A REVIEW OF CURRENT RESEARCH IN ANESTHESIA RELATED TO BREAST

CANCER RECCURENCE AND CHRONIC PAIN

BY
Emily Kujawa
BSN, Truman State University, 2013

Submitted to the School of Health Professions and

The Graduate Faculty of the University of Kansas
In partial fulfillment of the requirements for the degree of
Doctor of Nurse Anesthesia Practice

Chairperson Alissa Blau, DNAP, CRNA

Lauryn Rametta DNAP, CRNA

Date Senior Scholarly Project Accepted

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Abstract

Over 1.1 million new cases of breast cancer (BC) were reported in women in the United States,

from 2012-2016.1,2 These patients often require several procedures requiring anesthesia, such as:

port-a-cath placements, mastectomies, lymph node dissections and reconstructive surgeries.3,4

Recent research has suggested there may be reduced risk of cancer recurrence and chronic pain

with specific anesthetic techniques.3,5 Regional techniques, total intravenous anesthetics, and

select adjuncts have been reviewed to identify their role in BC recurrence and chronic pain. A

review of the pathophysiology as it pertains to volatile anesthetics, propofol as a total

intravenous anesthetic (TIVA), paravertebral nerve blocks (PVB), dexmedetomidine and

ketorolac, as well as the role each of these play in the prevention of chronic pain and cancer

recurrence is provided in this paper. Current research and recommendations for practice will be

presented in the context of providing anesthesia to mitigate chronic pain and cancer recurrence in

BC patients.

Data Sources: CINAHL, Pub MED, Google scholar

Keywords: breast cancer, total intravenous anesthesia (TIVA), propofol, paraverterbral block

(PVB), dexmedetomidine, ketorolac

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Introduction

According to the Centers for Disease Control and Prevention, cancer is the second

leading cause of death in the United States with breast cancer (BC) being the most common

cancer in women. From 2012-2016, over 1.1 million new cases of BC were reported in women in

the United States. Of these women, 206,231 died from BC.1 These patients often undergo several

procedures requiring anesthesia, such as: port-a-cath placements, mastectomies, lymph node

dissections, and reconstructive surgeries.3,4 Given the frequency that these patients undergo an

anesthetic, it bears considering the impact of anesthesia on their treatment and recovery. Recent

research has explored the connection between type of anesthetic and immune function in the

perioperative period which may have implications for these cancer patients.3,5,6

Patients with BC also face challenges related to acute and chronic pain. Oftentimes as

part of their treatment, these patients will undergo a mastectomy. Surgery is highly dependent on

the patient and may be unilateral, bilateral, include a tissue flap, and/or lymph node dissection.

Acute surgical pain and inflammation is well established to be a prerequisite for the development

of chronic pain. Given the extent of surgery required to remove the cancer and reconstruct the

breasts, it is common for these patients to develop chronic pain. The prevalence of chronic pain

for patients undergoing a mastectomy is 25-60%.4 Given the prevalence of BC, the high risk of

developing chronic pain, and the implications for a substantial number of surgical patients, it is

imperative anesthesia providers are well educated on the most current practice recommendations.

Anesthesia and Immune Modulation

Medications used in anesthesia have effects on the immune system and stress hormones,

both of which can contribute to immunomodulation in the perioperative period. In cancer

patients, this change in immune status has potential to impact outcomes. There are several
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components to an immune response. Neutrophils, macrophages, natural killer cells, T

lymphocytes, and B lymphocytes all contribute to an immune response, which is necessary both

for healing and control of cancer cells in the body.7 Neutrophil–lymphocyte ratio (NLR) and

platelet–lymphocyte ratio values are used when evaluating risk of recurrence in BC. 7–9 Several

studies found NLR values greater than three to be associated with adverse outcomes in breast

cancer patients. 5,8,9 Even with treatment, patients are still at risk of cancer recurrence. Risk

factors include lymph node involvement and tumor size for those undergoing a mastectomy.

Those undergoing breast conservation therapy are at higher risk if they are younger age, and the

type of tumor is determined to be ductal carcinoma in situ.10

It is known that volatile anesthetics have an immunosuppressive effect, specifically, they

decrease the number of neutrophils, T lymphocytes, macrophage, and B lymphocytes.7,11 Volatile

anesthetics also increase cortisol while decreasing cytokine release, phagocytosis, chemotaxis,

cytotoxicity, proliferation of T lymphocytes.7 This puts patients at increased risk for recurrence

of BC. Conversely, studies have shown that propofol suppresses migration and invasion of

cancer cells, as well as has an anti-inflammatory effect targeting neutrophil activity.8,11,12 With

this understanding, it is important to consider the ramifications of anesthetic choices in these

patients.

Acute and Chronic Pain in Breast Cancer

Acute pain occurs during the perioperative period regardless of the type of BC surgery

performed. The perception of pain is comprised of complex interactions from excitatory and

inhibitory neurotransmitters, psychological, environmental, and social factors.13 Patients are

typically educated about pain expected post operatively, however it may extend beyond the

immediate post-operative period. Historically, patients diagnosed with BC received

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chemotherapy, radiation, and radical mastectomy with sentinel lymph node dissection.14

Although procedures to treat BC have become less invasive, overall, chronic pain still remains an

issue. Prevalence of chronic pain in patients receiving breast conserving therapy, axillary lymph

node dissection, and radiation, which includes peri clavicular lymph nodes is 60%.4,15,16 These

patients are at risk of developing post mastectomy pain syndrome (PMPS), which is a

neuropathic pain condition localized in the axilla, medial upper arm, breast and/or chest wall.4 As

anesthesia providers it is imperative to implement perioperative interventions which address both

the acute, as well as potential for chronic pain for these patients.

The pathophysiology of acute pain involves multiple systems and causes. Peripheral,

spinal, and cerebral areas all contribute to the sensation of pain. Initially, damage to peripheral

tissue activates primary afferent neurons by a variety of thermal, mechanical, and chemical

stimuli.13,17 This leads to opening of cation channels in the neuronal membrane which is

conducted along the sensory axon to the dorsal horn of the spinal cord.13 From there, it is

projected to the brain by direct monosynaptic contact or multiple excitatory or inhibitory

neurons.13,17

Endogenous mechanisms have a role in counteracting this sensitization and decreasing

the perception of pain through pathways at the peripheral, spinal, and cerebral level described as

the “gate control theory of pain.”13,17 At the peripheral level, immune cell derived opioid peptides

accumulate in inflamed tissue in response to proinflammatory cytokines, chemokines, stress,

catecholamines, corticotropin-releasing factor, or bacteria.13 The secretion of opioids activates

opioid receptors in peripheral tissues which inhibit the excitability of nociceptors, the release of

excitatory neuropeptides, and produce analgesia.13 At the spinal cord level, similar inhibition is

achieved by the release of opioids, γ-aminobutyric acid (GABA), or glycine from

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interneurons.13,17 These substances activate presynaptic opioid- or GABA-receptors on the central

nociceptor terminal to decrease excitatory transmitter release.13 Finally, the brainstem contributes

potent descending inhibitory pathways which are activated through noradrenergic, serotonergic,

and opioid systems.13

Acute pain which is inadequately managed can cause persistent nociceptor stimulation

which causes a progressive increase of output in both peripheral and central neurons known as

wind-up.13,17 This persistent sensitization of peripheral and central neurons can cause

transcriptional changes in the expression of genes coding for transmitters, ion channels,

receptors, and signaling molecules including cyclooxygenase-2 (COX-2).13 Additionally, in the

peripheral and central nervous systems physical rearrangement of neuronal circuits occurs

through apoptosis, nerve growth, and sprouting.13,17Chronically, these changes are responsible for

the sustained sensitization in nociceptors and spinal neurons which contribute to the perception

of chronic pain.13 In order to counteract this sensitization, gene expression and the production of

opioid peptides is upregulated by spinal interneurons.13,17 However, in chronic pain states these

mechanisms are overwhelmed and the delicate balance between excitatory and inhibitory

neurotransmitters is disturbed.13

Chronic pain is described as dysfunction in one or more of these areas which renders

typical inhibitory mechanisms ineffective.17The International Association for the Study of Pain

describes chronic post-surgical pain as: “persistent pain, apparent more than two months

postoperatively, which has no other root causes such as recurrence of disease, apparent

inflammation, etc.”4,13,17,18 Chronic pain can have psychogenic, inflammatory, and neuropathic

etiology which makes treatment challenging. 4,13,15 These patients may have pain from the

primary tumors prior to intervention, trauma to tissue and nerves during a mastectomy
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procedure, as well as, psychological implications of a BC diagnosis. Therefore, these patients

may have components of each pathology.4,15,19 Higher postoperative pain scores and analgesia

consumption have been found in patients who develop chronic pain after BC surgery, suggesting

that optimization of acute pain management may decrease development of chronic pain.18

Typically, for BC surgery a standard general anesthetic is utilized. Induction is done with

narcotic, propofol, and muscle relaxant with volatile anesthetic gas used for maintenance of

anesthesia. 20–22Additional narcotic and muscle relaxant are administered as indicated. This

technique provided adequate amnesia and analgesia for duration of surgery and additional

intravenous and oral pain medications were administered immediately in the postoperative

setting as needed. 20,21 Recently, new research has called into question if this technique is best

practice for cancer patients.

Review of Literature

Propofol

A retrospective cohort study published in 2018 concluded propofol used as a total

intravenous anesthetic (TIVA) for colon cancer surgery was associated with better overall

survival.23 After matching for significant differences in baseline characteristics between the two

groups, overall survival for the TIVA group was 86.6% compared to 56.5% for a desflurane

anesthetic.23 The study also found a lower incidence of both local recurrence and distant

metastasis in the propofol group (5.6%) at 3.7 years when compared with desflurane (9.1%) at

3.2 years.23 Another retrospective study also reported the difference in overall one and five year

survival rates as 4.7% and 5.6% in favor of propofol over a sevoflurane anesthetic in all cancer

sites.11 However, when adjustments for confounders were made, there was no statistical

difference between the two techniques in overall survival.11

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Propofol may also have a role in the decreasing the development and severity of chronic

postoperative pain. A retrospective study reported patients who received a sevoflurane anesthetic

were 1.5 times more likely to have chronic pain 2 to 24 months postoperatively than those who

received propofol.12,16 When a propofol TIVA was paired with paravertebral blocks (PVB) there

was a reduction from 12.1% in PVB group compared to 45.3% in the control group when

evaluating six month chronic neuropathic pain risk while controlling for confounding factors.12,15

While this may be a useful adjunct, adequate and appropriate pain control in cancer patients

continues to be a challenge both for the patients and providers.

Regional Nerve Blocks

Considering the significance of the opioid epidemic, many providers are incorporating

opioid sparing techniques and adjuncts in their practice. Additionally, there is evidence to

suggest opioids may potentiate tumor cell survival and angiogenesis which could lead to

metastasis in cancer patients.5,12,24 Regional nerve blocks are often cited as an effective alternative

for intra operative and post-operative pain control and may also reduce the development of

chronic pain in BC patients.2,4,12,24 Several studies show a decrease in intraoperative opioid use

and postoperative pain score in patients receiving PVB as part of their anesthetic

management.21,25,26 Patients who received a PVB had lower visual analog scores at 0, 2, 4, 12 and

24 hours with significantly prolonged duration of analgesia with lesser rescue analgesic

consumption up to 24 hours when compared to patients who received pectoral nerve blocks (I

and II).27 More specifically, a randomized control trial comparing patients who received a PVB

and propofol anesthetic to patients who received sevoflurane and fentanyl anesthetic reported a

reduction in visual analog pain scale scores by 21% and a decrease in fentanyl dose by 62% in

patients who received a PVB.25

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Because managing acute pain may prevent the development of chronic pain it is

important to manage acute surgical pain in BC patients.18,28 A randomized controlled trial looked

at chronic pain after radical mastectomy with PVB combined with TIVA general anesthesia

versus TIVA general anesthesia alone. They found decreased rates of chronic pain symptoms at

three and six months in the PVB group.18 Another study comparing chronic neuropathic pain

assessment tools, found PVB decreased the risk of chronic neuropathic pain at six months

postoperatively.15 A randomized control trial evaluating the long term effects of thoracic PVB in

BC surgery found patients who received a PVB had 45%–50% reduction in the incidence and

50% reduction in severity of chronic pain at three and six months.29

Regional anesthesia also has long-term benefits for cancer patients by attenuating the

surgical stress response, preservation of immune function, and direct anti-tumor effects of local

anesthetics.2,8,24,30 Studies have shown treatment with PVB coupled with propofol preserved

natural killer cell function compared to general anesthesia with sevoflurane and opioids.5,8,29,30

Use of PVB with BC surgery was also associated with decreased levels of inflammation and

growth factors with proliferative or angiogenesis effects.29,30 Another study described a

difference in tumor recurrence in patients who received volatile anesthetic with PVB at 6%

versus a volatile anesthetic and morphine PCA at 24% after three years.31 However, this is a

retrospective study done through chart reviews which does not allow for randomization and

limits the generalizability of any conclusions.2,8,24,30 Several other studies describe trends which

could indicate reduced BC recurrence, but the data did not reach statistical significance.2,6 The

first randomized controlled trial evaluating the long term effects of thoracic PVB in BC surgery

found no difference in recurrence rates at five years, however, the authors acknowledge the

sample size was insufficient to detect a treatment effect.29 Overall, given the low risk, relative
10

ease, and benefit of a regional nerve block, incorporating it into the anesthetic for BC patients

could provide significant benefit.

Dexmedetomidine

Adjunct medications, such as dexmedetomidine, have also shown promise in addressing

chronic pain in BC patients. Dexmedetomidine when added in preoperative PVB, at a dose of

1mcg/kg, decreased the amount of intravenous pain medication needed and improved the quality

and duration of analgesia of the PVB.32–35 One study reported intraoperative fentanyl

requirements for the control group was 77.3 mcg versus 54.6 mcg in the group with PVB and

dexmedetomidine. Control group postoperative total consumption of morphine was 17.4 mg

compared to the PVB and dexmedetomidine group which was 2.4mg.33 Dexmedetomidine also

shows benefit as an infusion. In a study published in 2012, researchers evaluated a perioperative

infusion of dexmedetomidine of 0.5ml/kg bolus initiated prior to induction followed by an

infusion of 0.25 ml/kg/h until the completion of surgery then decreased to 0.1 ml/kg/h and

continued for up to 24 hours.36 They found this protocol decreased pain scores and analgesia

requirements in the first 72 hours as well as decreased severity of chronic pain three months after

BC surgery.36 Another study demonstrated decreased postoperative consumption of morphine

when dexmedetomidine was given at the same dose as part of a TIVA.37

While this could be very beneficial to patients, dexmedetomidine carries some risks for

cancer patients. Because it is an alpha-2 agonist, dexmedetomidine has been shown to activate

alpha2- adrenoreceptors found in human breast cancer cells, which enhances cell proliferation.3,38

In animal models, dexmedetomidine has been found to increase metastasis in mice and rat

models after only a single exposure.39 It is hypothesized that dexmedetomidine may have effects

on vascular dilation and constriction, alteration in the expression of epithelial adhesion

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molecules, and increased capillary permeability to circulating tumor cells.39 Another study in

animal models reported dexmedetomidine had an effect on the migration of colorectal cancer

cells, but it did not reach statistical significance.40 While this has not been seen with in vivo

experiments on humans or in large retrospective studies, several randomized control trials are

ongoing to explore this potential risk.5,41,42 Therefore, dexmedetomidine should be used with

caution in cancer patients until additional research is conducted.

Ketorolac

Another medication which has shown additional benefit in BC patients is ketorolac. As

previously discussed, the development of chronic pain is closely associated with the

inflammatory process. Persistent sensitization of peripheral and central neurons can cause

transcriptional changes in the expression of genes coding for transmitters, ion channels,

receptors, and signaling molecules including cyclooxygenase-2 (COX-2).13 Ketorolac works by

inhibiting the enzymes that catalyze the synthesis of prostaglandins and thromboxanes. These

substances sensitize nociceptors in the periphery and block glycinergic neuronal inhibition which

enhances excitatory amino acid release at the spinal level.13 The result is decreased sensitization

of peripheral sensory neurons and attenuation of pain sensation at the spinal cord.13 Ketorolac

inhibits of key components in the pain pathway to prevent “wind-up.” It has been used to combat

both acute and chronic pain, however its side effect profile limits long term use.

Inflammation has long been known to play a significant role in cancer pathophysiology.21,43

A study done in animal models found decreased tumor development and reduced invasiveness in

mice with mammary tumors treated with R-ketorolac, an enantiomer of ketorolac.44 Another

recent animal study found ketorolac given preoperatively, not postoperatively, eliminated

micrometastases in multiple tumor-resection models.43 The authors described that with

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preoperative suppression of systemic inflammation or stimulation of inflammation resolution via

T cell immunity, there is potent antitumor activity.43 In retrospective studies, when ketorolac was

given preoperatively there was a fivefold reduction in recurrence in the 9 – 18 months after BC

surgery.9,44 However, a recent randomized control trial found that a single dose of 30mg

ketorolac preoperatively did not increase disease-free survival for high risk patients who met one

of the following criteria: a NLR ≥4, node-positive disease, or a triple- negative histology, though

lower risk patients were not evaluated.5,45 Another retrospective study found intraoperative

administration of 20-30 mg of ketorolac was associated with a statistically significant reduction

in early metastases in patients with a BMI greater than 25kg/m2 after unadjusted and adjusted

analysis.46 With little evidence to demonstrate ketorolac causes clinically significant blood loss,

and the potential benefits it may confer, the use of ketorolac during breast cancer surgeries seems

appropriate.21

Discussion

While it is difficult to draw indisputable conclusions from the current state of research,

there are trends which demonstrate these interventions may improve patient outcomes with

minimal adverse effects. Based on the evidence examined, preoperative placement of regional

anesthesia in the form of PVB and dosing of ketorolac, followed by a general anesthetic utilizing

a TIVA technique would be ideal for these patients. The benefits of these interventions can be

seen in table 1.

Limitations to these recommendations are evident as the majority of published literature

citing patient outcomes are retrospective reviews. While retrospective studies can identify trends,

these types of studies are difficult to apply due to inability to control extraneous variables,

randomize groups, and confidently link outcomes to specific treatment. Assembling randomized
13

control trials has unique challenges as well. When evaluating recurrence or chronic pain, patients

must maintain contact with over an extended period of time. Attrition is a common problem as

patients move, have surgery outside of the study, or develop other health problems. Challenges

arise in maintaining the volume of patients required to achieve significance. These are just a few

aspects which demonstrate the challenges of conducting research within the population with BC.

Several studies are currently recruiting to fill some of these gaps in our knowledge base.

Study NCT02839668 is recruiting patients to investigate the impact of intravenous anesthesia on

angiogenesis in BC patients.47 The follow-up time period is 10 years to determine the rate of

cancer recurrence or metastasis among patients with BC undergoing surgical therapy. Another

study, NCT03782896, is investigating the link between the perioperative period, acute surgical

pain, and chronic pain for BC patients.48 These are only a few of the studies ongoing to

determine if there is a link between anesthetic choices for these patients and the development of

recurrence or metastasis.

Conclusion

There is a link between anesthetic medications, immune function, and inflammatory

processes. Given the link from immune function to cancer recurrence, inflammation to chronic

pain, and the prevalence of BC within the surgical population it is essential anesthesia providers

are knowledgeable about the potential long-term effects of their anesthetic. Providers may find

other adjuncts individualized to the patient may optimize the patient’s perioperative course.
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Table 1.

Anesthetic Considerations and Recommendations for Patients Undergoing Breast Cancer

Surgery
Anesthetic Timing of intervention Benefit
Regional Preoperative placement  attenuates the surgical stress response

PVB  preserves immune function

 direct anti-tumor effects of local anesthetics

 decreased levels of inflammation and growth

factors with proliferative/angiogenesis effects

Ketorolac Preoperative dosing  suppresses systemic inflammation

 stimulates resolution of inflammation via T cell

immunity

 potent antitumor activity

Propofol Induction and  suppresses migration and invasion of cancer cells

TIVA Maintenance of  anti-inflammatory effect targeting neutrophil

Anesthesia activity.

 decreases the likelihood of chronic pain

postoperatively
PVB = paravertebral nerve block; TIVA = total intravenous anesthetic [2,8,43,44,9,11,12,15,16,24,29,30]
15

References

1. U.S. Cancer Statistics Working Group. United States Cancer Statistics: Data

Visualizations. U.S. Department of Health and Human Services, Centers for Disease

Control and Prevention and National Cancer Institute.

2. Starnes-Ott K, Goravanchi F, Meininger JC. Anesthetic Choices and Breast Cancer

Recurrence: A Retrospective Pilot Study of Patient, Disease, and Treatment Factors. Crit

Care Nurs Q. 2015;38(2):200-210. doi:10.1097/CNQ.0000000000000062

3. Yang W, Cai J, Zabkiewicz C, Zhang H, Ruge F, Jiang WG. The Effects of Anesthetics on

Recurrence and Metastasis of Cancer, and Clinical Implications. World J Oncol.

2017;8(3):63-70. doi:10.14740/wjon1031e

4. Andersen KG, Kehlet H. Persistent pain after breast cancer treatment: A critical review of

risk factors and strategies for prevention. J Pain. 2011;12(7):725-746.

doi:10.1016/j.jpain.2010.12.005

5. Forget P, Aguirre JA, Bencic I, et al. How Anesthetic, Analgesic and Other Non-Surgical

Techniques During Cancer Surgery Might Affect Postoperative Oncologic Outcomes: A

Summary of Current State of Evidence. Cancers (Basel). 2019;11(5):592.

doi:10.3390/cancers11050592

6. Koonce SL, McLaughlin SA, Eck DL, et al. Breast cancer recurrence in patients receiving

epidural and paravertebral anesthesia: A retrospective, case-control study. Middle East J

Anesthesiol. 2014;22(6):567-571.

7. Stollings LM, Jia LJ, Tang P, Dou H, Lu B, Xu Y. Immune modulation by volatile

anesthetics. Anesthesiology. 2016;125(2):399-411. doi:10.1097/ALN.0000000000001195

8. Ní Eochagáin A, Burns D, Riedel B, Sessler DI, Buggy DJ. The effect of anaesthetic
16

technique during primary breast cancer surgery on neutrophil–lymphocyte ratio, platelet–

lymphocyte ratio and return to intended oncological therapy. Anaesthesia.

2018;73(5):603-611. doi:10.1111/anae.14207

9. Forget P, Bentin C, Machiels JP, Berliere M, Coulie PG, De Kock M. Intraoperative use

of ketorolac or diclofenac is associated with improved disease-free survival and overall

survival in conservative breast cancer surgery. Br J Anaesth. 2014;113(SUPPL. 1):i82-i87.

doi:10.1093/bja/aet464

10. Ahmad A. Pathways to Breast Cancer Recurrence. ISRN Oncol. 2013;2013:1-16.

doi:10.1155/2013/290568

11. Enlund M, Berglund A, Andreasson K, Cicek C, Enlund A, Bergkvist L. The choice of

anaesthetic-sevoflurane or propofol-and outcome from cancer surgery: A retrospective

analysis. Ups J Med Sci. 2014;119(3):251-261. doi:10.3109/03009734.2014.922649

12. Li R, Liu H, Dilger JP, Lin J. Effect of Propofol on breast Cancer cell, the immune

system, and patient outcome. BMC Anesthesiol. 2018;18(1):1-8. doi:10.1186/s12871-018-

0543-3

13. Stein C, Kopf A. Management of the patient with chronic pain. In: Miller’s Anesthesia.

Ninth Edit. Elsevier; 2019:1604-1621. doi:10.1016/j.cnc.2014.10.001

14. Shah R, Rosso K, Nathanson D. Pathogenesis, prevention, diagnosis and treatment of

breast cancer. World J Clin Oncol. 2014;5(3):283. doi:10.5306/wjco.v5.i3.283

15. Abdallah FW, Morgan PJ, Cil T, Escallon JM, Semple JL, Chan VW. Comparing the DN4

tool with the IASP grading system for chronic neuropathic pain screening after breast

tumor resection with and without paravertebral blocks: a prospective 6-month validation

study. Pain. 2015;156(4):740-749. doi:10.1097/j.pain.0000000000000108

17

16. Cho AR, Kwon JY, Kim KH, et al. The effects of anesthetics on chronic pain after breast

cancer surgery. Anesth Analg. 2013;116(3):685-693.

doi:10.1213/ANE.0b013e31827ee372

17. Wooden S, Nagelhout J, Elisha S. Chronic Pain: Physiology and Management. In: Nurse

Anesthesia. Vol 6. sixth. ; 2018:1183-1193. doi:10.7727/wimj.2014.285.63.

18. Karmakar MK, Samy W, Li JW, et al. Thoracic paravertebral block and its effects on

chronic pain and health-related quality of life after modified radical mastectomy. Reg

Anesth Pain Med. 2014;39(4):289-298. doi:10.1097/AAP.0000000000000113

19. Chiu M, Bryson GL, Lui A, Watters JM, Taljaard M, Nathan HJ. Reducing persistent

postoperative pain and disability 1 year after breast cancer surgery: A randomized,

controlled trial comparing thoracic paravertebral block to local anesthetic infiltration. Ann

Surg Oncol. 2014;21(3):795-801. doi:10.1245/s10434-013-3334-6

20. Yan T, Zhang GH, Wang BN, Sun L, Zheng H. Effects of propofol/remifentanil-based

total intravenous anesthesia versus sevoflurane-based inhalational anesthesia on the

release of VEGF-C and TGF-β and prognosis after breast cancer surgery: A prospective,

randomized and controlled study. BMC Anesthesiol. 2018;18(1):1-9. doi:10.1186/s12871-

018-0588-3

21. Eden C, Esses G, Katz D, DeMaria S. Effects of anesthetic interventions on breast cancer

behavior, cancer-related patient outcomes, and postoperative recovery. Surg Oncol.

2018;27(2):266-274. doi:10.1016/j.suronc.2018.05.001

22. Ash SA, Buggy DJ. Does regional anaesthesia and analgesia or opioid analgesia influence

recurrence after primary cancer surgery? An update of available evidence. Best Pract Res

Clin Anaesthesiol. 2013;27(4):441-456. doi:10.1016/j.bpa.2013.10.005

18

23. Wu ZF, Lee MS, Wong CS, et al. Propofol-based total intravenous anesthesia is

associated with better survival than desflurane anesthesia in colon cancer surgery.

Anesthesiology. 2018;129(5):932-941. doi:10.1097/ALN.0000000000002357

24. P Balakrishnan DK. Regional anaesthesia in breast cancer: Benefits beyond pain. Indian J

Anesth. 2017;61(18):622-628. doi:10.4103/ija.IJA

25. Pei L, Zhou Y, Tan G, et al. Ultrasound-assisted thoracic paravertebral block reduces

intraoperative opioid requirement and improves analgesia after breast cancer surgery: A

randomized, controlled, single-center trial. PLoS One. 2015;10(11):1-14.

doi:10.1371/journal.pone.0142249

26. Terkawi AS, Tsang S, Sessler DI, et al. Improving analgesic efficacy and safety of

thoracic paravertebral block for breast surgery: A mixed-effects meta-analysis. Pain

Physician. 2015;18(5):E757-E780.

27. Syal K, Chandel A. Comparison of the post-operative analgesic effect of paravertebral

block, pectoral nerve block and local infiltration in patients undergoing modified radical

mastectomy: A randomised double-blind trial. Indian J Anaesth. 2017.

doi:10.4103/ija.IJA_81_17

28. Ilfeld BM, Madison SJ, Suresh PJ, et al. Persistent Postmastectomy Pain and Pain-Related

Physical and Emotional Functioning With and Without a Continuous Paravertebral Nerve

Block: A Prospective 1-Year Follow-Up Assessment of a Randomized, Triple-Masked,

Placebo-Controlled Study. Ann Surg Oncol. 2015;22(6):2017-2025. doi:10.1245/s10434-

014-4248-7

29. Karmakar MK, Samy W, Lee A, et al. Survival analysis of patients with breast cancer

undergoing a modified radical mastectomy with or without a thoracic paravertebral block:

19

A 5-year follow-up of a randomized controlled trial. Anticancer Res. 2017;37(10):5813-

5820. doi:10.21873/anticanres.12024

30. Pérez-González O, Cuéllar-Guzmán LF, Soliz J, Cata JP. Impact of Regional Anesthesia

on Recurrence, Metastasis, and Immune Response in Breast Cancer Surgery. Reg Anesth

Pain Med. 2017;42(6):751-756. doi:10.1097/aap.0000000000000662

31. Exadaktylos AK, Buggy DJ, Moriarty DC, Mascha E, Sessler DI. Can anesthetic

technique for primary breast cancer surgery affect recurrence or metastasis?

Anesthesiology. 2006;105(4):660-664. doi:10.1097/00000542-200610000-00008

32. Mohamed SA, Fares KM, Mohamed AA, Alieldin NH. Dexmedetomidine as an

adjunctive analgesic with bupivacaine in paravertebral analgesia for breast cancer surgery.

Pain Physician. 2014;17(5):E589-98. http://www.ncbi.nlm.nih.gov/pubmed/25247908.

33. Mohta M, Kalra B, Sethi AK, Kaur N. Efficacy of dexmedetomidine as an adjuvant in

paravertebral block in breast cancer surgery. J Anesth. 2016;30(2):252-260.

doi:10.1007/s00540-015-2123-8

34. Kakkar B, Gupta L, Gupta A, Kakkar K. Comparative evaluation of analgesic sparing

efficacy between dexmedetomidine and clonidine used as adjuvant to ropivacaine in

thoracic paravertebral block for patients undergoing breast cancer surgery: A prospective,

randomized, double-blind study. Saudi J Anesth. 2017;11(4):1-2. doi:10.4103/sja.SJA

35. Bakr M, Mohamed S, Mohamad M, et al. Effect of Dexmedetomidine Added to Modified

Pectoral Block on Postoperative Pain and Stress Response in Patient Undergoing

Modified Radical Mastectomy. Pain Physician. 2018;21(2):87-96.

36. Jain G, Ahmad B, Yadav G, Bansal P, Singh D. Effect of the perioperative infusion of

dexmedetomidine on chronic pain after breast surgery. Indian J Palliat Care.

20

2012;18(1):45. doi:10.4103/0973-1075.97354

37. Fan W, Xue H, Sun Y, et al. Dexmedetomidine improves postoperative patient-controlled

analgesia following radical mastectomy. Front Pharmacol. 2017;8(MAY):1-5.

doi:10.3389/fphar.2017.00250

38. Xia M, Ji NN, Duan ML, et al. Dexmedetomidine regulate the malignancy of breast

cancer cells by activating α2-adrenoceptor/ERK signaling pathway. Eur Rev Med

Pharmacol Sci. 2016;20(16):3500-3506.

39. Lavon H, Matzner P, Benbenishty A, et al. Dexmedetomidine promotes metastasis in

rodent models of breast, lung, and colon cancers. Br J Anaesth. 2018;120(1):188-196.

doi:10.1016/j.bja.2017.11.004

40. Deng F, Ouyang M, Wang X, et al. Differential role of intravenous anesthetics in

colorectal cancer progression: Implications for clinical application. Oncotarget.

2016;7(47):77087-77095. doi:10.18632/oncotarget.12800

41. NCT03109990. Impact of Dexmedetomidine on Breast Cancer Recurrence After Surgery.

Https://clinicaltrials.gov/show/nct03109990. 2017.

42. NCT03108937. Effects of Dexmedetomidine on Breast Cancer Cell Function in Vitro.

Https://clinicaltrials.gov/show/nct03108937. 2017.

43. Panigrahy D, Gartung A, Yang J, et al. Preoperative stimulation of resolution and

inflammation blockade eradicates micrometastases. J Clin Invest. 2019;129(7):2964-2979.

doi:10.1172/JCI127282

44. Peretti AS, Dominguez D, Grimes MM, et al. The R-Enantiomer of Ketorolac Delays

Mammary Tumor Development in Mouse Mammary Tumor Virus-Polyoma Middle T

Antigen (MMTV-PyMT) Mice. Am J Pathol. 2018;188(2):515-524.

21

doi:10.1016/j.ajpath.2017.10.018

45. Berliere M, Bouche G, Duhoux FP, et al. Abstract P1-20-01: Intraoperative ketorolac in

high-risk breast cancer patients with and without inflammation. A prospective,

randomized, placebo-controlled clinical trial. In: Poster Session Abstracts. In Proceedings

of the 2018 San Antonio Breast Cancer Symposium, San Antonio, TX, USA, 4–8

December 2018.: American Association for Cancer Research; 2019:P1-20-01-P1-20-01.

doi:10.1158/1538-7445.SABCS18-P1-20-01

46. Desmedt C, Demicheli R, Fornili M, et al. Potential benefit of intra-operative

administration of ketorolac on breast cancer recurrence according to the patient’s body

mass index. J Natl Cancer Inst. 2018;110(10):1115-1122. doi:10.1093/jnci/djy042

47. NCT02839668. The Impact of Intravenous Anaesthesia on Angiogenesis in Patients With

Breast Cancer (TIVA/TCI-BC). https://clinicaltrials.gov/show/NCT02839668. 2016.

48. NCT03782896. The Effects of Anesthetics on Persistent Pain Following Breast Cancer

Surgery. https://clinicaltrials.gov/ct2/show/study/NCT03782896. 2018.