REVIEW

CURRENT
OPINION Anesthesia and brain tumor surgery: technical
considerations based on current research evidence
Junichi Saito a,b, Joe Masters b, Kazuyoshi Hirota a, and Daqing Ma b

Purpose of review
Anesthetics may influence cancer recurrence and metastasis following surgery by modulating the
neuroendocrine stress response or by directly affecting cancer cell biology. This review summarizes the
current evidence on whether commonly used anesthetics potentially affect postoperative outcomes following
Downloaded from https://journals.lww.com/co-anesthesiology by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3hIW04IhZ9AvNyXiDskTJpHrU+NEtsjmqiU3Ukzps0lU= on 09/08/2019

solid organ cancer surgery with particular focus on neurological malignancies.

Recent findings
Despite significant improvement in diagnostic and therapeutic technology over the past decades, mortality
rates after cancer surgery (including brain tumor resection) remains high. With regards to brain tumors,
interaction between microglia/macrophages and tumor cells by multiple biological factors play an
important role in tumor progression and metastasis. Preclinical studies have demonstrated an association
between anesthetics and brain tumor cell biology, and a potential effect on tumor progression and
metastasis has been revealed. However, in the clinical setting, the current evidence is inadequate to draw
firm conclusions on the optimal anesthetic technique for brain tumor surgery.
Summary
Further work at both the basic science and clinical level is urgently needed to evaluate the association
between perioperative factors, including anesthetics/technique, and postoperative brain tumor outcomes.
Keywords
anesthetics, brain tumor, metastasis, recurrence

INTRODUCTION and metastasis after surgery remain common and

leads to poor prognosis.
Epidemiology of brain tumor The potential impact of anesthetics in modulat-
&

Brain tumors are a relatively rare but serious health
burden in terms of morbidity and mortality. Glioma
is the most common primary brain tumor in adults,
and represents about 30% of all brain tumors and
80% of malignant brain tumors [1]. Despite signifi-
cant improvements in diagnosis and therapy over
the past decades, the 5-year survival rate of the most
severe form of glioblastoma is less than 5% [2,3].
Surgery remains the first-line treatment for
patients with a malignant brain tumor. Complete
surgical resection of brain tumor is generally recom-
mended, but care must be taken not to impair the
neurological function with tumors located in
eloquent regions. Hence, adjuvant or neo-adjuvant
therapy is often required to improve survival. How-
ever, resistance to radiation and chemotherapy is
the major problem in the treatment of glioblastoma
that may be because of resistance to regulated cell
death, attenuation of cytotoxicity by the microen-
vironmental changes, and the limited ability to
deliver drugs into the tumor. Therefore, recurrence
ing cancer cell biology [4–6,7 ] may either promote
or inhibit cancer recurrence and metastasis after
surgery. In addition, surgical stress and its associated
changes can massively affect cancer cell behaviors,
which has been well documented [8,9]. In this
review, we summarize the current preclinical data
on the potential effects of anesthetics on cancer cell
biology and the clinical evidence that anesthetic
a
Department of Anesthesiology, Hirosaki University Graduate School of
Medicine, Hirosaki, Japan and bAnaesthetics, Pain Medicine and Inten-
sive Care, Department of Surgery and Cancer, Faculty of Medicine,
Imperial College London, London, UK
Correspondence to Daqing Ma, Anaesthetics, Pain Medicine and Inten-
sive Care, Department of Surgery and Cancer, Faculty of Medicine,
Imperial College London, Chelsea & Westminster Hospital 369 Fulham
Road, London SW10 9NH, UK. Tel: +44 203315 8495;
fax: +44 203315 5109; e-mail: d.ma@imperial.ac.uk
Curr Opin Anesthesiol 2019, 32:553–562
DOI:10.1097/ACO.0000000000000749

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Neuroanesthesia
KEY POINTS
 Despite significant improvement in diagnostic and
therapeutic technology over the past decades, mortality
after surgery for brain tumors remains high.
 Anesthetics may have impact on brain tumor metastasis
or recurrence through the effects on tumor cell
signaling, the immune response, and modulation of the
neuro-endocrine stress response.
 Clinical evidence is inadequate to draw conclusion for
how to choose the anesthetics during brain
tumor surgery.
 Further clinical study is urgently needed to evaluate the
association between the anesthetic management and
long-term outcomes of brain tumor following surgery.
technique may influence outcomes following the
surgical management of brain tumors.
Brain cancer cell biology and mechanism of
tumor progression and metastasis
Current research reveals that the interaction between
microglia/macrophages and tumor cells by multiple
factors play an important role in tumor progression
&
and metastasis in neurological malignancies [10 ].
Microglia/macrophages are often recruited within
or close to the brain tumor mass. Reactivated micro-
glia are known to lead to local neuronal death
through the secretion of pro-inflammatory cytokines
and also chronic reactive microglia increase produc-
tion of cytokines and chemokines that escalate tumor
growth and invasion. Inhibition of microglial activa-
tion has been shown to significantly reduce glioma
proliferation [11]. Microglia/macrophages are differ-
entiated into two types: classical (M1) and alternative
(M2) phenotype. M1 cells have an anti-tumor
immune function and suppress glioma cell growth
[12]. In contrast, M2 cells have a pro-tumor immune
response via producing immunosuppressive media-
tors [13]. Both M1 and M2 microglia are found within
brain tumors, but the anti-tumor functions of M1
microglia in the brain tumor are often impaired [14].
The balance between the pro-tumor response of M2
and the anti-tumor response of M1 affects tumor
growth, invasion and progression.
Interaction between microglia/
macrophages and tumor
Soluble factors released from glioma cells are recog-
nized by Toll-like receptors (TLRs), especially TLR2,
on microglia. Interleukin (IL)-6 and transforming
growth factor (TGF)-b secreted by glioma and
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microglia stimulate the production of pro-matrix
metalloproteinase (MMP) 2 via TLR2 signaling
&
[10 ]. Secreted MMP2 activates the membrane type-
1 MMP (MT1-MMP) and facilitate glioma cell motility
[15]. TGF-b recruits microglia/macrophage to glioma
[16] and stimulates glioma migration. It has been
suggested that blocking TGF-b abolishes the effects
of microglia on glioma invasiveness [17] (Fig. 1).
For metastasis, vascular network development is
important to supply enough nutrients and oxygen
to tumor cells. Microglia/macrophages are located at
vascular branching points and release vascular
endothelial growth factor (VEGF) to stimulate the
growth of functional vasculature. Microglia-derived
MMPs have been shown to induce production of
angiogenic factors and stimulate angiogenesis in
&
glioma [10 ]. Hypoxia-inducible factors (HIFs) are
transcription factors that regulate cell proliferation
and survival and have been shown in active path-
ways in glioblastomas leading to enhanced invasion
[18]. Previous studies revealed that HIFs are modu-
lated by several anesthetics, especially inhalational
agents and propofol [4,19]. In renal and prostate
cancer cells, isoflurane significantly increases cell
proliferation and migration caused by the up-regu-
lation of HIFs via the phosphatidylinositide 3-
kinase/Akt/mammalian target of rapamycin path-
way [4,19]. In contrast, propofol inhibits HIF-1a
activation induced by hypoxia or cobalt chloride
in prostate cancer cells. Propofol also prevented
isoflurane-induced HIF-1a activation, and reduces
cancer cell malignant activities, including cell pro-
liferation, migration, invasion and resistance to the
chemotherapeutic agent [19].
Activated microglia cells significantly promote
colonization of breast tumor tissues in metastasis
[20]. Wnt pathway is one of the well established
signaling pathways during tumorigenesis and plays
an important role in the development of the central
nervous system [21]. The role of Wnt in vascular
development has been found using targeted deletion
mutants of Wnt signaling components in animal
models. Additionally, in clinical study, Wnt signaling
is elevated in breast cancer patients with brain metas-
&&
tasis [22 ]. Wnt signaling pathway is also associated
with the proliferation of glioma cells. Inhibiting
microglia function via a Wnt inhibitor significantly
diminished tumor cell invasion whereas treating
microglia with Wnt increases the production of
IL-6, tumor necrosis factor (TNF)-a and MMPs [23].
S100 calcium-binding protein B (S100B), a
receptor for advanced glycation end products
(RAGE) ligand, is secreted by glioma cells and has
been suggested to contribute tumorigenesis by pro-
moting IL-6 expression and signal transducer and
activator of transcription 3 (STAT3) activation [24].
Volume 32  Number 5  October 2019

S100B-RAGE-STAT3 signaling stimulates polariza-
tion of M2 microglia. M2 microglia polarization is
associated with maintaining local immunosuppres-
sion. Tumor-secreted S100B induces STAT3 activa-
tion through the activation of receptor for advanced
glycation end products. This signaling pathway acti-
vation results in the suppression of M1 microglia
function [24]. The unbalance between pro-tumor
response of M2 and anti-tumor response of M1 via
S100B-RAGE-STAT3 signaling promotes tumor
growth and invasion.
Mitochondria function and brain tumor
growth and development
There are two main signaling pathways that trigger
apoptosis for brain tumor cells; the intrinsic mito-
chondrial pathway and the extrinsic pathway [25].
Both pathways cause activating cleavage of caspases
3 and 7, which irreversibly instigates an apoptotic
cascade (Fig. 2). The intrinsic mitochondrial path-
way can be triggered by direct damage to the
cell from reactive oxygen species (ROS) and others.
Protein 53 (p53) accumulates in response to DNA
damage and oncogene activation. p53 enhances
DNA act as a nuclear transcription factor and enhan-
ces transcription of pro-apoptotic genes, which
interact with the B cell lymphoma-2 (BCL-2) family
members, BCL-2-associated X protein (BAX), BCL-2
homologous antagonist/killer and BCL-2-associated
death promoter [25]. The recruitment of pro-apo-
ptotic BCL-2 family members facilitates the opening
of a mitochondrial permeability transition pore
(MPTP). The opening of MPTP is a critical event
for apoptosis. Opening the pore allows the rapid
release of cytochrome C, second mitochondria-
derived activator of caspases (SMAC) and Omi
from the mitochondria. Cytochrome C binds with
caspases 9 to form an apoptosome, which cleaves
caspases 3 and 7 [25].
The association of the anti-apoptotic BCL-2 fam-
ily members with the mitochondrial membranes
contributes to mitochondrial dysfunction in glioma
[25]. The anti-apoptotic BCL-2 proteins is highly
over-expressed in human glioma cell and protects
the glioma cell from undergoing apoptosis after
chemically induced DNA damage [26].
The extrinsic pathway is initiated by the death
receptor [25]. Specific ligands bind and, in turn,
activate the death receptor, which results in intra-
cellular signal transduction. This signaling causes
activating cleavage of caspases 8 and 10, which
cleave caspases 3 and 7. In glioma cells, the extrinsic
pathway is suppressed, and this is related to tumor
resistance to regulated cell death. Additionally, this
tumor resistance is related to overactivation of
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Anesthesia and brain tumor surgery Saito et al.
phosphoinositide 3-kinase/Akt/mammalian target
of paramycin pathway [25].
ANESTHETICS AND IMMUNE
MODIFICATION, CANCER CELL BIOLOGY
AND POTENTIAL EFFECTS ON TUMOR
PROGRESSION AND METASTASIS
Current research suggests that perioperative anes-
thetics/technique impacts on metastasis and recur-
rence through effects on cancer cell signaling, the
immune response, and modulation of the neuroen-
docrine stress response. Anesthetics and analgesics
can independently suppress antitumor immune
function, even though surgical stress and perioper-
ative pain can activate neuroendocrine cascades
that inhibit natural killer cell activity during the
perioperative period [9]. This inhibition of natural
killer cell activity leads to immunosuppression and
promotes proliferation and metastasis of cancer.
Additionally, anesthetics may have impact on the
cancer cell biology and modulate gene expression
[27]. Changes in serum level of VEGF-C [28], MMPs
[29] and HIFs [30] by anesthetics may also have an
impact on metastasis or recurrence of cancers. Their
effects on molecular targets and/or cell signaling
pathway can be seen in Figs 1 and 2.
Intravenous agents
Propofol
Propofol has tumor-suppressive effects in various
types of cancer cells [31,32]. Its effects are because
of suppression of proliferation and invasion, and
induction of apoptosis in primary brain tumor cells
[33–36].
One such study evaluated the role of micro-
RNA218 in the effects of propofol on the biological
behavior of glioma cells. Treatment with propofol
reduced MMP2 protein expression levels, and over-
expression of microRNA218 also decreased MMP2
protein expression levels. The effects of propofol in
U373 cells was reversed by the antimicroRNA218
antibody [33]. Propofol suppresses proliferation and
invasion, and induces the apoptosis of glioma cells, at
least partially through upregulation of microRNA218
expression [33]. The other study also revealed that
propofol-mediated anti-tumor effects were because of
the regulation of NF-kB pathway, which is associated
with microRNA218 expression [34].
Wnt signaling is one of the important pathways
in gliomagenesis and b-catenin is a key component
of this signaling. Propofol decreases the protein
levels of b-catenin in glioma cells and has the
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Neuroanesthesia
Anesthetics & Analgesics
?
Brain tumour
Intra-cranial
inflammation
S100B
Soluble factors
Midazolam
Immunosuppression
RAGE
TLR
STAT3
Wnt
VEGF MMPs
Angiogenesis
HIFs
Volatile anesthetics
Tumour metastasis
Propofol
FIGURE 1. Interaction between microglia/macrophage and brain tumor, and possible anesthetic actions. HIF, hypoxia-
inducible factor; IL-6, interleukin6; MMP, matrix metalloproteinase; NMDAR, N-methyl-D-aspartate receptor; RAGE, receptor for
advanced glycation end products; S100B, S100 calcium-binding protein B; TGF-b, transforming growth factor beta; TLR, toll-
like receptors; VEGF, vascular endothelial growth factor.
potential to inhibit Wnt signaling in glioma cells
[37]. It has been shown that propofol dose-depen-
dently inhibits the viability of the glioma cells and
significantly increases apoptotic glioma cells [37].
Propofol showed cytotoxicity in glioblastoma
8401 cells but not in DI TNC1 rat normal astrocytes.
The cytotoxicity was induced through arrest of cell
cycle progression at the G2/M phase and increased
intracellular ROS levels only in glioblastoma 8401
cells but not normal astrocytes [36]. Another study
showed that propofol increased intracellular free
calcium, leading to cell death that might be through
ROS-mediated apoptosis [35].
Another preferable effect of propofol related to
the brain surgery has been reported. Aquaporin 4
and aquaporin 9 are known as important factors
influencing brain edema after traumatic brain injury
[38]. Propofol reduced postischemic cerebral edema
in rats, through the inhibiting aquaporin 4 over-
expression in the boundary zone of ischemia [39].
Additionally, propofol inhibited aquaporin 4
expression compared with sevoflurane in glioma
resection patients, even though the study did not
evaluate magnitude of edema after the surgery [40].
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Thiopental, Ketamine, Sevoflurane?
NMDAR
Tumour growth
Pro-
MMP2
MMP2 & invasion
microRNA218
TGF-β
IL-6
Propofol
Peripheral cancer cells
(breast cancer)
Thiopental
Thiopental has strong anti-inflammatory effects.
Excessive inflammatory response increases the
secretion of pro-inflammatory cytokines, such as
IL-1, IL-6, IL-8 and TNF-a and simultaneously leads
to increased counter-inflammatory cytokines, such
as IL-4 and IL-10 secretion. NF-kB is an important
transcription factor that is essential for expression of
pro-inflammatory cytokines. Thiopental suppressed
TNF-a production via inhibition of NF-kB activation
by lipopolysaccharide in human glioma cells [41].
Activation of N-methyl-D-aspartate (NMDA)
receptor of glutamine increases MMP2 activity in
glioma cells [42]. Thiopental reduces MMP2 activity
and decreases migration of glioma cells [43].
Ketamine
Ketamine is an NMDA receptor antagonist. Gluta-
mate is an excitatory neurotransmitter in the brain
that activates glutamate receptors including the
NMDA receptor. Glioma cells secrete glutamate
during proliferation, and treatment with the
NMDA receptor antagonists MK801 or memantine
inhibited the growth of glutamate-secreting tumors
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 Anesthesia and brain tumor surgery Saito et al.

<Extrinsic Pathway> <Proliferation Pathway> <Intrinsic mitochondrial Pathway>

TNF-α, Fas EDG, CXCL12 Hypoxia, Toxicity,

Ca2+
PDGF Oxidative stress

DR RTX CXCR4
Propofol Propofol
Dexmedetomidine Ca2+ ROS
PI3K
? Midazolam
mTOR Lidocaine
?
Akt δ-opioid
DNA
Midazolam TPRV1 Damage
Caspase 8 p53

Caspase 10 MCL-1
BCL-2 BAX
BCL-xL
BAK

MTPT Cyt C
Caspase 9

Apoptosis!
Midazolam Caspase3

Caspase7
Tumour proliferation & growth

FIGURE 2. Brain tumor growth and apoptotic pathways, and possible anesthetic actions. BAX, BCL-2-associated X protein,
BCL-2, B-cell lymphoma 2, BCL-xL, B-cell lymphoma-extra large, CXCL12, C-X-C motif chemokine 12, CXCR4, C-X-C
chemokine receptor type 4, Cyt C, cytochrome c, DNA, deoxyribonucleic acid, DR, death receptor, EDG, endothelial
differentiation gene, MCL-1, myeloid cell leukemia sequence 1, mTOR, mammalian target of rapamycin, MTPT, mitochondrial
permeability transition pore, PDGF, platelet-derived growth factor, PI3K, phosphatidylinositol-3 kinase, ROS, reactive oxygen
species, RTX, resiniferatoxin, TNF-a, tumor necrosis factor-alfa, TPRV1, transient receptor potential vanilloid 1.

in situ, suggesting that glutamate promoted glioma
cells proliferation via the activation of NMDA recep-
tor [44]. Ketamine-induced apoptosis in C6 glioma
cells, resulted in the suppression of C6 cell prolifer-
ation [45]. Treatment with the selective NMDA
receptor antagonist D-AP5 significantly suppressed
the proliferation of C6 glioma cells and induced
apoptosis [45]. On the other hand, ketamine has
adrenergic activity and is profoundly immunosup-
pressive by inhibition of natural killer cell activity.
Accordingly, use of ketamine can lead to increased
incidence of metastases showing in non-brain can-
cer models [46]. The ratio of risk and benefit of
ketamine use depends on the physiological status
of individuals per se.
Dexmedetomidine
The intracranial anti-inflammatory response and
neuroprotective effects of dexmedetomidine are
well documented in traumatic brain injury and
cerebral ischemia [47–50]. These properties may
be also beneficial for non-cancer neurosurgery.
However, dexmedetomidine might have a pro-
malignant effect on brain tumors. It has been dem-
onstrated that dexmedetomidine promoted neuro-
glioma cell proliferation and migration, which was
associated with the upregulation of anti-apoptotic
proteins (BCL2 and BCL-xL) via the a2-adrenoceptor
activation and promoted cancer growth in a xeno-
&
graft cancer model [7 ].
Midazolam
Midazolam suppresses neuroglioma cell prolifera-
tion and migration, induces apoptosis through
the intrinsic mitochondrial pathway, and increases
&
intracellular ROS [7 ]. These anti-cancer effects are
mediated by the peripheral benzodiazepine recep-
tor. Midazolam also inhibits IL-1b-stimulated IL-6
release from C6 glioma cells. IL-6 is suppressed by an
inhibitor of phospho-specific inhibitory kappa B
kinase, an inhibitor of phospho-specific stress-
activated protein kinase/c-Jun N-terminal kinase,

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Neuroanesthesia
and an inhibitor of Janus family of tyrosine kinase 1,
2 and 3. Midazolam markedly suppresses IL-1b-stim-
ulated STAT3 phosphorylation without affecting
the phosphorylation of p38 mitogen-activated pro-
tein kinase, phospho-specific stress-activated pro-
tein kinase/c-Jun N-terminal kinase or phospho-
specific inhibitory kappa B. Midazolam inhibits
IL-1b-induced IL-6 release in rat C6 glioma cells
via suppression of STAT3 activation [51].
Volatile agents
Exposure of human glioblastoma stem cells to 1.2%
isoflurane for 6 h results in increased proliferation
and decreased apoptosis when compared with the
control group. In addition, isoflurane exposure
causes increased migration capacity in vitro and
the distance migrated is increased in vivo [52]. This
may be because isoflurane increases the expression
of HIFs [4], which are transcription factors that
regulate cell proliferation and survival and have
been found as an active pathway in glioblastomas
leading to enhanced invasion. Similarly, exposure of
human primary glioma stem cells to 2% sevoflurane
for 6 h induced a larger number of proliferated cells.
The levels of CD133, VEGF, HIF-1a, HIF-2a, and
phospho-Akt are up-regulated by sevoflurane in a
time and/or concentration related manner [53].
Opioids
Intraoperative and postoperative pain has been
shown to activate the stress response and induce
immunosuppression postoperatively shown in both
animal and human studies [54,55]. Perioperative pain
control is important, but drugs used for perioperative
pain control also have an impact on the immune
system and on cancer progression and metastasis.
Indeed, opioids themselves have been shown to
reduce natural killer cell function and stimulate can-
cer cell proliferation through effects on angiogenesis
and tumor cell signaling pathways [9,56].
Differences in affinity for the opioid receptors
cause different effects on glioblastoma cells.
Morphine stimulates human glioblastoma T98G cell
proliferation in vitro in a dose-dependent manner
but biphalin, an enkephalin analog, shows inhibi-
tory effect on T98G cell proliferation. The inhibitory
effect of biphalin is associated with suppression of
Ki-67 expression [57].
The downregulation of the d-opioid receptor
promotes changes in BAX and BCL-2 protein expres-
sion in glioma cells. The BAX activates the caspase
family to cause apoptosis of glioma cells. The
specific inhibitor of d-opioid receptors inhibits
glioma cell proliferation in a dose-dependent and
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time-dependent manner [58]. The inhibition of the d-
opioid receptors results in brain glioma cell apoptosis
and is associated with the mitochondrial pathways
[58]. One clinical retrospective study in patients who
underwent brain tumor resection showed that
patients who received remifentanil during surgery
had significantly lower in-hospital mortality
(1.5 vs. 3.0%; P ¼ 0.029) compared with patients
who received fentanyl during surgery. The odds ratio
for use of remifentanil for in-hospital mortality was
0.47 (95% confidence interval, 0.25–0.91; P ¼ 0.025)
[59]. Further studies are needed to verify these bene-
fits because of its retrospective nature.
Local anesthetics
Local anesthetic agents may reduce the incidence of
cancer recurrence through systemic anti-inflamma-
tory effect in addition to direct effects on the pro-
liferation and migration of cancer cells [60,61].
Local anesthetics and regional anesthetic techni-
ques are associated with a decrease of stress response
[62]. This allows for a reduction in opioid usage as
well as decreased release of endogenous opioids [63].
Local anesthetics can reduce activation of intraop-
erative and postoperative neuroendocrine stress
response, which inhibits natural killer cell function
in several cancer surgeries.
Transient receptor potential (TRP) channels are a
group of ion channels that can be activated by several
factors [64]. TRP channels regulate cell differentia-
tion, proliferation and death [65]. Suppression of
TRP melastatin 7 (TRPM7) inhibits proliferation,
migration and invasion of glioma cells [66].
Lidocaine has the anti-proliferation effects on glioma
cells and its effect is mediated by inhibiting
TRPM7 [67]. Lidocaine also increases TRP
subfamily V, member 1 (TRPV1) gene expression
and induces the increase of intracellular calcium
ion concentration, mitochondrial potential and
apoptosis in a dose-dependent manner in U87-MG
glioma cells. Lidocaine increased TPRV1 gene
increase mitochondrial membrane potential, leading
to U87-MG glioma cell apoptosis [68]. Additionally,
recent study reveals that lidocaine induced protective
autophagy in rat C6 glioma cells [69].
CLINICAL SIGNIFICANCE
Retrospective studies have shown that general anes-
thesia combined with regional anesthesia or regional
anesthesia alone has been associated with a reduction
of recurrence rate and improve survival in breast
&
[70 ], prostate [71–73], ovarian [74], melanoma
[75] and colorectal cancer [76–78] when compared
with general anesthesia alone. Additionally, a retro-
spective study reveals that propofol-based total
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 Anesthesia and brain tumor surgery Saito et al.

Table 1. Anesthetics and prognosis of brain tumor patients

Author Journal Year Model Protocol Main finding

Dong et al. [82 ] J Neurosurg 2019 A single-center Propofol (n ¼ 154) Median PFS and median OS were
&

Anesthesiol retrospective study vs. Sevoflurane not significantly different between

(n ¼ 140) propofol anesthesia and
sevoflurane anesthesia
Cata et al. [83] J Clin Neurosci 2017 A single-center Isoflurane (n ¼ 117) Isoflurane or desflurane were not
retrospective study vs. Desflurane independent prognostic factors
(n ¼ 261) for PFS (HR, 95% CI: 1.07,
0.85–1.37, P ¼ 0.531) and OS
(HR, 95% CI: 1.13, 0.86–1.48,
P ¼ 0.531).
Uchida et al. [59] J Anesth 2012 A retrospective study Remifentanil Patients who received remifentanil
using the Japanese (n ¼ 936) vs. during surgery had significantly
Diagnosis Procedure Fentanyl lower in-hospital mortality (1.5 vs.
Combination (nonremifentanil) 3.0%; P ¼ 0.029). The odds ratio
Database (n ¼ 936) for use of remifentanil for in-
hospital mortality was 0.47 (95%
CI, 0.25–0.91; P ¼ 0.025).
Y. Peng et al. Unpublished - A single-center, Propofol vs. -
(NCT02756312) observation randomized, parallel Sevoflurane
group controlled
clinical trial

CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival.

intravenous anesthesia for colon cancer surgery was
associated with better survival compared with iso-
&
flurane [79] and desflurane anesthesia [80 ]. How-
ever, a randomized control trial did not show the
significant difference of the duration of recurrence-
free survival between general anesthesia alone and
general anesthesia combined with epidural anesthe-
sia in patients after major abdominal oncologic
surgery [81]. Further prospective studies are needed
to define the impact of anesthetics and anesthetic
technique on the prognosis of cancer patients.
With regards to brain tumors, the impact of
anesthesia on patient prognosis has not been well
evaluated (Table 1). A recent retrospective clinical
study revealed that sevoflurane (n ¼ 140) did not
worsen progression-free survival and overall survival
in the high-grade glioma patients who underwent
tumor resection when compared with propofol
(n ¼ 154) [82 ]. However, subgroup analysis revealed
&
that sevoflurane shortened the overall survival in
patients with Karnofsky performance status less
than 80 when compared with propofol. Another
retrospective study shows that the type of volatile
anesthetic used, isoflurane vs. desflurane, was not
associated with a difference in prognosis [83]. The
extent to which anesthetic agents and anesthetic
technique may affect short-term and long-term out-
comes in patients with brain tumor remains unclear.
Balanced anesthesia and multimodal analgesia are
used clinically and many drugs are therefore, used
during the perioperative period. Thus, it is difficult
to isolate respective contributions of each drug.
Interaction between the different drugs and techni-
ques is also inevitable and the impact of this is
largely unknown. Similarly, randomized control tri-
als (RCTs) are lacking, although one prospective
randomized controlled trial (NCT02756312) is
underway to evaluate the association between anes-
thetic management and postoperative malignant
glioma progression. However, it will be a few years
before meaningful conclusions can be drawn
from this, and so other forms of investigation must
continue in the meantime including basic
science studies.
FURTHER CONSIDERATION
The surgical procedure itself affects cancer recur-
rence and metastasis after excision. Among several
theories to explain this phenomenon, the adverse
impact of surgical stress on immunity [54,55] and
unintended seeding of tumor cells during surgery
[84] may be most considerable. Raised adrenocorti-
cotropic hormone because of surgical stress induces
excess cortisol release and leads to insulin resistance
and raising blood glucose concentration. All these
can have a negative impact on postoperative patient
recovery. For example, postoperative hyperglycemia
increases surgical site infection [85] and surgical
stress has also been shown to have an immunosup-
pressive effect by reducing natural killer cell func-
tion and T-cell responses [86].

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Neuroanesthesia
Maximal surgical resection in patients with a
malignant brain tumor has been shown to have a
positive effect on the duration of progression-free
survival [87,88]. As neuroanesthesia improved dra-
matically, awake craniotomy with brain mapping
has become popular all over the world [89], espe-
cially for intra-axial tumors in eloquent areas.
Compared with conventional craniotomy under
general anesthesia, awake craniotomy has shown
several advantages [90]. A systematic review reveals
that patients who underwent awake craniotomy
have shorter hospital stay and fewer postoperative
neurological deficits compared with those who
underwent conventional craniotomy under general
anesthesia [91]. A more recent systematic review and
meta-analysis also shows that the advantages of
awake craniotomy include a lower rate of postoper-
ative nausea and vomiting and shorter hospital stay
[92]. Additional potential benefits include, higher
rate of complete tumor resection (100%) [93], better
neurological outcomes [94], less postoperative pain
[95], less opioid usage [96] and less intra-operative
vasoactive drug usage [96], which have been dem-
onstrated in the small retrospective studies. Another
meta-analysis revealed that intra-operative brain
sensorimotor mapping was associated with a lower
rate of late, severe neurological deficits and greater
extent resection of tumor [97]. However, the long-
term outcomes of conventional vs. awake surgical
resection for brain tumor are unknown and sub-
jected to further studies.
CONCLUSION
Current evidence does not conclusively support the
superiority of a specific anesthetic technique for
&
brain tumor surgery [82 ,83]. However, the use of
local anesthesia seems to be particularly appealing
for patients with brain tumors and has a number of
theoretical benefits. Local anesthetics can reduce
surgical stress and the amount of general anesthetic
use, leading to decreased immunosuppression and
hence reduced risk of tumor progression and metas-
tasis. Compared with volatile anesthetics, a propo-
fol-based technique may also have some advantages
in brain tumor patients; a prospective RCT
(NCT02756312) is ongoing. Although current evi-
dence does not yet support the need for a change in
clinical practice, anesthesiologists should consider
anesthetic technique as a potentially modifiable risk
factor for brain cancer recurrence. Further clinical
trials to evaluate the association between periopera-
tive factors (including anesthetic technique) and
long-term outcomes following brain tumour surgery
are urgently needed.
560 www.co-anesthesiology.com
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
Acknowledgements
J.S. drafted the manuscript. D.M. conceived the study
idea. All authors participated to write the manuscript.
D.M. is the archival author.
Financial support and sponsorship
The work was supported by a BOC Chair grant, RCoA,
London, UK. J.S. as a research fellow was supported by
Hirosaki University Graduate School of Medicine, Hir-
osaki, Japan.
Conflicts of interest
There are no conflicts of interest.
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