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Anesth Analg 2005;100:244-249
© 2005 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000143336.37946.7D

REGIONAL ANESTHESIA

Terese T. Horlocker Section Editor

Inhibition of the Stress Response to Breast Cancer Surgery by Regional Anesthesia and Analgesia Does Not Affect Vascular Endothelial Growth Factor and Prostaglandin E2

S. C. O’Riain, FCARCSI*, D. J. Buggy, MD, MSc, DME, FRCPI, FCARCSI, FRCA*,{dagger},{ddagger}, M. J. Kerin, MCh, FRCSI, FRCSGen{dagger},{ddagger}, R. W. G. Watson, PhD{dagger}, and D. C. Moriarty, FCARCSI*,{ddagger}

*Department of Anaesthesia and Intensive Care Medicine, Mater Misericordiae University Hospital; {dagger}Conway Institute of Biomolecular and Biomedical Research, University College Dublin; and the {ddagger}National Breast Screening Programme, Dublin, Ireland

Address correspondence and reprint requests to Dr. Seosamh O’Riain, Department of Anaesthesia, Regional Hospital Limerick, Limerick, Ireland. Address e-mail to oriains{at}gofree.indigo.ie


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Angiogenesis is essential for breast cancer metastases formation and is mediated by vascular endothelial growth factor (VEGF) and prostaglandin E2 (PGE2). We hypothesized that serum levels of VEGF and PGE2 are increased by the stress response to breast cancer surgery and attenuated by paravertebral anesthesia and analgesia (PVAA). Thirty women undergoing mastectomy were enrolled in this prospective, randomized study, to receive general anesthesia (GA) and postoperative opioid analgesia (morphine 0.1 mg/kg bolus and patient-controlled infusion) or GA and PVAA (72-h infusion). All patients received rectal diclofenac. Venous blood samples were taken preoperatively and at 4 and 24 h postoperatively for serum glucose, cortisol, C-reactive protein, VEGF, and PGE2. PVAA inhibited the surgical stress response, as indicated by significantly less plasma glucose, cortisol, and C-reactive protein. VEGF and PGE2 values did not differ significantly between the groups. Mean (SD) percentage change in VEGF at 4 and 24 h respectively were 3% ± 44% versus 9% ± 80%, P = 0.29 and 5% ± 43% versus –10% ± 63%, P = 0.41 for patients with combined general and PVAA and GA alone, respectively. Mean percentage change in postoperative PGE2 at 4 and 24 h respectively was 10% ± 17% versus 11% ± 69%, P = 0.29 and 34% ± 19% versus 47% ± 18%, P = 0.15. We conclude that despite inhibiting the surgical stress response, PVAA had no effect on serum levels of putative breast cancer angiogenic factors, VEGF and PGE2.

IMPLICATIONS: In a prospective, randomized, double-blind study, inhibition of the surgical stress response by paravertebral regional anesthesia and analgesia had no effect on serum levels of putative breast cancer angiogenic factors, vascular endothelial growth factor and prostaglandin E2, compared with general anesthesia and postoperative opioid analgesia.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Breast cancer is the leading cause of cancer death among women (1). Like many other forms of cancer, it requires an independent blood supply to enlarge and develop metastases. This process, angiogenesis, is mediated by vascular endothelial growth factor (VEGF) and prostaglandin E2 (PGE2), which are associated with metastatic disease in breast cancer (2,3).

Over the last decade, many potentially angiogenic growth factors and their receptors have been found, both in serum and primary breast cancer tissue (4). VEGF is associated with breast cancer development, changes in cellular signaling, and local invasion (3). VEGF is also associated with blood-borne tumor metastases (5) and growth of lymphatic vessels by tumors (lymphangiogenesis) (6). Davies and Martin (7) suggested that suppression of prostaglandin synthesis via cyclooxygenase type-2 (COX-2) enzyme inhibition may reduce the incidence of some cancers, including breast cancer.

The stress response to surgery is a major neuroendocrine and cytokine response to surgical trauma, characterized by increases in catecholamine and steroid hormones, with predictable metabolic consequences, including hyperglycemic and negative nitrogen balance (8). This may be attenuated by regional anesthesia, even if given in conjunction with general anesthesia (GA) (9). It is possible that cytokines increased by the surgical stress response may be linked with some of the angiogenic factors associated with breast cancer metastases. Many interleukins and prostaglandins are directly increased by the stress response (10). Perhaps VEGF and PGE2 may also be affected directly or indirectly by the surgical stress response, but this has not been investigated.

Therefore, we tested the hypothesis that serum levels of breast cancer angiogenic factors VEGF and PGE2 are increased in association with the stress response to breast cancer surgery and that this may be attenuated by paravertebral regional anesthesia and analgesia (PVAA).


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After Hospital Ethics Committee approval and written informed consent, 30 women with biopsy-proven breast cancer requiring mastectomy with axillary node clearance were enrolled in this prospective, randomized study, to receive GA and postoperative opioid patient-controlled analgesia (PCA) (GA group) or combined GA and paravertebral anesthesia with continuous postoperative paravertebral analgesia (GA-PVAA group).

Inclusion criteria were patients with biopsy-proven breast cancer, aged 21–75 yr, scheduled for segmental mastectomy and axillary node dissection in a single procedure. Exclusion criteria were women who had previous surgery within the preceding 2 wk, those other than ASA physical status I or II, or patients with any contraindication to either paravertebral anesthesia or opioid analgesia. All patients were counseled preoperatively about paravertebral anesthesia, PCA, and visual analog scales (VAS) for pain assessment.

Patients randomized to the GA-PVAA group had a catheter positioned in the ipsilateral paravertebral space, at the third or fourth thoracic vertebral level, before induction of GA, using a standard technique (11). After a test dose of 5 mL bupivacaine 0.25%, a further 10 mL was added over the next 5 min and an infusion of the same was commenced at a rate of 10 mL/h. Paravertebral catheters were removed approximately 48 h after insertion, in line with our unit’s clinical practice. In the event of block failure (defined as requiring supplemental analgesia, excluding local), patients were to commence morphine PCA as per the GA group.

GA was then induced with fentanyl (1–2 µg/kg) and propofol (2.5 mg/kg). After placement of a laryngeal mask airway, anesthesia was maintained with sevoflurane (end-tidal concentrations 1%–3%) in a 50% oxygen/nitrous oxide mixture.

The method of anesthesia was identical for the GA group. For analgesia, they received bolus morphine totaling 0.1 mg/kg during surgery, and were commenced on PCA with a morphine bolus of 1 mg, lockout time 6 min, and a 4-h dose limit of 30 mg. Both groups of patients received 100 mg of diclofenac per rectum before surgery.

Immediately after surgery, patients were taken to the recovery room where static and dynamic pain were assessed using a VAS. The anesthesiologist involved in pain assessment was blinded to group assignment. Patients in the GA-PVAA group had dermatomal sensory level assessed using ice in a standard manner. Pain and dermatomal sensory level were also recorded at 4–6 h and again at 24 h. Patients in the GA group received bolus morphine totaling 0.1 mg/kg during surgery, and were commenced on PCA with a morphine bolus of 1 mg, lockout time 6 min, and a 4-h dose limit of 30 mg.

Peripheral venepuncture was performed before the induction of GA, 4–6 h postoperatively, and again at 20–24 h. Samples were sent for serum cortisol, glucose, and C-reactive protein (CRP). Additional samples underwent centrifugation at 1000g and plasma was stored at –20°C. Both VEGF and PGE2 were measured using a high sensitivity enzyme immunoassay kit using the QuantikineTM Enzyme Immunoassay System (R&D Systems Europe, Abingdon, UK), in accordance with the manufacturer’s instructions.

Previous work on VEGF has suggested that its standard deviation in vivo is in the order of 200 pg/mL (2,3,5). We took a reduction of 1 standard deviation, 200 pg/mL, as being clinically significant, therefore n = 15 patients would be required in each group to demonstrate this difference, assuming a Type I error of 0.05 and a Type II error of 0.2. Data were stored in coded form on an Excel 2000 spreadsheet and analyzed on GraphPad Prism version 3.0. Distribution of data was assessed using the Kolmogorov-Smirnov test. For VEGF and PGE2, preoperative values were taken as baseline and percentage change at 4 h and 24 h was calculated with preoperative values as denominator. Within-group and between-group differences for changes in serum values were tested using within-group and independent-group analysis of variance, respectively. Differences in interval data (VAS pain scores) were tested by the Kruskal-Wallis test. P < 0.05 was taken to indicate statistical significance.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
All 30 patients completed the study according to the protocol. Fifteen patients were allocated to both the GA-PVAA group and the GA group. The same team of anesthesiologists and surgeons performed all procedures. All paravertebral anesthetic blocks were successful. Patient characteristics and details of breast cancer pathology and surgical staging are shown in Table 1 (12, 13) . There were no significant differences between the groups.


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  		Table 1. Patient Characteristics
 
Serum glucose levels were lower at 4 h in the paravertebral group compared with patients receiving GA alone (102 ± 17 versus 130 ± 23 mg · dL–1 · L–1 respectively, P = 0.001) (Fig. 1A). Similarly, the group GA-PVAA had lower serum cortisol and CRP at 4 h than group GA (322 ± 152 versus 544 ± 216 µmol/L, respectively, P = 0.006 (Fig. 1, B and C). There were no significant differences in glucose or cortisol at 24 h. CRP, however, was increased in the GA group at 4 h and 24 h compared with the GA-PVAA group (4 h: 5.7 ± 2.9 versus 2.6 ± 1.5, P = 0.002; 24 h: 30.0 ± 7.2 versus 23.3 ± 6.0, P = 0.04, respectively).



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  		Figure 1. Serum glucose (A), cortisol (B), and C-reactive protein (CRP) (C) values at preoperative (zero), 4 h, and 24 h. In each case, patients in the general anesthesia (GA) and paravertebral anesthesia group (PVAA) had significantly lower values at 4 h compared with GA alone. *P < 0.05.

 
Both static and dynamic VAS pain scores are shown in Figure 2, A and B and were consistently lower in GA-PVAA than GA patients; median (interquartile range) VAS on movement at 4 h was 2 (1–4) versus 3.5 (2–5), respectively, P = 0.04 and 1.0 versus 2.5 (1–4), P = 0.03 at 24 h.



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  		Figure 2. Visual analog scale (VAS) of pain at rest (A) and on moving the ipsilateral arm in circumferential movements (B). Patients in the general and paravertebral anesthesia group (GA-PVAA) had significantly less pain at all time points. *P < 0.05.

 
Table 2 shows actual values of VEGF and PGE2. No significant differences were observed at any time interval. Similarly, no significant difference was observed between postoperative and preoperative values of VEGF and PGE2 in either group.


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  		Table 2. Vascular Endothelial Growth Factor (VEGF) and Prostaglandin E2 (PGE2)
 
The interbatch coefficients of variation for the PGE2 and VEGF assays were 7.2%–8% and there was no significant cross-reactivity or interference from related proteins. Because of large variability in normal levels for both VEGF and PGE2, preoperative values were taken as baseline and percentage change at 4 h and 24 h was calculated with preoperative values as denominator. Mean percentage change in VEGF values at 4 h were 3% ± 44% versus 9% ± 80% for patients receiving GA-PVAA and those receiving GA alone, respectively, which was not statistically significant. This was also demonstrated at 24 h: mean percentage change was 5% ± 43% versus –10% ± 63%, respectively, which was not statistically significant (Fig. 3).



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  		Figure 3. Percentage change in vascular endothelial growth factor (VEGF) postoperatively compared with preoperative values. GA = general anesthesia, PVAA = patients given general and paravertebral anesthesia.

 
Similarly, mean percentage change in postoperative PGE2 levels at 4 h was 10% ± 17% versus 11% ± 69% and at 24 h was 34% ± 19% versus 47% ± 88%, for the GA-PVAA combined and GA alone, respectively, reflecting no statistically significant differences (Fig. 4.)



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  		Figure 4. Percentage change in prostaglandin (PG)E2 values postoperatively compared with preoperative values. GA = general anesthesia, PVAA = patients given general and paravertebral anesthesia.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
This study has demonstrated that GA-PVAA reduces the surgical stress response to mastectomy and axillary node dissection and provides superior analgesia compared with GA alone, consistent with other studies (11,14). However, there were no significant changes in serum VEGF and PGE2 levels postoperatively compared with preoperative levels. Moreover, our observation of inhibition of the surgical stress response was not correlated with any significant reduction in postoperative VEGF and PGE2.

The stress response to cancer surgery has a tumor-promoting effect in an experimental model of breast cancer, possibly by catecholamine release from the adrenal glands leading to natural killer T-cell suppression and decreased host resistance to metastatic development (15). This effect has been reduced by regional (spinal) anesthesia in this experimental model (16). Inadvertent perioperative hypothermia may also inhibit natural killer T-cells possibly by an adrenergic mechanism (17), adding credibility to the suggestion that perioperative factors may potentially influence resistance to metastatic spread, and hence long-term outcome from breast cancer.

Encouragingly, there is also experimental evidence that optimizing perioperative pain management may attenuate surgery-induced decreases in host resistance against metastases (18). Although our patients receiving PVAA also had significantly lower postoperative pain scores, our study does not support the hypothesis that this may be associated with inhibition of putative angiogenic factors.

There is currently no evidence-based publication defining the dose of local anesthetic required for paravertebral block in breast anesthesia. A dose of 3 mL per dermatome has been recommended (19), suggesting that 15 mL of local anesthetic solution would block dermatomes T1–5 for breast surgery. In this study, dermatomal sensory levels in a range from C8 to T6 were observed. All paravertebral blocks were deemed successful because no supplemental analgesia was required. Although pain scores were significantly lower in the PVAA group, some low-intensity residual pain was documented. It is possible that a degree of incomplete block may partially explain our observed lack of difference in VEGF and PGE2 levels.

The nonsteroidal antiinflammatory drug (NSAID), diclofenac, was given to all patients. The decision to administer this drug was based on the potential for inadequate analgesia, which could have occurred with failure of block in the GA-PVAA group. Moreover, the addition of an NSAID is a standard component of our balanced analgesia after breast surgery. The potential confounding effect of diclofenac use on differences in postoperative prostaglandin levels is eliminated by its administration to both randomized groups.

VEGF is an angiogenic growth factor, which exists in four isoforms. Its physiological effects include enhanced vascular permeability, vasodilatation induced by nitric oxide, and ligand-binding properties (20,21). The expression of VEGF by breast tumors has been previously correlated with a poor prognosis in the pathogenesis of breast cancer (2). It is a prerequisite for tumor development, stimulating endothelial cells and is influenced by the menstrual cycle, as well as being an independent prognostic indicator in early breast cancer (22,23).

PGE2 is produced by the action of prostaglandin synthetase and COX on arachidonic acid liberated from membrane phospholipids. In the immune system, antigen presenting cells, such as macrophages and dendrite cells, mainly produce PGE2. Angiogenesis is reportedly enhanced by prostaglandins. One study suggested that the use of NSAIDs, particularly COX-2 inhibitors, may reduce the incidence of breast cancer (24). All patients in our study received diclofenac before surgical incision, which may have influenced PGE2 levels postoperatively.

We evaluated percentage change in VEGF and PGE2 because more biological variability is expected in levels of these cytokines. Our finding that the inhibition of the stress response to surgery did not influence PGE2 and VEGF levels may be related to several factors. Expression of VEGF and its receptors is increased in patients with coronary heart disease (25). In a study of 30 patients, 27 were postmenopausal, an age group with increased atherosclerosis. This study took no account of postmenopausal duration or use of hormone replacement therapy; however, previous studies suggest that neither of these factors are important (26).

In vivo studies show increased expression of VEGF protein after trauma and surgery (27), suggesting a direct link between surgical insult and VEGF levels. All patients in our study had mastectomy and axillary node dissection, and thus had comparable levels of surgical trauma, and formal tumor, node, and metastases staging levels.

This study has demonstrated no link between VEGF or PGE2 and the surgical stress response within the first 24 hours. Levels of the stress hormones had not fully returned to baseline levels by then, which left open the possibility that inhibition of the surgical stress response by paravertebral anesthesia might have influenced later VEGF levels, e.g., at one week after surgery, but this is unknown at present.

In summary, this prospective, randomized study has demonstrated that PVAA reduced the stress response to breast cancer surgery, but not VEGF and PGE2 levels, compared with GA and postoperative opioid analgesia. This raises important questions about the link between surgical stress and inflammatory activation. The potential influence of regional anesthetic techniques on breast cancer patient angiogenic factors and other immunological indices of resistance to metastatic spread of tumor remain to be elucidated.


   Acknowledgments
 
This study was funded by a grant from The Mater College.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication August 10, 2004.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2005 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press