Impact of Intraoperative Stimulation Brain Mapping on

Glioma Surgery Outcome: A Meta-Analysis

Philip C. De Witt Hamer, Santiago Gil Robles, Aeilko H. Zwinderman, Hugues Duffau, and Mitchel S. Berger
See accompanying editorial doi: 10.1200/JCO.2011.40.6959
Philip C. De Witt Hamer, Neurosurgical
Center Amsterdam, Vrije Universiteit
University Medical Center; Aeilko H.
Zwinderman, Academic Medical
Center, University of Amsterdam, the
Netherlands; Santiago Gil Robles,
Hospital Quiron, Madrid, Spain; Hugues
Duffau, Ho pital Gui de Chauliac, Le
Centre Hospitalier Regional Universita-
ire de Montpellier, and Institut National
de la Sant et de la Recherche Mdi-
cale 1051, Institute for Neurosciences
of Montpellier, Montpellier, France; and
Mitchel S. Berger, Brain Tumor
Research Center, University of Califor-
nia, San Francisco, San Francisco, CA.
Submitted July 24, 2011; accepted
February 29, 2012; published online
ahead of print at www.jco.org on April
23, 2012.
Authors disclosures of potential con-
icts of interest and author contribu-
tions are found at the end of this
article.
Corresponding author: Philip C. De Witt
Hamer, MD, PhD, Neurosurgical Center
Amsterdam, VU University Medical
Center, De Boelelaan 1117, 1081 HV
Amsterdam, the Netherlands; e-mail:
p.dewitthamer@vumc.nl.
2012 by American Society of Clinical
Oncology
0732-183X/12/3099-1/$20.00
DOI: 10.1200/JCO.2011.38.4818
A B S T R A C T
Purpose
Surgery for inltrative gliomas aims to balance tumor removal with preservation of functional
integrity. The usefulness of intraoperative stimulation mapping (ISM) has not been addressed in
randomized trials. This study addresses glioma surgery outcome on the basis of a meta-analysis
of observational studies.
Methods
A systematic search retrieved 90 reports published between 1990 and 2010 with 8,091 adult
patients who had resective surgery for supratentorial inltrative glioma, with or without ISM.
Quality criteria consisted of postoperative neurologic examination details and follow-up timing.
New postoperative neurologic decits were categorized on the basis of timing and severity.
Meta-analysis with a Bayesian random effects model determined summary event rates of decits
as well as gross total resection rate and eloquent locations. Meta-regression analysis explored
heterogeneity among studies.
Results
Late severe neurologic decits were observed in 3.4% (95% CI, 2.3% to 4.8%) of patients after
resections with ISM, and in 8.2% (95% CI, 5.7% to 11.4%) of patients after resections without
ISM (adjusted odds ratio, 0.39; 95% CI, 0.23 to 0.64). The percentages of radiologically conrmed
gross total resections were 75% (95% CI, 66% to 82%) with ISM and 58% (95% CI, 48% to 69%)
without ISM. Eloquent locations were involved in 99.9% (95% CI, 99.9% to 100%) of resections
with ISM and in 95.8% (95% CI, 73.1% to 99.8%) of resections without ISM. Relevant sources
of heterogeneity among studies were ISM, continent, and academic setting.
Conclusion
Glioma resections using ISM are associated with fewer late severe neurologic decits and more
extensive resection, and they involve eloquent locations more frequently. This indicates that ISM
should be universally implemented as standard of care for glioma surgery.
J Clin Oncol 30. 2012 by American Society of Clinical Oncology
INTRODUCTION
Resective surgery is a widely used treatment for in-
ltrative glioma, along with irradiation and chemo-
therapy. The annual incidence for glioma is six per
100,000. Inltrativegliomas invadethebrain, relent-
lessly recur, transform into higher-grade gliomas,
and are invariably lethal.
1-3
Brain surgery for inltrative gliomas aims to
balance extensive removal of glioma tissue inltrat-
ing the brain with preservation of functional integ-
rity by avoiding critical brain structures. The extent
of glioma resection independently correlates with
patient survival,
4-6
but when resective surgery ex-
tends too far into inltrated critical structures, the
patients condition permanently worsens and both
quality of life andsurvival are compromised. Several
neurosurgical advances aimto improve patient out-
come. To localize critical brain structures and tu-
mor, techniques such as preoperative functional
neuroimaging, neuronavigation, uorescent dyes,
magnetic resonance imaging (MRI) in the surgi-
cal eld, and intraoperative stimulation mapping
(ISM) have been used.
7
ISM is used to map brain
function and to monitor neurologic performance,
oftenunder local anesthesia.
8
Theusefulness of these
techniques andtheir impact onneurologic outcome
(as a measure of surgical safety) have not been ad-
dressed in randomized trials or by meta-analysis.
Here, we present event rates of newneurologic
decits after resective brain surgery in adults with
supratentorial inltrative glioma by performing a
JOURNAL OF CLINICAL ONCOLOGY
R E V I E W A R T I C L E
2012 by American Society of Clinical Oncology 1
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Published Ahead of Print on April 23, 2012 as 10.1200/JCO.2011.38.4818
Copyright 2012 by American Society of Clinical Oncology
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meta-analysis of published observational studies. In particular, we
addressed the impact of ISM and other determinants on neuro-
logic outcome.
METHODS
Search Strategy
Weaimedtoidentifyall publications reportingnewneurologicdecits in
adult patients after resective glioma surgery, irrespective of the study design,
setting, or language, inaccordance withMeta-Analysis of Observational Stud-
ies in Epidemiology (MOOSE) guidelines.
9
Our data sources included the
National Library of Medicine (PubMed/MEDLINE) andthe Excerpta Medica
Database (EMBASE). Relevant reviews and editorials were assessed for publi-
cations of potential interest, but no further publications were identied. The
publication period was restricted to January 1, 1990, to January 1, 2010 (ac-
cessed April 12, 2010). MeSHand EMTREE subject headings were combined
for patient-related, treatment-related, and outcome-related characteristics
(Data Supplement).
Abstracts of identied studies were reviewed, and any study reporting
neurologic outcome was included for full-text analysis by two independent
observers (with 3- and 4-year qualications as neurosurgical attendings, re-
spectively). In cases of multiple publications from the same cohort, the most
recent report was chosen.
Study Selection Criteria
Publications included in our analysis had an adult population of 20 or
more, provideddetails of newdecits todetermineseverityat patient level, and
described the postoperative timing of neurologic assessment. Publications
were excluded on the basis of location of gliomas other than supratentorial
intraparenchymal, event rates of specic neurologic decits only, or glioma
grading other than WHO grade 2 to 4. Disagreement on inclusion between
observers was resolved by discussion or by using a third observer for adjudi-
cation. The inter-rater agreement was calculated. In accordance with the
MOOSE guidelines, several other quality criteria were scored that were not
used for inclusion but were used to dene sets of publications of high and
intermediate quality: aim of the study, consecutive recruitment, data collec-
tion, loss of follow-up and missing data, surgical techniques, denition of
eloquence, preoperative neurologic condition, eligibility criteria, histopathol-
ogy, and discussion of possible confounders and bias. We searched the refer-
ences by hand to identify additional studies.
Outcome Measures and Denitions
The primary outcome measure was the event rate of new postoperative
neurologic decits. Decits were categorized according to severity (severe or
less severe) andtimingof assessment (earlyor late). This resultedinfour decit
event rates as end points. In addition, we included mortality from any cause
within 30 days after resection.
Decits were considered severe when they involved muscle strength
grade 1 to 3 on the Medical Research Council Scale, aphasia or severe dyspha-
sia, hemianopia, or a vegetative state. All other neurologic decits were con-
sidered less severe, including grade 4 monoparesis, isolated central facial palsy
or other cranial nerve decit, dysnomia, somatosensory syndrome, or parietal
syndrome. Decits within 3 months after surgery were considered early and
decits after 3 months were considered late, as is customarily considered the
cutoff for permanency of postoperative neurologic decits. To assess the
relation between ISMand neurologic outcome more specically, decits were
extractedat study level andalsowithinstudies for patient populations that had
resective surgery with and without ISM.
Because considerable heterogeneity was expected across observational
studies, several potential sources of heterogeneity were speciedandextracted
from the publications. We distinguished sources related to publication, pop-
ulation, or management characteristics. Publication-related characteristics
were publication quality, year and continent of publication, study setting and
design, prospective versus retrospective data collection, and the data source.
Patient populationrelated characteristics were mean age; glioma volume and
diameter; percentage of patients with preoperative decits, second surgery,
and large gliomas, according to the authors denition; patients with gliomas
located eloquently according to the authors denition; and patients with
low-grade glioma (WHO grade 2) compared with high-grade glioma (WHO
grade 3 or 4).
10
Treatment-related characteristics were preoperative diagnos-
tics and intraoperative techniques. Preoperative diagnostics included func-
tional MRI, white matter tractography, and functional magnetic source
imaging. Intraoperative techniques includedpercentage of patients withresec-
tions using ISM. For ISM, we distinguished electrostimulation frommotor or
somatosensory evoked potentials. Other intraoperative techniques included
intraoperativeMRI, neuronavigation, andultrasonography. Thepercentageof
patients in whomgross total resections were obtained according to postoper-
ative neuroimaging was also extracted.
Statistical Analysis
The endpoints were expressedas logit-transformedevent rates andwere
analyzed in a random effects meta-analysis model. A random effects model
was applied because indications for intervention, techniques, patient charac-
teristics, and outcome assessments were likely to be dissimilar across studies.
The randomeffects model took into account both within-study and between-
study variation. The I
2
statistic quanties the percentage of total variation
betweenstudies that is attributable toheterogeneity rather thantochance.
11-13
The relation between the potential sources of heterogeneity and outcome
measures was explored by using logistic meta-regression modeling of covari-
ates. Logistic regression coefcients were calculated. Odds ratios (ORs) and
95% Bayesian CIs were determined from regression coefcients and consid-
ered statistically signicant for covariates when the 95% CI excluded one. A
multivariate model was built on the basis of the deviance information crite-
rium.
14
Bayesianhierarchical meta-analysis andmeta-regressionwere applied
(Data Supplement), because event rates were frequently close to or equal to
zero, and end point and covariate data were partially missing.
15-18
Given the
event rates and the number of patients, the number of events in a study was
representedbyabinomial distribution. Thelogit-transformedevent rates were
assumed to be normally distributed with unknown means and unknown
precisions using mean 0 and variance 1 10
4
as vague priors. Vague priors
were chosen to primarily reect inference from the presented data without
substantive prior knowledge. For the precision of between-study variations,
we selected uniform distributions between 0 and 100. The median values of
posterior distributions were used as summary event rate estimates with 95%
credibility intervals based on three parallel chains of 50,000 Markov chain
Monte Carlo simulation samples after a sufcient number of burn-ins using
Gibbs sampling by JAGS software, version 2.2.0 (Jags Software, Newark, DE;
http://mcmc-jags.sourceforge.net) called from the R2jags package, version
0.02-11 (http://cran.r-project.org/web/packages/R2jags/index.html) for R,
version 2.12.1 (R Foundation for Statistical Computing, Vienna, Austria;
http://www.R-project.org). Sampling traces and distributions and Gelman-
Rubin diagnostics were obtained by using the coda package for R, version
0.14-2 (http://cran.r-project.org/web/packages/coda/index.html).
19
No evi-
dence against convergence was identied.
Sensitivity analysis was performed by using alternative vague priors and
by analyzing the high-quality subset. Similar posterior inferences were ob-
tained. Publication bias was explored by plotting the event rate versus sample
size and by funnel plot regression using the inverse variance as weight and
zero-cell correction by adding 0.5.
20,21
RESULTS
The search strategy retrieved 5,167 publications (Fig 1). After screen-
ing, 366candidate publications were reviewedinfull text, including14
additional publications retrieved from citations. Consensus was
reachedon90for inclusion, of which65were highquality and25were
intermediate quality. The initial agreement between observers was
substantial (Cohens 0.63).
The study characteristics of the 90 publications are listed in the
Data Supplement. The events mainlyconsistedof motor andlanguage
De Witt Hamer et al
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decits (DataSupplement). Themedianfollow-upwas 7days for early
outcome and 180 days for late outcome. The cohorts varied between
20 and 648 patients, with a median of 50 patients. Patients were
includedconsecutivelyin45studies. Datawere collectedprospectively
in14 studies. Nearly all studies reported observational cohorts, except
for two randomized studies. These trials were also considered obser-
vational with respect to neurologic outcome, because the primary
outcome measure consisted of extent of resection. One trial random-
ized the type of anesthesia, and the other randomized the use of
uorescent dye to detect tumor.
22,23
Neurologic Events
The overall meta-analysis of 90 studies included 8,091 patients.
Not all studies allowed extraction of all end points. The summarized
event rates are plotted in Figure 2. The event rates for each study are
provided in the Data Supplement. Early severe decits were observed
in 22.9% (95% CI, 16.5% to 30.6%) of 6,066 patients from 73 publi-
cations, andearly decits of any severity were observedin30.3%(95%
CI, 21.9%to 40.0%). Late severe decits were observed in 4.6%(95%
CI, 3.3% to 6.1%) of 6,095 patients from 75 publications, and late
decits of any severity were observedin7.1%(95%CI, 5.3%to9.0%).
Mortality rates could be extracted from all 90 studies and were ob-
served in 0.26%(95%CI, 0.01%to 0.50%). No evidence for publica-
tion bias due to lack of small studies with high event rates was
identied (P .814; Data Supplement).
The heterogeneity of event rates was considerable for early de-
cits (I
2
97.4%for severe decits and97.8%for any decits) andwas
substantial for late decits (86.1% and 87.0%, respectively). The het-
erogeneity for mortality was acceptable (56.7%).
Subgroup Analysis of Sources of Heterogeneity and
the Multivariate Model
Because of this heterogeneity, we deemed an exploration of po-
tential sources necessary (Data Supplement). Because avoiding per-
manent neurologic decits is of primary importance, we focused on
late severe decits for the subgroup analysis. The following factors
were indicated as being signicantly related to late severe decits (in
decreasing order of explainedvariance): (1) the percentage of patients
with resections using ISM, particularly with electrostimulation, was
3.4%(95%CI, 2.1%to 5.0%) of late severe events (OR, 0.42; 95%CI,
0.23 to 0.72) rather than evoked potentials (5.7%; 95% CI, 2.9% to
10.2%; OR, 0.72; 95% CI, 0.36 to 1.40) compared with resections
without ISM(7.7%; 95%CI, 5.0%to11.5%); (2) the continent, either
NorthAmerica (4.0%; 95%CI, 2.2%to6.6%; OR, 0.34; 95%CI, 0.2to
0.83) or Europe (4.1%; 95%CI, 2.7%to 5.9%; OR, 0.35; 95%CI, 0.14
to 0.76) compared with other continents (11.3%; 95% CI, 5.2% to
21.5%); and (3) an academic study setting (4.3%; 95% CI, 3.0% to
5.7%; OR, 0.29; 95% CI, 0.09 to 0.99) compared with other settings
(13.3%; 95% CI, 4.6% to 33.8%). A fourth signicant factor was
whether ISMwas used for all patients in the study cohort (3.1%; 95%
CI, 1.9% to 4.7%; OR, 0.43; 95% CI, 0.23 to 0.79) or in a subset of
patients (5.5%; 95% CI, 2.7% to 10.0%; OR, 0.77; 95% CI, 0.34 to
1.76) compared with cohorts in which ISMwas not used (7.0%; 95%
CI, 4.4%to10.6%). Obviously, this is avariant of the rst factor. These
Publications excluded on third pass (full text) (n = 276)
No details of neurologic deficits (n = 88)
) 4 6 = n ( y g o l o h t a p r e h t O
) 1 2 = n ( s t n e i t a p 0 2 n a h t r e w e F
) 7 1 = n ( e g a u g n a l e l b a t a l s n a r t n U
) 6 1 = n ( n o i t a c o l r e h t O
) 6 = n ( y r e g r u s e v i t c e s e r o N
) 5 = n ( w e i v e R
Report on single type of deficit (n = 4)
) 3 = n ( a t a d t l u d a e l b a r a p e s o N
) 3 = n ( t r o h o c e t a c i l p u D
) 3 = n ( y p a r e h t n o i t a n i b m o C
) 2 = n ( t n e m s s e s s a f o g n i m i t o N
Publications excluded on second pass (abstract) (n = 809)
) 7 3 3 = n ( e m o c t u o c i g o l o r u e n o N
) 0 9 1 = n ( s t n e i t a p 0 2 n a h t r e w e F
) 2 4 1 = n ( e l b a l i a v a n u t x e t l l u F
) 5 3 = n ( w e i v e R
) 4 3 = n ( y r e g r u s e v i t c e s e r o N
) 0 3 = n ( t n e m t a e r t n o i t a n i b m o C
Report on single type of deficit (n = 24)
) 1 2 = n ( n o i t a c o l r e h t O
) 0 2 = n ( y g o l o h t a p r e h t O
) 0 1 = n ( a t a d t l u d a e l b a r a p e s o N
Publications excluded on first pass (title) (n = 4,005)
) 8 6 6 = n ( s e t a c i l p u D
) 7 3 3 , 3 = n ( e l t i t f o s i s a b n O
Potentially relevant publications
identified by search (N = 5,167)
MEDLINE (n = 2,984)
EMBASE (n = 2,183)
Publications included (n = 90)
in meta-analysis
High quality (n = 65)
Intermediate quality (n = 25)
Publications retrieved
for more detailed evaluation
(n = 1,162)
Candidate publications
(n = 352)
Additional publications
from reference lists
(n = 14)
Fig 1. Flow chart of publication selection.
Meta-Analysis of Glioma Surgery Outcome
www.jco.org 2012 by American Society of Clinical Oncology 3
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factors were considered the major sources of heterogeneity, as also
substantiated by reduction of I
2
in the subgroups. The multivariate
model had anoptimal t by using the study setting as a confounder to
ISMon which the adjusted ORs were based.
Intraoperative Stimulation Mapping
Because ISM is the most important source of heterogeneity, we
extracted subpopulations that had resections with and without ISM
from the study cohorts (Fig 2). Early decits could be extracted from
42 publications for 3,602 patients after resections with ISM and from
26 publications for 1,537 patients after resections without ISM. Late
decits couldbe extractedfrom41publications for 3,230patients after
resections with ISM and from 33 publications for 1,731 patients after
resections without ISM. Earlysevere decits occurredmore frequently
inpatients after resections withISM(36.0%; 95%CI, 24.9%to49.1%)
thanwithout ISM(11.3%; 95%CI, 5.9%to20.2%; adjustedOR, 4.25;
95% CI, 1.80 to 10.2). Importantly, event rates subsided to substan-
tially fewer late severe decits withISM(3.4%; 95%CI, 2.3%to4.8%)
than without ISM (8.3%; 95% CI, 5.6% to 11.3%; adjusted OR, 0.39;
95%CI, 0.23to0.64). Comparable results were obtainedfor decits of
any severity. This indicates that reversible temporary loss of function
of critical brain structures is more frequent with ISM, but irreversible
neurologic damage is more effectively avoided, in comparison with
resective surgery, without ISM.
Of course, the favorable event rate needs to be in balance with
tumor control. Because fewsurvival data were reported, we decidedto
take extent of resection into account for tumor control. To illustrate
this with an extreme example, neurologic events can be further re-
duced by restricting resections to biopsy samples without having any
therapeutic impact. The relation between functional and oncologic
outcome for resective surgery with or without ISM was plotted in
Figure 3Aas a percentage of gross total resections versus percentage of
late severe decits. Evidently, the use of ISMdoes not compromise the
gross total resection rate. On the contrary, these results indicate that
gross total resections are achieved more frequently with ISM (74.9%;
95%CI, 67.1%to81.9%) thanwithout ISM(58.1%; 95%CI, 47.4%to
68.6%; OR, 2.15; 95%CI, 1.18 to 3.87).
Moreover, the patient populations with ISM appear to be
more complex because eloquent locations were involved in all
patients. This is depicted in Figure 3B as percentage of eloquent
localizations versus percentage of late severe decits. Gross total
resections are generally more likely achieved in patients with less
complex gliomas that are not in proximity to critical brain regions.
Conversely, the closer the relation between glioma and critical
brain region, the more likely a partial resection is. In this respect,
the meta-regression lines in Figure 3 support the idea that ISM is
generally not useful in patients with gliomas in non-eloquent loca-
tions but is all the more important in patients with more complex
gliomas to determine where to end a partial resection to avoid
permanent neurologic decits. Thus, ISMis valuable in optimizing
resective surgery by minimizing the rate of late severe decits and
maximizing the extent of (partial) resection, particularly for glio-
mas involving eloquent brain regions.
DISCUSSION
The main nding of this meta-analysis is that resective surgery
with ISM is associated with reduction in late severe neurologic
decits in adult patients with supratentorial inltrative gliomas
two times greater thanthat with surgery without ISM, after anearly
increase in temporary severe decits. The benecial neurologic
A
B
I
2
(%) 95% CI (%)
97.8 96.8 to 98.5
97.5 96.4 to 98.4
95.3 92.9 to 97.0
Percentage 95% CI (%)
22.9 16.5 to 30.6
36.0 24.9 to 49.1
11.3 5.9 to 20.2
Early Neurologic Outcome
Any Deficits Severe Deficits
Late Neurologic Outcome
Glioma resections
With stimulation mapping
Without stimulation mapping
Glioma resections
With stimulation mapping
Without stimulation mapping
Percentage 95% CI (%)
30.3 21.9 to 40.0
47.9 35.0 to 61.7
14.2 7.4 to 25.4
Publications
73
42
26
N
6,066
3,602
1,537
Publications
75
41
33
N
6,095
3,230
1,731
I
2
(%) 95% CI (%)
97.4 96.2 to 98.3
97.4 96.1 to 98.3
94.8 92.1 to 96.6
I
2
(%) 95% CI (%)
87.0 80.0 to 92.3
81.5 70.7 to 89.1
82.5 72.2 to 89.5
I
2
(%) 95% CI (%)
86.1 78.0 to 91.8
70.4 53.8 to 82.6
78.5 64.7 to 88.0
Percentage 95% CI (%)
7.1 5.3 to 9.0
6.4 4.4 to 8.8
9.4 6.4 to 13.1
Percentage 95% CI (%)
4.6 3.3 to 6.1
3.4 2.3 to 4.8
8.3 5.6 to 11.3
0 20 40 60 80 0 20 40 60 80
0 5 10 15 20 0 5 10 15 20
Any Deficits Severe Deficits
e g a t n e c r e P e g a t n e c r e P
e g a t n e c r e P e g a t n e c r e P
Fig 2. Neurologic outcome of glioma resections. Meta-analysis results using a Bayesian random effects model have been summarized with 95% Bayesian CIs for all
glioma resections (black diamonds), for glioma resections with intraoperative stimulation mapping (large gold squares), and without intraoperative stimulation mapping
(small blue squares). Square sizes are drawn proportional to precision. Neurologic outcome is categorized by timing and severity. Timing distinguishes between early
and late outcome at least 3 months after resection. Severity distinguishes between severe neurologic decits and any neurologic decits, including severe and less
severe decits. The number of publications from which relevant data could be extracted is listed along with corresponding numbers of patients, the summary
percentages with 95% CIs, and the measures of heterogeneity between studies (I
2
with 95% CIs).
De Witt Hamer et al
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outcome from resective glioma surgery with ISM does not com-
promise the extent of resection and involves eloquent locations
more frequently.
These ndings are in accordance with the concept that critical
structures exist in the brain that cannot be resected without loss of
functional integrity but that can be reliably mapped by electrostimu-
lation during brain surgery. Electrostimulation interferes with neuro-
logic performance by temporarily inactivating brainregions withhigh
resolution, to judge before tissue removal whether a tumor can be
resected without permanent loss of function. The observed transient
neurologic decits usually subside within a few weeks to 3 months
after resectionandare due tothe nearness of critical brainstructures to
the resection cavity. In the margin of the resection cavity, resection-
induced contusion, edema, and hypoperfusion are factors that likely
contribute to these reversible decits. Another explanation could be
the relocation of involved brain networks.
24
ISMenables more exten-
sive tumor removal for better tumor control,
25
while reliably identify-
ing critical brain structures so that permanent decits can be avoided
at the price of transient decits.
Several strategies can be used to minimize these transient
decits in patients for whoma transient decit is considered unac-
ceptable. First, the distance to the critical structures can be varied
to create a safety margin by either increasing the stimulator current
or by impinging the stimulator in the resection cavity wall for
stimulation ahead of the resection margin. This distance has been
shown to be an important factor for the time to recovery from
transient decits.
26,27
Obviously, an increase of this distance com-
petes with maximizing tumor removal, which may be considered
more acceptable in poor-prognosis patients with less benet from
an aggressive approach. Second, subpial dissection and particular
care to avoid vascular damage helps minimize hypoperfusion and
ischemia. Late and permanent decits are usually due to inadvertent
postresection ischemia which can be evaluated by using diffusion-
weighted MRI.
28,29
Third, perioperative corticosteroids minimize re-
active edema. Fourth, relocation of functional networks may be
facilitated by intense and specic rehabilitationafter surgery or, inthe
future, by preoperative enhancement of brain plasticity, for instance
by using transcranial magnetic stimulation.
24,30
To the best of our knowledge, this is the rst study to system-
atically summarize safety of resective glioma surgery. The compar-
ison of absolute risks of events with subgroup analysis of
confounding factors is the best evidence available to assess the
value of ISMwithout data fromrandomized trials. One strength of
our study was the broad search strategy for articles covering mod-
ern neurosurgical practice that were published over the last two
decades. Thus, we were able to reasonably estimate the rate of
postoperative neurologic events. In addition, the impact of several
factors, including management techniques such as ISM, was as-
sessed by meta-regression analysis. Sensitivity analysis indicates
that our ndings were robust to model assumptions.
Clearly, these ndings should be interpreted within the limita-
tions of a meta-analysis based on observational studies, because data
B A
0
With stimulation mapping
Without stimulation mapping
Publications
27
23
56
N
2,372
1,557
5,451
Percentage 95% CI (%)
74.8 66.5 to 81.7
58.3 48.4 to 68.0
68.6 62.6 to 74.4
Publications
46
24
69
N
3,783
1,232
5,752
Percentage 95% CI (%)
99.9 99.9 to 100
95.8 73.1 to 99.8
99.9 99.8 to 100
P
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l
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c
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t
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s
7
5
4
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C
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(
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2
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4
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8
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D
e
f
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s

(
%
)
Gross Total Resections (%)
25
20
15
10
5
20 40 60 80 0 0 0 1
With stimulation mapping
Without stimulation mapping
L
a
t
e

S
e
v
e
r
e

D
e
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s

(
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)
Eloquent Locations (%)
25
20
15
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20 40 60 80 100
240
120
60
20
Fig 3. Glioma surgery outcome after resections with and without intraoperative stimulation mapping. (A) The relation between oncologic and neurologic outcome is
plotted as a bubble chart with percentages of gross total resections (x-axis) and percentages of late severe neurologic decits (y-axis) for patient populations after
resection with (gold circles) and without (blue circles) intraoperative stimulation mapping. Sizes of circles are proportional to study cohort size. Regression lines are
plotted. Lines are not straight because of inverse logit transformation. Summary estimates and 95% Bayesian CIs for all glioma resections (black diamonds), resections
with intraoperative stimulation mapping (large gold squares), and without intraoperative stimulation mapping (small blue squares) are plotted and listed in the axis
margins. (B) The relation between eloquent localization and neurologic outcome is plotted with percentage of eloquent localizations (x-axis) and percentages of late
severe neurologic decits (y-axis). Color codes, sizes of circles, and logistic regression lines are similar to those in (A).
Meta-Analysis of Glioma Surgery Outcome
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are liable to be confounded by many factors, which is reected by the
levels of heterogeneity. We therefore restrictedinclusionby methodo-
logic quality and, within the restricted set, we distinguished studies of
high and intermediate quality. In addition, we analyzed potential
confounders by subgroup analysis. Furthermore, several sources of
bias are possible. First, publicationbias canresult inour ndings being
rather precise, withsmall 95%CIs, but less accurateas anestimationof
the ground truth of outcome in general neurosurgical practice, be-
cause published neurologic outcome does not necessarily reect gen-
eral clinical practice. Our results pertain more to glioma patients
treatedinlarge-volume academic hospitals dedicatedtoneuro-oncol-
ogy than to patients treated in general hospital settings that infre-
quently provide neuro-oncologic care. This is substantiated by the
overall low rate of mortality, which is known to correlate with large-
volume centers.
31,32
Second, the selectionbias of our ndings couldbe
due to patient selection with various indications for surgical interven-
tion. In this respect, the course of disease in patients who were denied
surgerywouldbe of interest. Astricter indicationpolicylikelyprovides
better neurologic outcome in a published cohort, whereas in referral
centers, patients with more complex tumors are treated. Another
source of bias concerns patient selection criteria for ISM, which is
mainly considered in eloquently located gliomas, as is conrmed by
the data. As a result, patients selected for ISM are more prone to
neurologic decits. It is inconceivable that baseline risk levels are
different because of the relative contraindications for ISMunder local
anesthesia, such as dense presurgical motor or language decits, ex-
tensive tumor mass effect, emotional instability, extreme obesity, or
infancy. Third, neurologic assessment is subject to a certain level of
suspicion. This observation bias can result in overestimation of neu-
rologic events in studies that aim to assess functional outcome and,
conversely, in underestimation of events in studies that determine
other disease aspects, such as oncologic outcome. The frequency and
timing of follow-up can be similarly affected by study perspective.
Fourth, in meta-analyses the effect size can be inaccurate when many
small studies are included, because these are liable to less quality of
design, execution, and analysis, or because these focus on a subgroup
of selected patients. Taking together the potential impact of this bias
and differential baseline risks of study cohorts, the true difference in
event rates between glioma resections with and without ISM is more
likely to be larger than that observed rather than smaller.
These ndings could have several implications for clinical
practice. The estimates of neurologic events will likely serve patient
counseling anddecisions for surgical management. Hence, our obser-
vations consolidate arguments for universal adoption of ISMas stan-
dard of care for glioma surgery because ISMincreases both safety and
efcacy of tumor removal, particularly in eloquent locations. ISM
shouldbe universally implementedinacademic neurosurgical centers
withdedicatedneuro-oncologic care andcalls for more liberal referral
patterns. ISMwas usedinonly19%of gliomaresections between1997
and 2000 in the United States.
33
There seems to be two general exceptions to the standard use of
ISM. First, patients inwhomaradiologicallycompleteresectioncanbe
achieved at a distance from critical brain structures do not benet
fromISM. To verify eloquence, a reasonably pragmatic approachis to
use empirical maps of residual tumor after resection rather than the
intuition of the individual surgeon.
34
The second exception concerns
patients in whom the advantage of decreased late neurologic decits
does not offset the time to resolution of the transient decits. For
instance, an older patient who is not in optimal condition with a
presumed glioblastoma in an eloquent region of which an extent of
resection of at least 80%
35
cannot be attained, is probably a poor
candidate for ISM. As a rule of thumb this applies when the expected
increase in survival from an aggressive resection approximates reha-
bilitation time.
Ultimately, a randomized controlled trial to determine the im-
pact of ISM on surgical safety and survival could account for the bias
and confounders inherent in our observations. So far, randomized
controlled trials for surgical interventions have proven difcult to
accomplish. Even more so, because our observations reinforce the
assumption that it is notoriously difcult, if not impossible for ethical
reasons, torecruit a control groupof patients withgliomas ineloquent
brain regions for resective surgery without ISM.
In conclusion, glioma resections using ISMare associated with a
reductionof late severe neurologic decits more thantwotimes that of
surgery without ISM and more extensive resection while involving
eloquent locations more frequently. These observations indicate that
ISM should be universally implemented as standard of care for gli-
oma resections.
AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
The author(s) indicated no potential conicts of interest.
AUTHOR CONTRIBUTIONS
Conception and design: All authors
Collection and assembly of data: Philip C. De Witt Hamer, Santiago
Gil Robles
Data analysis and interpretation: All authors
Manuscript writing: All authors
Final approval of manuscript: All authors
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