experienced chronic post surgical pain (CPSP) whereas none did who 
received regional analgesia.133 A retrospective analysis among 220 patients who had Caesarean deliveries 
showed that patients with persistent pain were more likely to have had general rather than spinal anesthesia.154 
Regional anesthesia appears to reduce chronic post-surgical pain135,137,155-162 in a variety of surgical procedures 
including herniorrhaphy163 and vasectomy. Other studies, though, fail to identify any benefit.164,165 Available 
data are mostly retrospective; a large prospective trial has yet to be published.   
Study Objectives 
 
Cancer surgery promotes metastases by the following mechanisms: 1) immune suppression from 
surgery per se; 2) immune suppression by general anesthetics; 3) opioid-induced immune suppression; and 4) 
direct promotion of tumor proliferation and angiogenesis by morphine and stress hormones. Because regional 

Regional analgesia and breast cancer recurrence 
Sessler, et al. 
11 
anesthesia and analgesia block the neuroendocrine response to surgery and obviate the need for 
postoperative opioids, regional techniques may reduce metastatic risk during cancer surgery. This overall 
mechanism is shown in Fig. 6. Our preliminary results (Section C, below) are consistent with this theory: 
paravertebral anesthesia and analgesia reduced the recurrence rate after breast cancer surgery by 79%. We 
note that this reduction was observed even though all patients were given general anesthesia. 
We propose to determine whether recurrence rates after breast cancer surgery are reduced in patients 
who have intraoperative and postoperative regional anesthesia and analgesia, combined with propofol 
sedation or light anesthesia compared with those who receive intraoperative volatile general anesthesia and 
postoperative opioid analgesia. We will simultaneously evaluate the effects of regional analgesia on chronic 
post-surgical pain and quality-of-life.   
Fig. 6. Cancer surgery is usually 
performed under general anesthesia with 
postoperative analgesia provided by 
opioids. The stress of surgery, general 
anesthetics, and opioid analgesics are all 
immunosuppressive and specifically inhibit 
cell-mediated immunity that is critical for 
control of minimal residual disease. 
Opioids and stress also increase 
angiogenesis, which promotes growth of 
cancer cells. Regional anesthesia and 
analgesia blocks the neuroendocrine 
stress response, decreases or eliminates 
the need for general anesthetics, and 
obviates the need for postoperative 
opioids.  
 
Regional techniques such as paravertebral and epidural anesthesia/analgesia are easy to implement, 
inexpensive, and no riskier than general anesthesia. If we were able to demonstrate that regional techniques 
improve the prognosis of patients undergoing breast cancer surgery, increasing the use of regional blocks 
would be a simple change in anesthetic practice.  
C. Preliminary Results 
Breast Cancer 
We examined the medical records of 129 consecutive patients undergoing mastectomy and axillary 
clearance for breast cancer between September 2001 and December 2002.  
50 patients had surgery with paravertebral anesthesia and analgesia combined with general anesthesia 
and 79 patients had general anesthesia combined with postoperative morphine analgesia. The follow-up time 
was 32±5 months (mean±SD). There were no significant differences in patients or surgical details, tumor 
presentation, or prognostic factors. Recurrence and metastasis-free survival, with multivariate analysis, was 
94% (95% CI 87,100) versus 82% (74, 91) at 24 months, and 94 (87, 100) versus 77 (68, 87) at 36 months in 
the paravertebral and general anesthesia patients, respectively, P=0.013 (Fig. 7). 

Regional analgesia and breast cancer recurrence 
Sessler, et al. 
12 
 
 
 
 
Fig 7. Association between paravertebral block and cancer 
recurrence (P=0.013); P= 0.012 (log-rank test) in a 
multivariable model that adjusts for histological grade and 
number of axillary nodes. 
This retrospective analysis suggests that paravertebral anesthesia and analgesia for breast cancer 
surgery markedly reduces the risk of recurrence or metastasis during the initial years of follow-up. The full 
paper describing this study was published in Anesthesiology.166 
Prostate Cancer 
We evaluated the recurrence of prostate cancer after open radical prostatectomy in patients who 
received either general anesthesia combined with epidural analgesia or general anesthesia and postoperative 
opioid analgesia. Patients had either general anesthesia with postoperative opioid analgesia (n=123) or 
general anesthesia combined with epidural analgesia (n=102). Our major outcome was incidence of metastatic 
spread or local prostate cancer recurrence through October 2006.  
After adjusting for tumor size, Gleason score, preoperative prostate specific antigen status (PSA), and 
margin, the epidural plus general anesthesia group had an estimated 61% (95% CI 37% to 79%) lower risk of 
recurrence compared with the general anesthesia plus opioids group, with a corresponding hazard ratio of 0.39 
(95% CI 0.21 to 0.73; P=0.0003) in a multivariable Cox regression model (fig. 8). Gleason score and baseline 
PSA were also strong independent predictors of recurrence (hazards ratios of 1.32 [1.12, 1.56], P=0.001, and 
1.02 [1.00, 1.04], P=0.020, respectively). 
 
 
 
Fig 8. Kaplan-Meier recurrence-free survival estimates for 123 
patients given general anesthesia and postoperative opioids 
(General/Opioid) and for 102 patients given general 
anesthesia combined with epidural analgesia 
(Epidural/General) during radical prostatectomy for prostate 
cancer; univariable P value < 0.001. Vertical tick marks 
represent censored values.  
In patients having open prostatectomy surgery with general anesthesia, substituting epidural analgesia 
for postoperative opioids substantially reduced the risk of cancer recurrence. The full paper describing this 
study was published in Anesthesiology.167 
Transfusion of Older Blood Promotes Cancer Recurrence 
While surgery remains the primary treatment for most cancers, minimal residual malignancy is 
common. Whether residual tumor progresses to clinical metastases is largely a function of host defense. Blood 
transfusions are immunosuppressive and increase recurrence risk after cancer surgery. Prolonged storage 
degrades transfused cells, perhaps augmenting immunosupression. We therefore tested the hypothesis that 
prolonged red cell storage duration increases the risk of cancer recurrence after colorectal cancer surgery. 
We examined data from patients given red cell transfusions for colorectal cancer surgery between 1992 
and 2005; 218 patients were given 557 units of blood stored for 12 or fewer days (“Newer tercile”), 194 patients 

Regional analgesia and breast cancer recurrence 
Sessler, et al. 
13 
were given 441 units of blood stored between 12 and 17 days (“Middle tercile”), and 229 patients were given 
632 units of blood stored 17 days or longer (“Older tercile”). Disease-free survival was estimated with Kaplan-
Meier methods.  Median [1st quartile, 3rd quartile] storage duration for the three groups were 9 [8, 11]; 14 [13, 
15]; and 22 [19, 28]; respectively.  Maximum storage duration was 42 days. Each of the disease-free survival 
curves differed significantly (Fig. 8). 
Fig 8. 
Kaplan-Meier recurrence-free 
survival estimates for 218 patients given 
557 units of blood stored for 12 or fewer 
days (“Newer tercile”), 194 patients 
given 441 units of blood stored between 
12 and 17 days (“Middle tercile”), and 
229 patients given 632 units of blood 
stored 17 days or longer (“Older 
tercile”). Each of the disease-free 
survival curves differed significantly. 
 
The risk for colorectal cancer recurrence increased significantly and progressively with older blood. 
Restricting the storage duration of transfused blood may reduce the risk of recurrence after colorectal cancer. 
These unpublished data provide additional evidence that perioperative management choices have long-term 
effects on the risk of cancer recurrence.  
Tumorigenic and Anti-tumorogenic Cytokine Concentrations 
We tested the hypothesis that patients who receive combined propofol/paravertebral anesthesia with 
paravertebral analgesia exhibited reduced serum levels of protumorigenic cytokines and elevated levels of 
antitumorigenic cytokines compared to patients who receive sevoflurane general anesthesia with opioid 
analgesia. We simultaneously tested the hypothesis that matrix metalloproteinase (MMP) concentrations (pro-
tumorigenic factors) are increased more with sevoflurane than paravertebral anesthesia.  
Primary breast cancer surgery patients were randomly assigned to Propofol/Paravertebral (n=15) or 
Sevoflurane/Opioid (n=17) anesthesia. Pre- and post-operative serum cytokine and matrix metalloproteinase 
concentrations were measured. The protective cytokine IL-10 increased more with paravertebral analgesia; 
IL-8, IL-1ß, MMP-9, and MMP-3 all increased significantly more with sevoflurane/opioid anesthesia (Table 1).  
Table 1. Serum Cytokine and Metalloproeinase Concentrations as a function of Anesthetic Technique. 
 
Sevoflurane/Opioid % Change (n=17) 
Propofol/Paravertebral % Change (n=15) 
P Value 
IL-10 
-5.5 ± 8.8 
190 ± 82 
0.02 
IL-8 
50 ± 8.9 
-6.0 ± 10 
0.02 
IL-1ß 
-10.0 ± 2.2 
-30 ± 6.5 
0.004 
MMP-9 
87 ± 16.6 
28 ± 10 
0.006 
MMP-3 
82 ± 37 
-6.0 ± 10 
0.03 
MMP-1 
-11 ± 5.6 
-1.0 ± 9.9 
0.39 
Values are reported as the means ± SDs. 
These data indicate that propofol/paravertebral anesthesia and analgesia help preserve the immune 
defenses, and potential resistance to tumor progression, metastasis, and recurrence. 
Propofol Reduces and Morphine Increases Breast Cancer Cell Migration and Proliferation in 
vitro 
We tested the hypothesis that propofol reduces and morphine increases in vitro proliferation and 
migration of two breast cancer cell lines, each with different metastatic potential. 

Regional analgesia and breast cancer recurrence 
Sessler, et al. 
14 
MDA-MB-231 (estrogen receptor negative) and MCF7 (estrogen and progesterone receptor positive) breast 
cancer cells were incubated with anaesthetic drugs using clinically relevant concentrations of propofol (1-10 
µg/ml) and morphine (10-100 µg/ml). Cell proliferation was determined with CellTiter 96 Aqueous One Solution 
Cell Proliferation Assay. Cell migration was determined using a Chemotaxis 96-well Migration Assay.  
Propofol decreased cell proliferation in both cell lines by up to 22% in MDA-MB-231 cell line and 44% in 
MCF7. Morphine increased overall cell proliferation in both cell lines by up to 18% in MDA-MB-231.  Propofol 
reduced cell migration by up to 31% in MDA-MB-231 and 73% in MCF7. Morphine increased migration by up 
to 105% in MDA-MB-231 and by 25% in MCF7. Each effect was statistically significant. 
Enhanced proliferation and migration of breast cancer cells with morphine, and reduced proliferation 
and migration with propofol, suggests that combining a regional block with propofol for cancer surgery may 
reduce metastatic risk compared with general anesthesia and opioid analgesia. 
Paravertebral Blocks Prevent Sevoflurane-induced Breast Cancer Proliferation 
We tested the hypothesis that serum from patients given paravertebral analgesia and propofol for 
breast cancer surgery reduces migration and proliferation of breast cancer cells in vitro compared with serum 
from patients given sevoflurane anesthesia and morphine.  
Primary breast cancer surgery patients (n=22) were randomised to receive either propofol/paravertebral 
anaesthesia and paravertebral analgesia (Propofol/Paravertebral, n=11) or sevoflurane general anesthesia 
with opioid analgesia (Sevoflurane/Opioid, n=11). The estrogen-receptor negative MDA-MB-231 cell line was 
treated with patient serum from each group, and the effects on cell proliferation (measured by MTS assay) and 
migration (wound closure and chemotaxis migration assay) were measured.  
The treatment groups were well-balanced for age, weight, surgical procedure, and cancer pathology. 
Pain scores were lower at 1 and 2 hrs with paravertebral analgesia than with morphine, but were similar at 24 
hours. Pain scores and opioid consumption were significantly lower in the Propofol/Paravertebral group. 
Compared with preoperative values, proliferation of MDA-MB-231 cells treated with postoperative patient 
serum at 10% concentration from the Propofol/Paravertebral group was significantly reduced compared to the 
Sevoflurane/Opioid group (-24% vs. 73%, p=0.01). There was no significant change in MDA-MB-231 migration.  
Paravertebral analgesia, combined with propofol, prevents the increase in breast cancer cell 
proliferation that normally accompanies sevoflurane anesthesia. Regional analgesia may thus help reduce 
recurrence of breast cancer after potentially curative surgery. 
 
D. Research Design & Methods 
We propose to compare recurrence rates in patients with breast cancer who will be randomly assigned 
to paravertebral or thoracic epidural anesthesia and analgesia or to general anesthesia followed by opioid 
analgesia. This multi-center protocol will be coordinated by the OUTCOMES RESEARCH Department at the 
Cleveland Clinic.   
Regional anesthesia and analgesia help maintain perioperative immune function by reducing general 
anesthesia requirements, by ameliorating the stress response to surgery, and by sparing postoperative 
opioids. We propose a prospective randomized trial to determine the effects of paravertebral or thoracic 
epidural anesthesia and analgesia on breast cancer recurrence. Specifically, we will test the following 
hypotheses: 
Primary Hypothesis: Recurrence of local and metastatic cancer after primary breast cancer 
surgery is lower in patients randomized to paravertebral or thoracic epidural analgesia and 
propofol sedation than to sevoflurane general anesthesia and opioid analgesia. 
Secondary Hypotheses: Persistent post-surgical pain at 6 and 12 months is reduced by 
paravertebral or thoracic epidural analgesia. 
The background168 and methodology169 for our proposed trial have been published. The study is registered at 
ClinTrials.gov: NCT00418457.  

Regional analgesia and breast cancer recurrence 
Sessler, et al. 
15 
Setting and Population 
Patients meeting the following enrollment criteria will be considered: 
1) 
Primary breast cancer without known extension beyond the breast and axillary 
nodes (i.e. believed to be Tumor Stage 1-3, Nodes 0-2) as determined according to 
the NCI stage definitions: 
(http://www.cancer.gov/cancertopics/pdq/treatment/breast/HealthProfessional/page
3/print); 
2) 
Scheduled for unilateral or bilateral mastectomy with or without implant  
3) 
Wide local excision (lumpectomy) with node dissection; 
4) 
Written informed consent, including willingness to be randomized to general 
anesthesia and opioid analgesia or regional analgesia/analgesia. 
Exclusion criteria will include: 
1) 
Previous surgery for breast cancer (except diagnostic biopsies and guide-wire 
insertion); 
2) 
Inflammatory breast cancer; 
3) 
Age <18 or >85 years old; 
4) 
Scheduled free flap reconstruction; 
5) 
ASA Physical Status ≥4; 
6) 
Any contraindication to paravertebral or epidural anesthesia and analgesia 
(including coagulopathy, abnormal anatomy); 
7) 
Any contraindication to midazolam, propofol, sevoflurane, fentanyl, or morphine 
8) 
Other cancer not believed by the attending surgeon to be in long-term remission; 
9) 
Systemic disease believed by the attending surgeon to present ≥25% two-year 
mortality.  
Protocol 
Patients will be premedicated with 0-3 mg IV midazolam and 0-2 µg/kg fentanyl per clinician 
preference. Prophylactic antibiotics will be given per surgical routine. Patients will be randomly assigned to 
paravertebral or epidural anesthesia and analgesia with propofol sedation or to sevoflurane general anesthesia 
after they have met the inclusion/exclusion criteria and consent to the study. Computer-generated assignments 
(using Proc Plan in SAS statistical software) will be stratified by study site. Randomization will be web-based, 
using a system designed and controlled by the Department of Quantitative Health Sciences at the Cleveland 
Clinic (out of the control of any investigator). Patients will be randomized after consent is obtained, shortly 
before surgery.  
General Anesthesia and Opioid Analgesia  
In patients assigned to general anesthesia and opioid analgesia (General Anesthesia Group), general 
anesthesia will be induced with 1-3 µg/kg fentanyl and 2-4 mg/kg propofol. Tracheal intubation will be 
facilitated by succinylcholine or a non-depolarizing muscle relaxant; alternatively, a supraglottic airway (such 
as a laryngeal mask) will be used. Additional non-depolarizing muscle relaxant will be administered as deemed 
necessary by the attending anesthesiologist.  
Anesthesia will be maintained with sevoflurane in oxygen, with or without nitrous oxide, and fentanyl. 
Isoflurane may be substituted if sevoflurane is not available. Volatile anesthetic and fentanyl administration will 
be adjusted to maintain blood pressure and heart rate within ≈20% of pre-operative values. The lungs will be 
mechanically ventilated to maintain end-tidal PCO2 near 35 mmHg. Because hypothermia impairs immune 
function, normothermia170-173 — a distal esophageal temperature near 36°C — will be maintained.174 
Ondansetron will be given as needed for postoperative nausea and vomiting.  
Intravenous morphine sulfate or other opioid will be titrated to a respiratory rate of 12-14 breaths per 
minute near the end of surgery. When surgery is complete, muscle relaxant will be antagonized, if necessary, 
and the trachea extubated. Post-operative analgesia will be morphine, provided as needed IV or via patient-
controlled pump. A typical initial pump setting will be for 1-mg boluses with a 6-minute lockout period and no 
background infusion. Additional morphine will be provided as necessary to maintain good pain control, either 
as needed or by changing the pump settings. Morphine will be the first-line drug; but hydromorphone will be 

Regional analgesia and breast cancer recurrence 
Sessler, et al. 
16 
substituted at one-fifth the morphine dose in patients who do not tolerate morphine. After approximately 24 
hours, patients will be transitioned to acetaminophen, tramcontin, tramadol, and/or non-steroidal anti-
inflammatory analgesics; oral opioids will also be permitted if necessary. Nearly all patients tolerate morphine. 
Bio-availability and individual responses of other opioids differ from patient to patient,175-178 but can be 
converted into morphine equivalents.179 This approach is used routinely in analgesia studies. 
Regional Anesthesia and Analgesia 
In patients assigned to paravertebral or epidural anesthesia & analgesia (Regional Analgesia Group), 
analgesia will be provided by paravertebral or epidural blocks.28-32,180 Paravertebral anesthesia will be provided 
either with a thoracic (T) interspace 2-4 catheter or multi-level injections from thoracic interspace 1 to 5, or as 
clinically appropriate depending on the anticipated scope of surgery.32 When a catheter is used, it will be 
inserted into the ipsilateral paravertebral space at the level of T2/3 or T3/4 using a standard technique.181  
Briefly, patients will be positioned laterally, curled so their knees approach the chest. The upper 
thoracic spinous processes (T1) will be identified with a marking pen. Opposite these, a series of points, 3 cm 
lateral to the midline, will be marked ipsilateral to the site of surgery. A vertical line between these points, 
parallel to the midline, corresponds to the vertebral transverse processes. Under aseptic conditions, a Tuohy 
needle will be advanced to contact the transverse process at a depth of 3-4 cm. The needle will then be 
“walked off” the caudal surface of the transverse process and further advanced 1-2 cm. Loss of resistance to 
saline indicates passage of the needle through the costo-transverse ligament into the paravertebral space.  
A multi-lumen paravertebral catheter will then be advanced into the space 3-4 cm. Each patient will be 
given a 10 to 20-ml bolus of 0.5% bupivacaine or 0.5% ropivacaine with or without epinephrine after a test 
dose with 1.5-2.0% lidocaine and 1:200,000 epinephrine. Near the end of surgery, an infusion of 6-10 ml/h of 
either solution will be started; the infusion rate will be reduced or increased as deemed necessary by the 
attending anesthesiologist. Local anesthetic infusion will continue as clinically necessary, but not longer than 
48 hours; the catheter will be removed before hospital discharge.  
When a multi-level technique is to be used, separate injections at thoracic interspace 1 to 5 will be 
performed with a graded 22-gauge Tuohy needle. The needle will be inserted 2.5 cm lateral to the superior 
aspect of the spinous process on the ipsilateral side of surgery and "walked off" the transverse process in a 
caudal direction 1 cm distal to the transverse process. Ropivacaine or bupivacaine  0.75%, 5 ml, will be given 
at each of the 5 levels via extension tubing attached to the syringe. Additionally, injections of ropivacaine or 
bupivacaine 0.5% will be given by the surgeon to block cervical and contralateral thoracic nerves that also 
contribute to the innervation of the breast. A comparable dose of bupivacaine may be substituted. 
Paravertebral anesthesia will be supplemented with propofol (usually infused at a rate of 60-
90 µg/kg/min) which can also be administered during insertion of the block. However larger amounts can be 
given per discretion of the attending anesthesiologist depending on the adequacy of the block, extent and 
duration of surgery, and patient cooperation. We expect that most patients will be able to breathe 
spontaneously with nasal cannula oxygen; however, a laryngeal mask can be inserted if necessary in patients 
receiving larger propofol doses. Volatile anesthesia and/or opioids can be given at the discretion of the 
attending anesthesiologist if clinically required; similarly, an endotracheal tube can be inserted if necessary. 
However, we expect that volatile anesthesia and intubation will rarely be required in patients assigned to 
paravertebral anesthesia & analgesia.  
When epidural anesthesia is chosen, a T4 epidural catheter will be inserted using a standard technique. 
If T4 insertion proves difficult, catheter insertion will be attempted at T3 or T5. After negative aspiration for 
blood, patients will be given a test dose of 3 ml of 1.5% lidocaine and 1:200,000 epinephrine. The catheter will 
be re-inserted or repositioned as necessary until both aspiration and test dose are negative. Each patient will 
be given an additional 3-ml bolus of the same solution to provide intraoperative analgesia. The catheter will be 
repositioned or reinserted as necessary if a sensory block to temperature cannot be confirmed in the surgical 
dermatomes. Additional 3-ml boluses of 0.5% bupivacaine or 0.5% ropivacaine with epinephrine will be given 
hourly during surgery to maintain anesthesia; additional boluses will be permitted at the discretion of the 
attending anesthesiologist.  
Postoperatively, continuous or patient-controlled epidural analgesia will be provided by an infusion of 
ropivacaine 0.1-0.2% and 2 µg/ml fentanyl with epinephrine or similar solution that will start shortly before the 
patient emerges from general anesthesia. The infusion basal rate will be 4-8 ml/hour with 2 ml per demand and 

Regional analgesia and breast cancer recurrence 
Sessler, et al. 
17 
a lockout period of 20-30 minutes. The local anesthetic concentration, infusion rate, and demand volume will 
be adjusted as clinically indicated to provide excellent analgesia while avoiding hypotension.  
Postoperatively, analgesia will be primarily provided by the regional block. It will be supplemented with 
acetaminophen, tramcontin, tramadol, and/or NSAIDs if needed, or per individual sites’ routine protocol. 
However, supplemental morphine will be provided if pain relief is inadequate, either “as needed” or by patient-
controlled infusion. As soon as practical, usually at about 24 hours, patients will be transitioned to 
acetaminophen and/or non-steroidal analgesics and, if necessary, oral opioids. In our experience, patients 
given epidural or paravertebral analgesia rarely require intravenous opioids, and few even require oral opioids. 
Catheters, if used, will be removed before hospital discharge, but no later than the second postoperative day. 
Similar local anesthetics, or combinations of local anesthetics may be substituted by the attending 
anesthesiologist. 
Fig. 9. Trial Profile. 
 
All anesthesiologists participating in the study will have experience with high thoracic or paravertebral 
blocks and have done at least ten recent non-study cases. But even in experienced hands, we can anticipate 
that a few percent of the blocks will fail (the failure rate was 5% in our preliminary study) and our sample-size 
estimate (below) compensates for patients crossing over from regional to general anesthesia. Patients with 
unsuccessful blocks will be switched too the alternative regional technique if practical, or given general 
anesthesia and morphine postoperative analgesia as described above. The overall trial profile is shown in 
figure 9. 
Fluid Management 
The primary fluid management will be lactated Ringer’s or similar crystalloid solution. Up to 500 ml will 
be given with induction of anesthesia at the anesthesiologist’s discretion. Subsequently, lactated Ringer’s 
solution will be given at a rate of 2-4 ml/hr. Blood loss will be replaced with lactated Ringer’s solution at a 3:1 
ratio, colloid at a 2:1 ratio, or red cells at a 1:1 ratio. It is unlikely that many patients having breast surgery will 
require blood transfusions. However, red blood cell transfusions are immunosuppressive, an effect that is only 
partially ameliorated by leukocyte filtering. Red cell transfusions will thus be strictly controlled by protocol. 
Target minimum hematocrit (HCT) will thus be determined prospectively (before randomization) based on the 
patient’s age and cardiovascular status. Boluses of ephedrine (5 mg) or neosynephrine (100 µg) will be given 
as necessary at the discretion of the attending anesthesiologist. 
The target HCT will be 26% in patients aged <65 yr having no significant cardiovascular disease. The 
HCT will be maintained at 28% or above in patients aged ≥65 yr or having cardiovascular disease. Significant 
cardiovascular disease will be defined as previous myocardial infarction, angina, congestive heart failure, 
cardiomyopathy, hypertension requiring treatment (or having a diastolic blood pressure exceeding 90 mmHg), 

Regional analgesia and breast cancer recurrence 
Sessler, et al. 
18 
or peripheral vascular disease. HCT will be maintained ≥30% in patients having both cardiovascular disease 
and an age ≥65 yr. Leukocyte-depleted allogeneic blood will be administered only as necessary to maintain the 
prospectively-determined target HCTs. 
Prophylaxis for postoperative nausea and vomiting will be provided per clinical routine, typically 4 mg of 
ondansetron. Rescue treatment will be provided per clinical routine with additional ondansetron, 
metacloprimide, droperidol, or other agents. However, dexamethasone will be specifically avoided since the 
drug is immunosuppressive.  
In all cases, good clinical judgment will predominant and the attending anesthesiologist will modify the 
protocol as necessary to provide optimal and safe care. However, the proposed methods are routine and we 
expect modifications to be necessary only rarely. 
Measurements 
Morphometric and demographic characteristics of the patients in each treatment group will be 
tabulated. For follow-up purposes, we will obtain contact information for the patient, a family member, and the 
names of the patient’s oncologist and primary physician. The date of the last menstruation will be recorded in 
pre-menopausal women since cycle phase influences natural killer cell function74 and metastasis risk.182,183 
Perioperative use of beta-blockers and COX inhibitors will be recorded since both impact the 
immunosuppressive and tumor-promoting effects of surgery.66 
Anesthetic data in the patients given general anesthesia will include volatile anesthetic dose in MAC-
hours. In the patients given regional anesthesia, upper and lower block levels, the type of anesthesia 
(paravertebral vs. epidural), and the initial dose of local anesthetic will be recorded — as will the amount given 
via infusion over the first 48 postoperative hours. Anesthetic depth will be estimated using the Bispectral Index 
(BIS, Aspect Medical, Newton, MA) when available, which is by far the best-validated monitor of anesthetic 
effect. BIS will be recorded at no longer than 15-minute intervals. But in most cases, BIS will be electronically 
down-loaded from the monitors where the signal is automatically recorded at 1-minute intervals. The software 
version will also be recorded. 
BIS is a processed EEG parameter that results from a multivariate discriminate analysis of the time 
domain, frequency domain, and high order spectral sub-parameter features of the EEG.184 The 
electroencephalographic (EEG) Bispectral Index has proven to be a quantifiable measure of the effects of 
anesthetic agents on the central nervous system and it can be related to the hypnotic component of the 
anesthetic state. BIS is a dimensionless number scaled from 0 to 100, with 0 being complete brain electrical 
silence and 100 representing an awake EEG.185 A BIS index of 40-60 is regarded as adequate surgical 
anesthesia. BIS is a reliable, predictable, convenient and practical means of measuring the level of 
consciousness186 and is therefore a suitable surrogate to the depth of anesthesia. More than 800 publications 
related to BIS are listed at the National Library of Medicine and BIS is the only system that has been shown to 
reduce recall of intraoperative events.187  
Upper and lower sensory block levels (in terms of dermatomes and pin-prick) will be recorded in the 
regional patients before surgery and shortly after arriving in the post-anesthesia care unit. 
In both groups, the total dose of propofol and other drugs (including antiemetics) will be recorded. 
Blood loss will be recorded, along with fluid administration including allogeneic blood. Blood pressure and  
heart rate,  will be recorded at 15-minute intervals final intraoperative core temperature will also be recorded. 
Total fentanyl and morphine use during surgery will be recorded, as will morphine use over the first 48 
postoperative hours; morphine use will be broken into the first two postoperative hours, from two hours until the 
first postoperative morning, and from the first to second postoperative morning. For analysis purposes, other 
postoperative opioids will be converted into equivalents of morphine sulphate using ratios in Principles of 
Analgesic Use in the Treatment of Acute and Chronic Cancer Pain.179 Patients will be asked to rate their pain 
on an 11-point Likert scale after one and two hours of recovery, 24 hours after surgery, and on the second 
postoperative morning. Complications related to the assigned anesthesia and analgesia will be recorded.  
Postoperative nausea and vomiting will be evaluated after two hours of recovery, and on the first and 
second postoperative mornings. Patients will be asked if they had any nausea. If yes, nausea will be assessed 
on a numeric rating scale (NRS, 0-10). Patients will also be asked about any emetic episodes, defined by 
vomiting or retching. As the mechanism of retching and vomiting is similar, and the latter is much more 

Regional analgesia and breast cancer recurrence 
Sessler, et al. 
19 
frequent, retching is often considered as vomiting (without expulsion of gastric contents). For the sake of 
simplicity we will therefore consider retching and vomiting synonymous. The duration of hospitalization will be 
recorded. 
If patients are no longer in the hospital by the second postoperative morning, they will be called by an 
investigator who will query them about pain and opioid use. Clinical experience suggests that nearly all 
patients will tolerate morphine. But if clinically necessary, other opioids will be used at equivalent doses as 
shown in Table 3. Bio-availability and individual responses differ from patient to patient.175-178 Nonetheless, the 
following table, adapted from Principles Of Analgesic Use In The Treatment Of Acute And Cancer Pain (Fifth 
Edition) 2003,179 is a reasonable basis for converting various opioids into morphine equivalents in the 
perioperative period. Piritramide188,189 is included because the drug is commonly used in Europe. 
 
Table 3. Opioid Equivalents. 
 
Oral Dose (mg) 
Parenteral Dose (mg) 
Morphine 
30 
10 
Hydromorphone 
7.5 
2 
Oxycodone 
20 
- 
Methadone 
10 
5 
Levorphanol 
4 
2 
Oxymorphone 
- 
1 
Meperidine 
300 
75 
Nalbuphine 
- 
10 
Butorphanol 
- 
2 
Pentazocine 
50 
30 
Buprenorphine 
- 
0.4 
Piritramid 
- 
15 
Prognostic factors related to the risk of breast cancer recurrence will include details of the tumor size, 
grade, type, and estrogen receptor status; the extent of axillary nodal disease; and whether preoperative or 
postoperative adjuvant chemotherapy and radiotherapy was used. For staging, we will use the 10/21/05 
National Cancer Institute TMN Definitions.  
Additionally, we will compute the Nottingham Prognostic Index, a score for which the prognosis for 
breast cancer is based on the formula: 0.2 (tumor size) + histological grade (1 = Grade 1, least aggressive 
histology, Grade 2 = intermediate histology, Grade 3 = most aggressive histology) + axillary lymph node 
involvement (1 = no nodes involved, 2 = up to 3 nodes involved, 3 = more than 3 nodes involved).193 A score 
below 3.4 suggests a good outcome whereas a score between 3.4 and 5.4 suggests an intermediate 
prognosis. Additionally, we will determine whether the resection margins are clear of tumor.  
Cancer recurrence will be evaluated by tracking all patients at six-month intervals for up to seven years, 
until the end of the study, or until recurrence is documented. Patients and/or their health-care providers will be 
contacted at each six month follow-up interval for up to seven years to confirm recurrence status, and to obtain 
details of recurrence if there is one. Yearly mammograms are standard in these patients and abnormal results 
usually provoke a biopsy. Biopsy results will be obtained whenever possible. The site of initial detected 
recurrence will be determined.   
At each contact, we will determine if additional surgery was required, what the reason was, and what 
kind of anesthesia was used (general vs. regional vs. monitored anesthesia care). Trained investigators who 
will be guided by scripts prepared by our social worker will contact patients and their families. All follow-up 
contact with patients, families, and care-givers will be conducted by investigators who are strictly blinded to 
group assignment and intraoperative management; questions that might unblind the follow-up investigators will 
be specifically avoided.  
All cases of apparent recurrence will be evaluated by a committee that will make the final determination 
using all available laboratory and clinical evidence. Members of the Adjudication Committee will be strictly 
blinded to randomization and actual perioperative management. The Committee will consist of the site 
directors; however, directors will be excused when cases from their own sites are discussed to keep the 

Regional analgesia and breast cancer recurrence 
Sessler, et al. 
20 
process completely blinded. The diagnosis of a first breast cancer recurrence should normally only be made 
only when both the clinical and laboratory findings meet criteria specified by the National Surgical Adjuvant 
Breast and Bowel Project Protocol B-39. Suspicious findings do not constitute criteria for breast cancer 
recurrence.  
Quality-of-Life and Chronic Pain Measures 
We will evaluate the SF-12 Health Survey (SF-12), the modified brief pain inventory (mBPI), and the 
Neuropathic Pain Questionnaire Short Form (NPQ-SM) at six months and one year.  
The SF-12 is an abbreviated version of the SF-36 Health Survey, a well-established instrument to 
assess psychological and physical aspects of health related quality of life (QoL).194 The principal scores from 
the SF-12 are a physical health composite (PCS-12) and a mental health score (MCS-12). In addition, an 
eight-domain profile can be produced, providing scores for Physical Function, Role Physical, Bodily Pain, 
General Health, Vitality, Social Functioning, Role-Emotional, and Mental Health. Theta reliability estimates 
range from 0.73 to 0.87 across the eight scales, whereas the value for the PCS-12 is 0.89 and that of the 
MCS-12, 0.86. The SF-12 is thus our choice survey of global health because it is well validated, accurate, 
precise, and requires less than two minutes to administer.195  
The BPI is a practical method of evaluating pain severity and its impact on patient function. The BPI 
was created because the McGill Pain Questionnaire is too long and difficult, and doesn’t evaluate pain history 
or the extent to which pain interference with daily activities. The BPI includes four rating pain intensity, and 
seven covering the impact of pain. Intensity is recorded on an ordinal scale from zero (no pain) to ten (worst 
imaginable pain). In the impact of pain section, these ratings are made on zero-to-ten numeric scales running 
from no interference to complete interference.195-197 The reliability alpha values for the four pain intensity items 
of 0.87 (N=1,106). Alphas for the interference scale are 0.91. The internal structure of BPI is logically 
consistent: as ratings of pain intensity increase, the interference items are endorsed in a sequence running 
from work, to mood, sleep, activity, walking, and finally, relations with others.195 
The NPQ-SF is an abbreviated version of the Neuropathic Pain Questionnaire (NPQ), a clinical tool 
with the ability to differentiate neuropathic from other types of pain. Stepwise discriminate analysis identified 
three items: Tingling Pain, Numbness, and Increased Pain due to Touch. The resulting canonical discriminate 
function was able to predict neuropathic pain wRevRith a sensitivity of 64.5%, sensitivity of 78.6%, and total 
predictive accuracy of 73%. This straight-forward questionnaire will allow us to use the power of clinical 
symptoms and signs for purposes effectively identifying patients with neuropathic pain.198,199  
The English version has a reliability alpha values for the four pain intensity items of 0.87 (N=1,106). 
Alphas for the interference scale are 0.91 for the English version. Factors analyses have consistently 
supported the division into severity and interference factors in studies in United States, France, China, and 
Philippines. The BPI detects expected differences in severity of pain between groups of patients who different 
in the site of their disease, in their requirements for analgesics, and in the presence of metastases. The 
correlations among the pain intensity ratings (e.g. now, least, worst, average) fell in the range of 0.57 to 0.80, 
whereas correlations among the inferences scales ranged from 0.44 to 0.83. Correlations between the intensity 
and interference ratings ran from 0.27 to 0.63. The internal structure of BPI appears logically consistent: as 
ratings of pain intensity increase, the interference items are endorsed in a sequence running from work, to 
mood, sleep, activity, walking, and finally, relations with others.195 
Data Analysis 
Our primary outcome is time to metastatic spread or local cancer recurrence, and the secondary 
outcome is chronic pain. The randomized groups will be descriptively compared on all baseline variables using 
summary statistics such as mean and standard deviation, median and quartiles or frequency and percent, as 
appropriate. All tests will be 2-tailed and the significance level for primary analyses will be 0.05. SAS statistical 
software, Carey, NC, will be used for all data analysis. 

Regional analgesia and breast cancer recurrence 
Sessler, et al. 
21 
Primary analysis  
The primary analysis will be intent-to-treat (ITT), where all subjects are analyzed in the group to which 
they were randomized. We expect that 5% of the regional blocks will fail, and that these patients will then be 
converted to general anesthesia. Such cases will be analyzed in the group to which they were randomized.  
We will first assess the effect of regional versus general anesthesia on time to recurrence of local or 
metastatic cancer univariably by comparing the randomized groups with Kaplan-Meier analysis and a log-rank 
test.. Equal precision 95% confidence bands200 will be constructed and plotted for each of the randomized 
groups along with the Kaplan-Meier product-limit recurrence-free estimates. As usual for survival analysis, 
patients lost to follow-up due to uncontrollable factors during the study will be censored at the time of last 
contact.    
Our primary analysis will be a Cox proportional hazards model in which we will assess the effect of 
regional versus general anesthesia via a hazard ratio (95% CI) for cancer recurrence/metastatic spread while 
adjusting for the following a-priori determined baseline and perioperative factors: clinical center,TNM, stage, 
center, age, race, ethnicity, type of surgery, estrogen-receptor status, and whether preoperative or 
postoperative adjuvant chemotherapy, radiotherapy, or endocrine therapy was used.  Postoperative therapies 
a patient receives after the index surgery (and before a patient’s recurrence) will be included via time-varying 
covariates.  These covariables (other than clinical center) are either known or highly suspected to be related to 
breast cancer recurrence. We will adjust for them regardless of statistical significance in the model order to 
estimate the treatment effect conditional on these factors. The interaction between treatment effect and clinical 
center will also be assessed.  Postoperative therapies are included since these are such important predictors 
of outcome, and unrelated to the intervention. All of our interim analyses will use this same covariable-adjusted 
model.  
We choose a covariable-adjusted model as our primary outcome in order obtain a more generalizable 
treatment effect estimate than would be given with a non-adjusted model. The covariable-adjusted model  
allows risk calculation for individual patients based on the included characteristics, and averages the treatment 
effect for covariables not included. Our results will thus be more useful to individual patients and more 
generalizable to patient populations with perhaps different distributions of the included covariables.201,202 Our 
choice is not based on concern for confounding factors (i.e., those related to both the intervention and the 
outcome), since the randomized groups will likely be well balanced on baseline factors. Although multivariable 
analysis for a continuous outcome (linear regression) increases the precision of the estimated treatment effect 
and thus add power to a randomized trial even if perfect balance is achieved, 203  such is not typically the case 
for survival or binary outcomes.201,202,204 The Cox regression treatment effect estimate adjusted for strong 
prognostic variables will tend to be slightly farther from the null effect and have slightly larger or the same 
standard error as the unadjusted model, usually with slightly improved power. 
Interim analyses for efficacy and futility during this group sequential design will be conducted at every 
25% of the maximum number of required recurrences. See details in Sample-size Calculations, Interim 
Analyses and Stopping Boundaries. 
 
Secondary analyses  
Our main secondary outcome will be chronic pain.  We will assess the effect of regional versus general 
anesthesia separately on pain measures (mBPI and NPQ-SM) and quality of life (Sf-12) using linear mixed 
effects models, considering patient as random effect, and incorporating the repeated measurements within 
patient at six month intervals, beginning 6 months after surgery.  In these models we will first assess the 
interaction between treatment and time.  Treatment effect will be estimated marginally (collapsing over time) if 
no interaction observed, and separately at various times in presence of an interaction. Within-patient 
covariance structure for the mixed effects models will be chosen based on comparing reasonable models on 
the AIC criterion.  
In secondary analyses we will also specifically evaluate the relationship between the bispectral index 
and cancer recurrence using Cox proportional hazards survival analysis. In particular, we will consider 
cumulative time with BIS<45, since that has previously been associated with mortality in general surgical 
populations, with most of the observed mortality being due to cancer.205,206 Also, a more sophisticated 

Regional analgesia and breast cancer recurrence 
Sessler, et al. 
22 
approach of accounting for the post-randomization variables by considered them as outcomes themselves will 
be considered, potentially by adapting the methods of Rochon207,208 to survival analysis.   We will also test for 
interactions between the treatment effect and the following selected covariables: red cell transfusion; tumor 
size, grade, and type; estrogen receptor status; and whether preoperative or postoperative adjuvant 
chemotherapy, radiotherapy, or endocrine therapy was used. These analyses may help identify specific 
subgroups of patients for whom the intervention appears especially helpful or not helpful. Although pre-
specified, we will interpret the estimated interactions and their statistical significance with much caution since 
there are several of them (increased false positive conclusions) and they are not the primary analysis or focus. 
Our assessment of interactions will be viewed as exploratory and hypothesis generating. 
An as-treated analysis will be conducted using the same methods as described above for the intent-to-
treat analysis. Because it is well known that as-treated analyses often lead to quite biased estimates of the true 
treatment effect, these results will be interpreted with much caution and always secondary to the intent-to-treat 
results.    
Analyses will be conducted using SAS statistical software, Cary, NC.  The significance level (i.e, Type I 
error) will be 0.05 for each hypothesis. Accordingly, correction to the significance criterion for multiple 
comparisons within a hypothesis (eg, comparisons at various time points) will be made in order to maintain the 
overall significance level. 
Sample-size Calculations and Sequential Monitoring 
Primary Outcome: Cancer Recurrence  
We hypothesize that our control group (general anesthesia with opioid use) will have a pattern of 
recurrence similar to that observed in the summary of trials reported by Saphner,209 and that stage will be 
similar to that for patients previously treated at the Cleveland Clinic. The stage distribution of patients in the 
Cleveland Clinic Breast Center Registry for women diagnosed and/or initially treated at the Cleveland Clinic 
between 1998 and 2002 was N=1097 (49.7%) Stage I, N=956 (43.3%) Stage II, and N=156 (7%) Stage III. For 
the combined 3,585 patients across seven Eastern Cooperative Oncology Group studies, Saphner et.al. 
reported the hazard of recurrence (percent recurring) for each year of follow-up as: year 0-1= 7.7, year 1-
2=13.3, year 2-3=11.9, year 3-4=9.0, year 4-5=6.7, year 5-6=4.5 and year 6-7=4.7. These hazard estimates 
may be somewhat conservative because the Saphner data include stage 0 and stage IV patients (a lesser 
percentage) and our study will not include such patients. Our narrower population at both spectrum ends is 
expected to give similar estimates. 
Given the above hazard rates for the general anesthesia group, we would need to observe a maximum 
of 356 recurrences to have 85% power at the 0.05 significance level to detect a 30% reduction in the risk of 
cancer recurrence (i.e., hazard ratio 0.70), allowing for 3 interim analyses at 25%, 50% and 75% of the 
maximum number of events, plus a final analysis. These calculations include a 3% dropout rate per year and 
the assumption that 5% of the regional blocks will fail (and thus be converted to general anesthesia which 
dilutes the treatment effect by 5%, although analyzed as intent-to-treat, Fig. 10). Under the alternative 
hypothesis, the probabilities of stopping the trial for either efficacy or futility at the first, second or third interim 
analyses are 0.07, 0.26, and 0.37, with a probability of 0.30 of continuing to the final look. Larger true treatment 
effects would have larger probabilities of stopping for efficacy before the final look. 
Our calculations assume non-binding stopping rules (the Data and Safety Monitoring Board will have 
ultimate authority) and account for monitoring both the null and alternative hypotheses. We use the gamma 
family spending function of Hwang, Shi, and Decani (1990),210 where the parameter gamma controls how fast 
alpha or beta is spent throughout the trial. We use gamma=-4 for efficacy (i.e., alpha spending), which closely 
resembles the O’Brien-Fleming spending function, and gamma=-2 for futility (i.e., beta spending), which is 
between the Pocock and O’Brien-Fleming approaches (Fig 10). We are thus spending the beta somewhat 
faster than the alpha during the trial. The boundaries meet at the end of the maximum accrual, so that a 
decision for either efficacy or futility will be made at some point during the trial (Fig. 11). Stopping boundaries 
for efficacy (and futility in parentheses) are as follows (Fig 12): first look P ≤ 0.0016 (P > 0.9478); second look 
P ≤ 0.0048 (P > 0.7136); third look P ≤ 0.0147 (P > 0.2429); last look P ≤ 0.044 (P > 0.044). These power 
analyses are conservative since they are based on a univariable analysis, whereas our primary covariable-
adjusted analysis will presumably have somewhat higher power.   
 

Regional analgesia and breast cancer recurrence 
Sessler, et al. 
23 
 
Figure 10 
Figure 11 
Figure 12 
 
The original protocol assumed a recurrence-free survival (RFS) curve for the control group similar 
to that in Saphner et al (1999).  We revised the sample size calculations using the data in the article by 
Haviland (2013, Lancet) in January 2105.  Specifically, we assume our control group will have a RFS curve 
similar to the combined 3 groups in Figure 2 of Haviland et al.  We thus assume the hazards (percent 
recurring each year) which correspond to those survival estimates of year 1: 2.5%, year 2: 2.6%, year 3: 
3.2%, year 4: 2.2%, year 5: 3.3%, year 6: 2.3%, year 7: 2.4%, year 8: 2.4%, year 9: 1.2%, year 10: 1.2%.  
 
These adjustments do not change the statistical properties of the interim monitoring plan, and so 
this is not an adaptive trial (i.e., the planned hazard ratio is unchanged).  We still need to observe a 
maximum of 351 events to have 85% power to detect a hazard ratio of 0.70 or stronger (assuming 5% 
dropout per year).   The change is that instead of the original 1100 patients that we planned to enroll in a 
maximum of 8 years (6.3 years expected study duration), we now plan to enroll a maximum of 3196 
patients in a maximum of 12.7 years with an expected study duration (including stopping when a 
boundary is crossed) of 11.1 years. Table 4 below gives the number of recurrent events (column 2) 
required for each interim analysis.  
 
Table 4.  New projections on accrual and time to analysis given new sites coming onboard in 2014 
Information 
Fraction 
Cumulative 
Events 
Boundary Crossing 
Probabilities 
Estimated  
Cumulative Accrual 
Estimated  
Analysis Time (yrs) 
Since 2008 
Under H0 
Under H1 
Under 
H0 
Under H1 
Under H0 
Under H1 
0.250 
88 
0.054 
0.072 
1213 
1423 
7.4 
7.9 
0.500 
175 
0.270 
0.253 
2715 
3096 
9.5 
9.9 
0.750 
263 
0.472 
0.373 
3196 
         3196 
10.7 
11.3 
1.000 
351 
0.204 
0.302 
   3196 
3196 
11.9 
12.7 
 
 
Data Management and Quality Assurance  
The proposed study will be registered with ClinicalTrials.Gov before the first patients are enrolled. We 
will also publish a “methods” paper that will identify important aspects of the protocol and our a priori 
outcomes.  

Regional analgesia and breast cancer recurrence 
Sessler, et al. 
24 
The trial will be directed by an Executive Committee consisting of Daniel I. Sessler, M.D., Donal 
Buggy, M.D., and Andrea Kurz, M.D. Our principal statistician, Edward Mascha, Ph.D., will attend Executive 
Committee meetings in a non-voting capacity. Principal data quality and auditing personnel will be available 
should the Committee need to meet with them.    
The Executive Committee will evaluate all results from the proposed trial as the Committee deems it 
necessary. It will be the responsibility of this committee to alert the IRB via letter to any untoward toxicity in one 
of the study groups. This committee, along with the IRB, will have exclusive authority to stop the study either 
because the hypotheses have been confirmed or denied, or because adverse events are detected.  
All interviewers will undergo training and must demonstrate a high level of proficiency before being 
certified to interview subjects. Procedures used to assure the integrity of data include (1) quarterly external 
audits by OUTCOMES RESEARCH staff, (2) data entry procedures following standard operating procedures 
(SOPs), and (3) data queries and resolution processes following SOPs. Frequent interaction among members 
of the study Executive Committee (PI, co-investigators, consultants), RAs, and others as necessary, will 
maintain overall quality assurance.   
Hard-copy forms will be stored in locked cabinets within a secured area. To protect electronic records 
and files against loss, duplicate files will be maintained and on Division of Anesthesiology servers at the 
Cleveland Clinic. These servers are highly secured because they already contain much patient-related 
information and are backed up daily to tape that is maintained in a remote location. The system fully meets all 
applicable HIPAA Privacy and Security rules. Access to the database and backups are strictly monitored 
according to need. 
At least 80% of the data will be independently audited to confirm consistency among patient records, 
study data sheets, and the main database. Data will be maintained on a custom-designed FileMaker or SQL 
relational database. Data will be transcribed by separate sets of investigators. We have programmed and used 
similar password-protected databases in our previous major outcome trials.211-213 Trial management will be 
coordinated from Cleveland. The PI will visit each site at reasonable intervals.  
Strength, Limitations, and Significance  
Strengths 
The mission of the OUTCOMES RESEARCH Consortium is to evaluate simple, inexpensive, low-risk 
interventions that have the potential to markedly improve perioperative outcomes. For example, we have 
shown that maintaining intraoperative normothermia (at a cost of $8/patient) reduces blood loss214 and 
transfusion requirement,215 decreases the duration of recovery216 and hospitalization,170 reduces wound 
infection risk by a factor of three,170 prevents most shivering,217 and improves thermal comfort.218 Similarly, we 
have shown that providing supplemental oxygen (at a cost of $0.03/patient) halves the risk of surgical wound 
infection.211,219 More recently, we have shown that restricting storage duration of transfused red cells to less 
than 14 days reduces the relative risk for one-year mortality after cardiac surgery by 30%.220 The proposed 
study continues this tradition by asking if a straightforward change in anesthetic management can reduce the 
risk of cancer recurrence.   
The major risk of cancer surgery is neither the surgery per se nor the anesthesia: it is recurrence of 
cancer — which is usually a lethal event. We expect to demonstrate that switching to regional anesthesia and 
analgesia reduces the risk of cancer recurrence by about the same amount as postoperative radiation or 
chemotherapy. But this switch is considerably safer and less expensive than radiation or chemotherapy. 
Confirming our primary hypotheses, that a straightforward change in anesthetic management reduces the risk 
of cancer recurrence, would be a major advance and would markedly improve the outcome from surgery for 
breast cancer. Although we propose to evaluate only one type of cancer, it seems likely that the putative 
benefits of regional anesthesia would apply to other cancer surgery as well. 
A strength of our study is that we will evaluate “hard” outcomes (cancer recurrence) rather than 
intermediate or indicator outcomes. Paravertebral and thoracic epidural blocks are routine techniques and 
most anesthesiologists are familiar with the methods. In any case, all anesthesiologists could easily learn these 
blocks if a convincing benefit were demonstrated. Our results will thus be immediately applicable to clinical 
practice.  

Regional analgesia and breast cancer recurrence 
Sessler, et al. 
25 
We propose to study breast cancer for three reasons. First, this disease is common: breast cancer is 
the leading type of cancer in women. This high incidence will make recruiting patients easier and speed 
completion of the study. Just as important, our results will be immediately applicable to large numbers of 
women without extrapolation — although extrapolation to other forms of cancer would seem reasonable. The 
second reason to study breast cancer is that it poses an intermediate risk of recurrence and death, an 
important consideration since regional anesthesia is unlikely to be helpful in tumors that kill nearly everyone 
(such as lung cancer). Conversely, it would be difficult to demonstrate a benefit for slow-growing tumors that 
metastasize only in the very latest stage (such as prostate cancer). Our third reason for focusing on breast 
cancer is that the surgery is amenable to regional anesthesia using techniques familiar to most 
anesthesiologists.  
The proposed study is powered to detect moderately sized treatment effects. We will have an 85% 
power to detect a treatment effect of only 30%, which is much smaller than the one observed in either of our 
preliminary studies. There is thus little chance of a Type II statistical error; that is, missing a substantive 
treatment effect. Furthermore, we will be able to accurately characterize the magnitude of any identified 
treatment effect. This is an important consideration since clinicians need to know how good proposed 
treatments are, not just that they are “significant.”  
Limitations 
That a simple change in anesthetic technique might reduce cancer recurrence is an innovative concept, 
perhaps to the point of seeming unlikely. However, there exists strong in vitro and animal data to support our 
theory. The underlying mechanisms by which general anesthesia and opioid analgesia might promote tumor 
dissemination are fairly well established. And finally, our preliminary study supports a substantial clinical effect. 
Given available information and the importance of the question, it is surprising that a randomized clinical trial 
has yet to be published. Yet to the best of our knowledge, none is in progress or has even been attempted. 
It might seem surprising that an effect of anesthesia on cancer recurrence has not been noticed 
previously. But most centers use either general or regional anesthesia, and outcome differences amongst 
centers are usually attributed to surgical technique and other center-related effects. Furthermore, cancer 
recurs years after surgery and would not normally be attributed to anesthetic management. In this regard, an 
effect of anesthetic management on tumor recurrence may be similar to surgical wound infections which were 
conventionally attributed to surgical technique, although studies by the OUTCOMES RESEARCH Consortium 
subsequently demonstrated that two simple anesthetic techniques (maintaining normothermia170 and providing 
supplemental oxygen211,219) each reduce infection risk by a factor of two or three. Clinicians had noted neither 
of these benefits and neither intervention was considered to be routine management at the time.  
A reasonable question would be whether it might be preferable to first conduct additional retrospective 
analysis. We queried a number of large databases including those at the Cleveland Clinic, Duke University, 
and the Center for Medicaid and Medicare Services, but none contains terms for both anesthetic technique and 
cancer outcome. A retrospective analysis would thus be non-trivial. But more importantly, a chart review will 
suffer the limitations of any retrospective study including treatment bias, poor control of confounding factors, 
and inadequate record detail. Thus, the only type of study that can definitively confirm (or deny) our 
hypotheses is a randomized, blinded trial of the sort we propose.  
Both thoracic epidural or paravertebral anesthesia block the neuro-endocrine stress response to 
surgery and minimize or eliminate the need for general anesthetics and opioids.28-32 They are, therefore, 
functionally identical from the perspective of reducing risk of cancer recurrence. Clinicians nonetheless often 
have a personal preference — and therefore greater experience and comfort — with one technique than the 
other. Consequently, we will allow either method. While perhaps sounding unlikely, previous large studies have 
randomized patients to regional versus general anesthesia to evaluate other outcomes. We thus do not 
anticipate difficulty finding a suitable number of consenting patients. And in fact, we have not so far had 
unusual difficulty enrolling more than 100 patients. 
Paravertebral anesthesia can be performed with or without a catheter, and there are advantages and 
disadvantages to each. For example, the multi-level approach is technically easier, provides better 
intraoperative coverage, can be used bilaterally, and is probably safer. On the other hand, postoperative 
analgesia usually lasts only until the first postoperative morning whereas analgesia can be continued as long 
as necessary with a catheter. We note, though, that many patients (by far the majority at the Cleveland Clinic) 

Regional analgesia and breast cancer recurrence 
Sessler, et al. 
26 
are discharged on the first postoperative day; furthermore, the first postoperative day and evening is the period 
during which most opioids are required. These patients would benefit little from a catheter since it would be 
removed before discharge in any case. Accordingly, we will leave the choice of paravertebral technique to the 
discretion of the attending anesthesiologist who will best be able to judge the relative merits of each approach 
in particular patients. Either technique will well serve our goal of minimizing or eliminating surgical stress 
response and the need for postoperative opioids. 
In most patients having paravertebral or epidural anesthesia, the regional block will be combined with 
propofol sedation. However, not all patients tolerate regional anesthesia alone. A “light” propofol-based general 
anesthesia will be permitted when clinically indicated. Since propofol has little or no effect on tumor cells in 
vitro79 or in vivo,93 it is unlikely that either approach will prevent the putative benefits of regional anesthesia on 
surgical stress and opioid requirement. We note that all patients in our preliminary study, in which a large 
benefit of regional analgesia was demonstrated, received general anesthesia with sevoflurane. It is unlikely 
that light general anesthesia in a fraction of the patients assigned to regional anesthesia will much influence 
cancer recurrence.  
We will give fentanyl during induction of regional or general anesthesia because doing so limits 
hemodynamic responses and makes induction safer. However, the small dose intravenous fentanyl we 
propose has a short context-sensitive half life so plasma concentrations will approach zero within 15 
minutes.221  
As mentioned in the Background section, the relative central and peripheral contributions to opioid-
induced impairment of cell-mediated immunity remain controversial. While the “cleanest” approach would be to 
avoid combining opioids with local anesthetic infusions, these drugs usually are combined in clinical practice 
because adding tiny-dose opioid permits use of a lower anesthetic concentration with improved analgesia. 
Furthermore, fentanyl — the drug usually used with local anesthetics — is highly soluble and thus poorly 
transmitted by cerebrospinal fluid. And finally, only subcutaneous opioid impaired cell-mediated immunity when 
equi-analgesic doses of subcutaneous and intrathecal morphine were injected.106 It is therefore unlikely that 
much epidural opioid will reach the peri-aqueductal gray area where opioid-induced immune suppression 
seems centered.105  
Intravenous postoperative analgesia will be restricted to morphine (if tolerated), although other opioids 
could be used (i.e., fentanyl patch). However, there is little reason to believe morphine differs markedly from 
other µ-receptor opioids in regards to immune suppression and release of tumor-promoting factors.21,97 
Restricting analgesia to a single opioid to the extent possible will facilitate comparison of doses in each 
treatment group. When clinically necessary, other opioids will be permitted and converted to “morphine 
equivalents” for analysis purposes.  
The major factors determining cancer recurrence risk are tumor histology, size, margins, estrogen-
receptor status, and the number of positive nodes. Most will be unknown at the time of surgery, making it 
difficult to use a stratified randomization. Furthermore, stratification is unnecessary in large trials.222 For 
example, we stratified only by study site in all the trials listed in the appendix. It is highly unlikely that 
stratification for any recurrence risk factor would add value to the large trials we plan, and therefore propose a 
randomization stratified only by study site.  
A more serious issue is that we will not attempt to standardize postoperative chemotherapy or radiation, 
although both influence recurrence risk. For example, women who undergo breast conservation surgery 
without radiation therapy have a higher rate of local recurrence compared to those who receive radiation 
therapy: 39 versus 14 percent in one study with twenty-year follow-up.223 Although we would obviously prefer 
to control such important confounding factors, we do not believe that it will be practical since both are highly 
influenced by patient preference and national norms. However, there is no reason to believe that use of 
chemotherapy or radiation will be anything but randomly distributed in the large study we propose. 
Furthermore, our statistical plan includes a multivariable analysis that will normalize all major potential 
confounding factors; although the results of this analysis will not be the primary outcome for the study, the 
univariable analysis will provide additional important information on our understanding of the relative efficacy of 
regional versus general anesthesia. 
Patients will not be specifically told to which group they were assigned, but most will recognize which 
type of analgesia they received. It seems highly unlikely, though, that this information will influence cancer 

Regional analgesia and breast cancer recurrence 
Sessler, et al. 
27 
recurrence rates, especially as participants will only be told that we are testing two techniques rather than the 
specific hypothesis that regional analgesia reduces risk. Similarly, it will not be possible to blind the 
perioperative personnel or the surgeons. However, all post-discharge evaluations will be performed by 
investigators who are fully blinded to randomization and actual treatment received. Contact with study patients 
will be highly scripted by our social worker and will avoid questions that might unbind the studies. In the event 
that one follow-up investigator is inadvertently unblinded to a particular patient’s treatment, another blinded 
investigator will be substituted.  
Opioids impair numerous immune functions, including those most important for containing tumors. 
However, opioids appear beneficial in certain circumstances. For example, withdrawal from morphine in 
dependent mice is immunosuppressive.224 Furthermore, low analgesic perioperative doses of morphine have a 
favorable immunomodulatory effect on surgical stress and metastasis promotion225-227 compared to no 
analgesia. These studies simply show that opioids are preferable to unrelieved stress of opioid withdrawal or 
untreated surgical pain in animals. However, humans are always given postoperative analgesia; our question 
is whether opioids are worse than other analgesic techniques such as regional analgesia. Existing data and 
our preliminary results suggest that they are.  
That surgery provokes a neuroendocrine stress response that impairs immune function, including cell-
mediated immunity, is well established in animals and humans. Similarly, that general anesthetics and opioids 
impair cell-mediated immunity in animals and humans is well established. Additional studies of stress 
mediators or cellular immunity will not answer the clinical question we ask which is whether blocking these 
known pathways with regional anesthesia and analgesia reduces the clinical risk of cancer recurrence. We 
thus do not propose to evaluate measures of stress and immune function.  
We recognize that some participating patients will require re-operation either for control of their cancers 
or for unrelated reasons. Most will occur outside our control and without our knowledge. We will thus make no 
attempt to control anesthetic management for additional operations. However, we will record the nature of the 
surgery and the type of anesthesia used. These factors will be included in our multi-variate analysis.  
Significance 
One woman in eight develops breast cancer. Effective treatment hinges on surgical removal of the 
primary tumor, but surgery is usually associated with release of tumor cells into the blood stream or lymphatic 
system, and pre-existing scattered micrometastases most commonly remain. Whether this minimal residual 
disease succeeds in establishing itself as recurrence or metastases is a function of host defense and other 
aspects of the physiological milieu. In practice, the immune system frequently fails to neutralize remaining 
malignant tissue; consequently, one patient in three develops postoperative metastatic disease — and breast 
cancer remains the second leading cause of cancer death in women.  
Considerable in vitro data and in vivo animal studies suggest that three factors associated with cancer 
surgery impair cellular immunity (i.e., natural killer cell function): stress response to tissue injury, general 
anesthesia, and opioid analgesia. Our preliminary results support this possibility: the breast cancer recurrence 
rate was reduced by a factor-of-four (P = 0.01) in patients given regional analgesia rather than post-operative 
morphine. Results were similar in patients given epidural or opioid analgesia for prostate cancer.  
Confirming our hypothesis that regional anesthesia & analgesia for breast cancer surgery reduces the 
risk of recurrence would be immediately applicable since regional blocks are routine procedures that are 
familiar to most anesthesiologists. Our study has the potential to convincingly demonstrate that a small 
modification to anesthetic management — one that can be implemented with little risk or cost — will reduce the 
risk of metastases, a complication that is ultimately lethal in most cases.  

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28 
E. Human Subjects Risks and Protection 
The proposed trial has already been approved by the Cleveland Clinic Human Subjects Protection 
Program and the IRB at five of the seven participating institutions. Written informed consent will be obtained 
from each participating patient. Patients who decline to participate will be given regional or general anesthesia 
and analgesia per their preference and that of their attending anesthesiologist; research data will not be 
collected from these patients.  
E1. Human Subjects Involvement and Characteristics: 
1,100 patients will be required to provide a 85% power to detect a 30% treatment effect at an alpha 
level of 0.05. Please see the section titled “Sample-size Calculations and Sequential Monitoring” for additional 
detail.  
An Executive Committee will evaluate all results from the proposed trial. This committee, along with the 
IRB, will have exclusive authority to stop the studies either because the hypotheses have been confirmed or 
denied or because adverse events are detected. It will be the responsibility of this committee to alert the IRB at 
each participating institution to any untoward toxicity in one of the study groups.  
E2. Sources of Material 
Data obtained routinely for clinical purposes will be used in this study. Such data include 1) anesthetic 
dose and safety monitoring; 2) fluid balance and transfusion requirement; 3) post-operative nausea and 
vomiting; 4) details of surgery and tumor histology and spread; and 5) morphometric and demographic 
information.  
Most importantly, we will contact patients at six-month intervals to determine whether they have 
experienced a recurrence of their cancer. When a recurrence is reported, we will also contact their local 
physician to determine details of the recurrence. If the patient is unavailable, we will contact one of at least two 
designated “contact people” — normally one of these will be a family member — to determine whether the 
patient has died. If so, we will again contact health providers to determine the details including whether the 
death was cancer-related.  
E3. Potential risks to Subjects 
The primary risk of our study is randomized assignment to regional anesthesia and analgesia or to 
general anesthesia and morphine analgesia. Regional and general anesthesia have different risks; however, 
there is no evidence or consensus that either is intrinsically safer or preferable for breast surgery. Both 
techniques are used routinely at the preference of patients and their anesthesiologists and surgeons.  
The most common risks of general anesthesia are dental damage (≈1%), post-operative nausea and 
vomiting (30%), and a “hung-over” feeling lasting a day or two (>50%). The most severe complications 
associated with general anesthesia are aspiration pneumonia, peripheral nerve damage (usually attributed to 
positioning problems), and brain damage or death, which usually result from airway disasters. Fortunately, 
these serious complications are rare (<1%). 
Inserting epidural or paravertebral needles can cause a small amount of discomfort. However, patients 
will be given midazolam and fentanyl, generous amounts of local anesthesia, and propofol, if necessary, during 
blocks. Most patients don’t remember the experience at all, and those that do rarely recall it as being 
uncomfortable. Infection associated with regional anesthesia and catheters is a theoretical risk, but extremely 
rare (<1%) when catheters are removed before 48 hours. 
Epidural or paravertebral blocks can also cause inadvertent “high” spinal anesthesia (<1%). This 
complication is easily manageable, but usually requires airway control and conversion to general anesthesia. 
About 5% of the attempted epidural or paravertebral anesthetics will fail and need to be converted to general 
anesthesia; some of these patients will nonetheless have adequate postoperative analgesia, but others will 
require patient-controlled analgesia.  
Epidural anesthesia can cause epidural hematomas that compress the spinal cord. However, 
hematomas are exceedingly rare complication (<1%) because a history of coagulopathy or anticoagulant 
medications is a contraindication to these blocks. Epidural hematomas are treatable and usually resolve 
without neurological damage, but treatment is usually surgical. Paravertebral anesthesia can cause a 

Regional analgesia and breast cancer recurrence 
Sessler, et al. 
29 
pneumothorax; however, this complication is rare. Treatment sometimes requires insertion of a chest drainage 
tube, although most resolve spontaneously.  
Patients and/or family members may be bothered by questions about cancer recurrence and death. 
However, discomfort will be reduced by restricting contact to investigators who have been trained in this 
process. Follow-up interactions will follow specific scripts.  
Patient privacy will be fully respected. Site investigators will discuss with the subjects and their 
assigned representatives, the IRB-approved informed consent explaining all procedures and potential risks and 
the HIPAA regulations regarding privacy of their medical information. Participating patients will complete the 
appropriate HIPAA forms.  
Confidentiality will be maintained per institutional procedures. Access to medical records is limited to 
the investigative staff. Data will be managed by study number and analyzed anonymously. All reports will be of 
a summary nature, and no individual will be identified. The investigators and study coordinators are keenly 
aware of the increasing ethical concerns of using medical information in research and its potential misuse in 
clinical care. They will insure that data will be handled appropriately and that confidentiality is strictly 
maintained. All members of the study staff will sign agreements of confidentiality.  
E4. Recruitment and Informed Consent 
Patients will be recruited from the Operating Room schedules. A member of the study staff will 
approach potential subjects in the Preoperative Clinic or surgeon’s office and give a general description of the 
study and its purpose to the patient. Patients will not be initially recruited on the day of surgery. Patients who 
orally agree will be given the Informed Consent document and asked to read it carefully. If for some reason 
they cannot read it themselves, it will be read to them. Any questions will be fully answered. Once patients 
completely understand the procedure, benefits, and risks involved, they will be asked to sign and date the 
consent form.  
Two copies of the Informed Consent form will be made. One copy remains with the patient’s chart, 
another copy will be given to the patient, and the original will be filed in the case report form. The original 
consent will thus be available to the investigators, their staff, study monitors, and each institution’s IRB. 
E5. Protection Against Risks 
The Executive Committee will have responsibility for evaluating all major morbidity occurring in study 
patients, and be authorized to stop the studies if excessive morbidity in one group appears related to study 
interventions. Additionally, any morbidity potentially related to the protocol will be reported to the IRB/Ethics 
Committees at each participating institution; these Committees also can stop the studies at any time for any 
reason.  
E6. Collaborating Sites 
The studies will be approved by the IRB at each of the participating sites (most already have approval). 
Each site will provide written confirmation that the four criteria specified by the Public Health Service for 
Protection of Human Subjects have been addressed.  
E7. Risk-Benefit to Subjects and Importance of Knowledge to be Gained 
Neuraxial anesthesia (epidural or spinal) has been best studied for hip arthroplasty. Neuraxial 
anesthesia reduces blood loss during hip arthroplasty228 and usually provides better postoperative pain relief 
than the combination of general anesthesia and postoperative opioids. However, epidural anesthesia does not 
reduce mortality or the risk of myocardial infarction after hip arthroplasty, even in high risk populations.229 
Perhaps consequently, general anesthesia and opioid analgesia remain common even for hip arthroplasty and 
is certainly used far more often than regional anesthesia/analgesia for nearly all other operations. And as 
mentioned above, there is neither evidence nor consensus that any particular anesthetic or analgesic 
technique is preferable for breast surgery; a variety of techniques are therefore used at the preference of 
patients, anesthesiologists, and surgeons.  
The major risk of cancer surgery is neither the surgery per se nor the anesthesia: it is recurrence of 
cancer — which is usually a lethal event. Our studies are powered to detect a reduction in recurrence risk of 
30%, which is similar to that provided by postoperative radiation or chemotherapy. But switching from general 
anesthesia and opioid analgesia to regional anesthesia and analgesia is clearly safer and less expensive than 

Regional analgesia and breast cancer recurrence 
Sessler, et al. 
30 
radiation or chemotherapy. Confirming our primary hypothesis, that a straightforward change in anesthetic 
management reduces the risk of breast cancer recurrence, would therefore be a major advance.  
E8. Gender and Minority Inclusion 
Breast cancer is largely a disease of women. It is unlikely that more than a few cases in men would be 
available during the entire study period. Furthermore, the occasional man who gets breast cancer usually has 
an extremely aggressive form of the disease. We will, therefore, restrict the study to women.  
We have no reason to believe that the effects of general anesthesia or morphine on immune function 
and release of tumor-promoting factors is substantively related to race or ethnicity. We will consequently 
include patients of all races and ethnicities and make a special effort to include minorities. We assume that our 
study population will reflect the patient population of each participating health system. In Cleveland, our 
participants will be roughly 10% Hispanic and 15% African American. At the other sites, there will be fewer 
minorities, but minorities will be specifically solicited for enrollment at all sites to provide good ethnic/racial 
balance. 
 Cancer may be diagnosed at later stages in minorities because they often have limited access to 
health care; however, minority participants will be roughly equally distributed into the two treatment groups. 
Our multivariable analysis will include race and ethnicity as categorical variables to adjust for an (unlikely) 
effect of either factor on our primary outcome.  
 
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