British Journal of Anaesthesia 109 (2): 2539 (2012)

Advance Access publication 15 June 2012 . doi:10.1093/bja/aes176

REGIONAL ANAESTHESIA

Can regional anaesthesia for lymph-node dissection improve

the prognosis in malignant melanoma?
A. Gottschalk 1*, G. Brodner 2, H. K. Van Aken 1, B. Ellger 1, S. Althaus 1 and H.-J. Schulze 3
1
Department of Anaesthesiology, Intensive Care and Pain Medicine, University Hospital Munster, Munster, Germany
2
Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy and 3 Department of Dermatology, Hornheide Specialist
Hospital, Munster, Germany
* Corresponding author: Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Munster, Albert-Schweitzer-
Campus 1, Building A1, 48149 Munster, Germany. E-mail: antjegottschalk@gmx.net

Editors key points
Understanding the
impact of anaesthetic
technique on cancer
survival is important.
There is some evidence
that regional techniques
may improve long-term
outcomes after cancer
surgery.
This retrospective study
of malignant melanoma
patients found a
non-significant trend for
improved survival after
spinal anaesthesia.
While there are
limitations in a
retrospective study, this
important area clearly
warrants further
research.
Background. Optimized anaesthetic management might improve the outcome after cancer
surgery. A retrospective analysis was performed to assess the association between spinal
anaesthesia (SpA) or general anaesthesia (GA) and survival in patients undergoing
surgery for malignant melanoma (MM).
Methods. Records for 275 patients who required SpA or GA for inguinal lymph-node dissection
after primary MM in the lower extremity between 1998 and 2005 were reviewed. The follow-up
ended in 2009. Survival was calculated as days from surgery to the date of death or last
patient contact. The primary endpoint was mortality during a 10 yr observation period.
Results. Of 273 patients included, 52 received SpA and 221 GA, either as balanced
anaesthesia (sevoflurane/sufentanil, n118) or as total i.v. anaesthesia (propofol/
remifentanil, n103). The mean follow-up period was 52.2 (SD 35.69) months after
operation. Significant effects on cumulative survival were observed for gender, ASA
status, tumour size, and type of surgery (P0.000). After matched-pairs adjustment, no
differences in these variables were found between patients with SpA and GA. A trend
towards a better cumulative survival rate for patients with SpA was demonstrated [mean
survival (months), SpA: 95.9, 95% confidence interval (CI), 81.2110.5; GA: 70.4, 95% CI,
53.6 87.1; P0.087]. Further analysis comparing SpA with the subgroup of balanced
volatile GA confirmed this trend [mean survival (months), SpA: 95.9, 95% CI, 81.2 110.5;
volatile balanced anaesthesia: 68.5, 95% CI, 49.6 87.5, P0.081].
Conclusions. These data suggest an association between anaesthetic technique and cancer
outcome in MM patients after lymph-node dissection. Prospective controlled trials on this
topic are warranted.
Keywords: anaesthesia, general; anaesthesia, spinal; melanoma; surgery; survival
Accepted for publication: 5 March 2012

Cancer is a heterogeneous disease. In most cases, surgeons
can successfully remove the primary tumour, but a large pro-
portion of cancer-related deaths are due to the development
of metastases rather than directly related to the primary
cancer. Potentially, curative surgery may contribute to meta-
static spread: it suppresses the immune system, facilitates
the growth of pre-existing micrometastases, and allows ma-
lignant cells to disseminate during tumour manipulation.1 2
Preventing immunosuppression during the immediate post-
operative period might be extremely important, as there is
a high risk of tumour cells spreading during this period.3
Both cell-mediated and humoural immune responses are ad-
versely affected by general anaesthesia (GA) and surgical
trauma, and this may result in tumour progression. In vitro
studies have shown dose-dependent alterations in neutro-
phil, monocyte, and lymphocyte functions after exposure to
different anaesthetics.3
Spinal anaesthesia (SpA), which for most operations in the
lower body provides very good analgesia, attenuates the sur-
gical stress response and prevents inhibition of the immune

These authors contributed equally to this paper.

This article is accompanied by Editorial III.

& The Author [2012]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.
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BJA
system. In an animal model, it has been shown that innate
tumour immunity is impaired through inhibition of the cyto-
toxic Th1 response of hepatic mononuclear cells after lower
abdominal surgery. Spinal block attenuates this impairment,
thereby inhibiting the promotion of metastatic spread after
surgery.4 5
A survival analysis of patients with malignant melanoma
(MM) showed an improved survival rate after primary excision
of the malignant tumour under local anaesthesia in compari-
son with GA.6 Sole use of local anaesthesia is, however, often
not possible in various types of surgery. In addition, there
have been no prospective clinical trials so far that have
been adequately powered to assess long-term survival rela-
tive to different anaesthetic techniques, and no definitive
conclusions can therefore be drawn.
The prognostic impact of the type of anaesthesia used for
excision of malignant tumours is thus currently a matter of
controversy. The present retrospective study was therefore
carried out to allow improved hypothesis formation regard-
ing the long-term effects of anaesthesia. The aim of the
study was to assess the association between SpA or GA
and cancer survival after lymph-node dissection in patients
with MM. It was hypothesized that the use of SpA would
improve the survival rate in these patients.
Methods
After ethical approval for the retrospective study had been
received (from the ethical committee of the Medical
Council of Westphalia-Lippe and from the Medical School of
the University of Munster, Germany), records were reviewed
for all patients who had required anaesthesia for inguinal
lymph-node dissection after primary MM in the lower extrem-
ity between February 1998 and April 2005 at the Department
of Anaesthesia, Intensive Care and Pain Medicine, Hornheide
Hospital, Munster, Germany. The follow-up period ended in
May 2009.
A total of 353 surgical records were reviewed. The proce-
dures included 247 sentinel lymph-node biopsies (SLNBs)
and 101 complete lymph-node dissections (CLNDs), and the
type of surgery could not be determined in five records.
These five operations were excluded from further analyses.
Seventy-three operations were identified as duplicatesthat
is, with SLNB followed by CLND in the same patient. In these
duplicates, the SLNB was excluded and only the CLND was
used for analysis. Records for a total of 275 cases were thus
analysed: 174 SLNBs (247 73) and 101 CLNDs. Two patients
were excluded due to incomplete data sheets lacking import-
ant information, and 273 patients remained for the final ana-
lyses. Fifty-two patients received SpA and 221 underwent
surgery with GA. GA was administered either as balanced GA
(n118) or as total i.v. anaesthesia (n103) (Fig. 1).
Hornheide Specialist Hospital is the main national cancer
institute for the treatment of skin malignancies in Germany
and is one of the major institutes for this type of cancer in
Europe. The hospital incidence of MM amounted to more
than 1000 patients in 2009. The centre has been certified in
254
Gottschalk et al.
accordance with DIN EN ISO 9001/2000 as a centre for the
treatment of skin cancer. The melanoma team consists of a
combination of specialists, including surgeons, dermatologists,
pathologists, medical oncologists, and also anaesthesiologists.
The hospitals Department of Medical Documentation is re-
sponsible for maintaining the database of primary and follow-
up information on patients tumour status.
After the primary operation, patients receive annual
follow-up examinations, which include an interview, physical
examination, ultrasound of the lymph nodes, and if neces-
sary a computed tomography scan. If patients do not
appear for the annual follow-up appointment, their family
or family practitioner is contacted to obtain information
about the patients health status.
An electronic database (megaMANAGER 4.0.0.0, 2008
version; megapharm Ltd, St Augustin, Germany) was used
to determine baseline variables (for patient characteristic
factors, tumour, physical condition, risk factors for survival),
surgical variables, and follow-up variables in all patients
treated for MM. The patients charts were also screened for
additional information if necessary. The type of anaesthesia
was recorded from the original anaesthesia charts. The
patients underwent surgery either under SpA with 2.53.0
ml hyperbaric bupivacaine 0.5% or GA. GA was administered
as balanced volatile anaesthesia using isoflurane and sufen-
tanil, or as total i.v. anaesthesia with continuous infusions of
propofol and remifentanil.
All data were transferred to the SPSS program for statistic-
al analysis (IBM SPSS Statistics, PASWPredictive Analytics
Software, version 18). The following potential confounders
were tested in the statistical analyses to identify any signifi-
cant differences between SpA and GA:
Baseline variables: age, gender, BMI, smoking status,
alcohol abuse, ASA status.
Medical history: myocardial infarction, coronary artery
disease, arrhythmias, hypertension, chronic obstructive
pulmonary disease (COPD), diabetes, renal insufficiency,
liver diseases, coagulopathies, and immunosuppression.
Tumour stage: tumour thickness, tumour ulcerations.
American Joint Committee on Cancer (AJCC) classifica-
tion: Stage 0 melanoma involves the epidermis, but has
not reached the underlying dermis melanoma in situ.
Stage I melanoma is characterized by tumour thick-
ness, presence and number of mitoses, and ulceration
status. There is no evidence of regional lymph-node
metastasis or distant metastasis. Stage II melanoma
is characterized by tumour thickness and ulceration
status. There is no evidence of regional lymph-node
metastasis or distant metastasis. Stage III melanoma
is characterized by the level of lymph-node metastasis.
There is no evidence of distant metastasis. Stage IV
melanoma is characterized by the location of distant
metastases and the level of serum lactate dehydrogenase.
Postoperative variables: signs of infection, use of anti-
biotics, seromas, repeat surgery.
Long-term variables: additional malignancies.
Regional anaesthesia and cancer prognosis BJA

Surgeries
Kind of surgery n = 353

SLNB CLND No information

n = 247 n = 101 n=5
excluded

Duplicates: Primary cases:

SLNB followed by CLND Only SLNB
n = 73 n = 174
excluded
selected
Number of cases

n = 275

Complete data set missing data

n = 273 n=2
excluded
selected

Spinal anaesthesia General anaesthesia

Type of anaesthesia

n = 52 n = 221

Balanced volatile anaesthesia Total intravenous anaesthesia

n = 118 n = 103

Fig 1 Flow diagram presenting the enrolment, intervention allocation, and data analysis with numbers of patients in each group. SLNB, sen-
tinel lymph-node biopsy; CLND, complete lymph-node dissection.

Statistics SpA subgroup. The KaplanMeier analysis and subsequent

The primary endpoint of the study was mortality during a
postoperative observation period of 10 yr. Survival was calcu-
lated as the number of days from the date of surgery to the
date of death or last contact with the patient.
Nominal scale variables were described using relative and
absolute frequencies. Variables with interval or higher-scale
levels were described as means and standard deviation.
log-rank tests were done to compare the survival rate of
patients in the two groups.
The following alternative hypothesis was tested in the
matched-pairs analysis: the long-term survival rate after in-
guinal lymph-node dissection in MM is different for patients
undergoing surgery in SpA in comparison with GA (H0: mgeneral
anaesthesia mspinal anaesthesia; H1: mgeneral anaesthesia =mspinal

Patient characteristic and physiological basic data were com- anaesthesia). To reduce the risk of type I error, no direction for

pared using Students t-test, the x 2 test, or Fishers test, as
appropriate. Survival was analysed in two steps using the
KaplanMeier curves and subsequent log-rank tests.
In the first step, the overall group was analysed for vari-
ables that might confound the effects of anaesthesia on sur-
vival. The following variables were included: type of surgery,
tumour thickness, gender, and ASA status. In the second
step using these variables, matched pairs of patients with
SpA and GA were built for further statistical analyses. This
was due to the small study group of only 52 patients in the
the difference was defined, statistical tests were two-tailed,
and a P-value of 0.05 was regarded as significant.
Results
A total of 273 patients who required anaesthesia for inguinal
lymph-node dissection after primary MM in the lower extrem-
ity between February 1998 and April 2005 at the Department
of Anaesthesia, Intensive Care and Pain Medicine, Hornheide
Specialist Hospital, Munster, Germany, were included in this
analysis. The follow-up ended in May 2009. The mean follow-up

255
BJA
time for all patients was 52.2 (SD 35.69) months (with a
minimum of 0 months for patients who died within the first
month after operation, and a maximum of 122 months for
patients who survived for the whole study period).
After testing for confounders of the effects of the type of
anaesthesia on long-term survival, x 2 analyses comparing
the SpA group (n52) and the GA group (n221) did show
a significant difference with regard to gender (P0.021),
ASA status (P0.004), arrhythmias in the medical history
(P0.033), or coagulopathies (P0.008). There were no sig-
nificant differences with regard to tumour stage, post-
operative surgical complications, or long-term variables
(Tables 13). Patients in the GA group were significantly
younger than those in the SpA group (P0.003). In addition,
the duration of surgery (P0.026) and hospital stay
(P0.007) were significantly longer for patients in the GA
group in comparison with the SpA group (Tables 1 and 3).
The Kaplan Meier analysis showed that patients with
SLNBs had a significantly longer survival in comparison
with patients with CLNDs (P0.000). Patients with a higher
ASA class had a significantly higher risk for a shorter survival
after surgery, as did male patients and patients with a
greater tumour thickness (all P0.000).
Using these variables (type of surgery, ASA status, tumour
thickness, gender), matched pairs of the 52 patients with SpA
and 52 corresponding patients with GA were built and tested
once again for the following variables: age, gender, BMI,
smoking, alcohol abuse, ASA status, medical history (myocar-
dial infarction, coronary artery disease, arrhythmias, hyper-
tension, diabetes, COPD, renal insufficiency, liver diseases,
coagulopathies, immunosuppression), tumour stage
(tumour thickness, tumour ulcerations, AJCC classification),
postoperative variables such as signs of infection, use of anti-
biotics, seromas, and repeat surgery. No significant differ-
ences between the groups now remained. However,
differences in the duration of surgery [SpA 59.00 min (SD
20.59), GA 71.00 min (SD 35.77) (P0.039)] and length of hos-
pital stay [SpA 16.08 days (SD 9.91), GA 21.58 (SD 12.09)
(P0.013)] remained significant.
A trend towards longer survival in patients in the SpA
group was now detected [mean survival time for SpA: 95.9
months; 95% confidence interval (CI), 81.2 110.5 months;
GA: 70.4 months; 95% CI, 53.6 87.1 months; P0.087]
(Fig. 2).
Discussion
The results of this retrospective study of patients undergoing
lymph-node dissection after MM are in accordance with the
hypothesis that surgery with SpA might improve the long-
term prognosis in patients with MM.
Animal studies have indicated that immune-response
control over the circulation of tumour cells and micrometas-
tases takes place mainly through cell-mediated immunity.
The main cell types involved are cytotoxic T lymphocytes,
natural killer (NK) cells, NK T cells, dendritic cells, and macro-
phages. 7 NK cells are particularly important, as they can
256
Gottschalk et al.
spontaneously recognize and kill malignant cells. NK cell sup-
pression is also associated with increased rates of metasta-
sis. Studies in humans have also shown that low
perioperative levels of NK cell activity are associated with
increased cancer-related morbidity and mortality.8 9
The specific anaesthesia approach used is likely to be of
relevance, as animal studies have shown that the choice of
anaesthetic drugs and techniques has a profound influence
on the immune response and, as a result, on cancer metas-
tasis.3 In particular, regional anaesthesia, including SpA,
reduces the stress response caused by surgery, which is
believed to be a mediator of postoperative immunosuppres-
sion.10 12 This prevents noxious afferent input from reaching
the central nervous system. In addition, SpA avoids inhaled
anaesthetics and reduces the opioid requirements, both of
which have been shown to decrease the activity of NK
cells. SpA also effectively blunts the neuroendocrine re-
sponse and thus decreases the production of catechola-
mines, which reduce NK cell activity.3 In a mouse model,
for example, it has been shown that laparotomy during sevo-
flurane anaesthesia significantly increased the number of
liver metastases in comparison with sevoflurane anaesthesia
plus SpA.4 The addition of intrathecal local anaesthetics atte-
nuated the suppression of tumoricidal function in hepatic
mononuclear cells and thereby reduced tumour metastasis.4
Data from retrospective studies in humans have demon-
strated that the long-term outcome for patients undergoing
cancer surgery is improved if they receive a neuraxial or re-
gional block. Exadaktylos and colleagues13 reported that
the use of paravertebral nerve block in combination with
GA was associated with a longer cancer-free interval and a
lower incidence of recurrence in patients with breast
cancer. Another retrospective trial was able to show that
the epidural technique was associated with a 65% reduction
in biochemical recurrences of prostate cancer, as defined by
increased prostate-specific antigen after operation.14 In con-
trast to these results, the use of epidural analgesia for peri-
operative pain control during colorectal cancer surgery was
not found to be associated with a decreased rate of cancer
recurrence; a potential benefit was observed in older
patients.15 These findings suggest that the benefit of region-
al anaesthesia relative to cancer recurrence, if it exists, may
depend critically on the specific cancer type. However, no
clinical trials have been conducted to investigate the
effects of SpA on the long-term outcome after cancer
surgery. The data obtained in the present study may
suggest that SpA perioperatively may improve the long-term
prognosis for patients with MM. However, only prospective
randomized trials can fully address the relationship
between regional analgesia and cancer recurrence.
In principle, two different models of cancer are at issue
here. On the one hand, the existence of a metastatic
cascade has been proposed, with a number of sequential
events being required for disseminated cancer to develop.16
The idea behind this concept is that tumour cells migrate
through the lymphatic vessels to the lymph nodes and
then disseminate to distant sites. On the other hand,
Regional anaesthesia and cancer prognosis BJA

Table 1 Patient characteristic data, type of anaesthesia used, and Table 1 Continued
preoperative physical condition
Spinal General P-value
Spinal General P-value anaesthesia anaesthesia
anaesthesia anaesthesia
.6 months 2 (3.8) 8 (3.6)
Gender 0.021 ,6 months 0 (0) 3 (1.4)
Male (%) 24 (46.2) 64 (29.0) Immunosuppression 1.000
Female (%) 28 (53.8) 157 (71.0) (%)
Age (yr) mean (range 58.13 (32/86) 50.64 (4/93) 0.003 No 52 (100) 218 (98.6)
min/max) .6 months 0 (0) 3 (1.4)
ASA classification (%) 0.004 ,6 months 0 (0) 0 (0)
I 7 (13.5) 57 (25.8) Smoking (%) 0.345
II 34 (65.4) 148 (67.0) No 44 (84.6) 172 (77.8)
III 10 (19.2) 16 (7.2) Yes 8 (15.4) 49 (22.2)
IV 1 (1.9) 0 (0) Alcohol consumption 0.179
Coronary artery 0.053 (%)
disease (%) ,1week 45 (86.5) 204 (92.3)
No history 45 (86.5) 211 (95.5) Weekend 1 (1.9) 8 (3.6)
Minimal risk 3 (5.8) 5 (2.3) .1week 1 (1.9) 2 (0.9)
High risk 4 (7.7) 5 (2.3) Daily 5 (9.6) 7 (3.2)
History of myocardial 1.000
infarction (%)
No 51 (98.1) 215 (97.3)
.6 months 1 (1.9) 6 (2.7) Table 2 Oncological data
,6 months 0 (0) 0 (0)
Arrhythmia (%) 0.033 Spinal General P-value
No history 49 (94.2) 217 (98.2) anaesthesia anaesthesia

Bradycardia 0 (0) 1 (0.5) Tumour thickness 1.00

Pacemaker 0 (0) 2 (0.9) (%)

Ventricular 1 (1.9) 1 (0.5) ,2 mm 25 (48.1) 105 (47.5)

arrhythmia 2 mm 27 (51.9) 116 (52.5)
Atrial fibrillation 2 (3.8) 0 (0) Tumour ulcerations 0.321
Hypertension (%) 0.474 (%)

No 37 (71.2) 169 (76.5) No 33 (63.5) 156 (70.6)

Yes 15 (28.8) 52 (23.5) Yes 19 (36.5) 65 (29.4)

Coagulopathy (%) 0.008 AJCC classification 0.472

(%)
No history 50 (96.2) 216 (97.7)
No data 0 (0) 1 (0.4)
Over 6 months 0 (0) 5 (2.3)
previously IA 1 (1.9) 6 (2.7)

Within the last 6 2 (3.8) 0 (0) IB 19 (36.5) 70 (31.7)

months IIA 8 (15.4) 39 (17.6)
COPD (%) 0.592 IIB 11 (21.2) 22 (10.0)
No 48 (92.3) 208 (94.1) IIC 2 (3.8) 8 (3.6)
Dyspnoea during 4 (7.7) 11 (5.0) IIIA 5 (9.6) 27 (12.2)
stress IIIB 3 (5.8) 26 (11.8)
Dyspnoea during 0 (0) 2 (0.9) IIIC 3 (5.8) 22 (10.0)
rest IV 0 (0) 0 (0)
Renal failure (%) 0.085 Additional 1.000
No 49 (94.2) 218 (98.6) malignancies (%)
Compensated 3 (5.8) 3 (1.4) No 52 (100) 217 (98.2)
retention Yes 0 (0) 4 (1.8)
Liver failure (%) 1.00
No 52 (100) 220 (99.5)
Yes 0 (0) 1 (0.5)
Diabetes mellitus (%) 0.699 Paget17 proposed the seed and soil hypothesis in order to
No 50 (96.2) 210 (95.0) explain the unusual organ-specific metastatic pattern.
According to the seed and soil theory, which appears to
Continued reflect clinical reality better, metastaseseven from small

257
BJA Gottschalk et al.

tumoursmay be initiated before the primary tumour is

Table 3 Surgical information diagnosed. The growth of the primary tumour and the
Spinal General P-value
process of metastasis may thus be two autonomous pro-
anaesthesia anaesthesia cesses. In that case, perioperative compromise of the
Duration of 59.00 (20.59) 68.72 (29.57) 0.026
immune system might be fatal, as it might promote the
surgery (min) (SD) growth of micrometastases in distant organs.
Postoperative
status (%) Limitations of the study
Wound infection 0.839 Potential weaknesses of this study, which is retrospective in
No 44 (84.6) 182 (82.4) nature, might be inaccuracies in the written records, with
Yes 8 (15.4) 39 (17.6) important data missing, and the difficulty of controlling
Use of 0.168 bias and confounders. For example, differences in surgical
antibiotics time and hospital stay might be caused by confounders
No 42 (80.8) 156 (70.6) that were not recorded. The results of this study have there-
Yes 10 (19.2) 65 (29.4) fore been used to generate hypotheses and will require con-
Seromas 0.285 firmation with further prospective studies. To minimize the
No 47 (90.4) 184 (83.3) risk for a-error, an alternative hypothesis for a two-sided
Yes 5 (9.6) 37 (16.7) test was selected for statistical analyses. To compensate
Repeat surgery 1.000 for this, a matched case control study design was chosen
No 51 (98.1) 217 (98.2) to adjust for potential confounders and to increase the pre-
Yes 1 (1.9) 4 (1.8) cision of the comparison. The poor prognosis in patients
Hospital stay 16.08 (9.91) 20.81 (11.58) 0.007 with MM, particularly with positive lymph nodes, may also
(days) (SD)
have masked true benefits of regional anaesthesia.18 19
However, this is the largest study to date providing
support for the view that the use of SpA in patients

1.0

Type of anasthesia
1: spinal
2: general
0.8
1: censored
2: censored
Cumulative survival

0.6

0.4

0.2

0.0

0 20 40 60 80 100 120

Months

Fig 2 Kaplan Meier survival curve after adjustment of matched-pairs samples: SpA vs GA.

258
Regional anaesthesia and cancer prognosis
presenting with MM and undergoing inguinal lymph-node
dissection may improve the long-term outcome.
The study is not capable of revealing any potential mech-
anism of SpA relative to the tumour outcome in patients with
MM. Long-term prospective studies will be required before it
can be determined whether the choice of anaesthesia tech-
nique for cancer surgery has a significant impact on patient
safety in the long run. Since 90% of cancer-related deaths
are due to metastatic development rather than directly
related to the primary cancer, there is a considerable poten-
tial for improving the patient outcome.20 A prospective clin-
ical study in patients with MMs is therefore now in progress
to help to clarify a number of questions, including whether
SpA alters patients perioperative immune status, which
cells are affected, and how SpA impacts on the immune
tumour interaction. Additionally, the impact of this on long-
term survival and risk of cancer recurrence will be studied.
The data presented here suggest that after lymph-node
dissection, there may be an association between the anaes-
thetic technique used and the cancer outcome in patients
with MM. A prospective randomized controlled trial on this
topic is therefore warranted.
Declaration of interest
None declared.
Funding
The study was supported solely by departmental funding.
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