Escolar Documentos
Profissional Documentos
Cultura Documentos
Randy S. DAmico, MD, Zachary K. Englander, BA, Peter Canoll, MD, PhD, Jeffrey N.
Bruce, MD
PII: S1878-8750(17)30536-3
DOI: 10.1016/j.wneu.2017.04.041
Reference: WNEU 5558
Please cite this article as: DAmico RS, Englander ZK, Canoll P, Bruce JN, Extent of resection in glioma
a review of the cutting edge, World Neurosurgery (2017), doi: 10.1016/j.wneu.2017.04.041.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
PT
8
9 Corresponding Author: Randy S. DAmico
10 Phone: (212) 305-4118
RI
11 Fax: (212) 305-2026
12 Email: rd2398@cumc.columbia.edu
13
SC
14 Key Words: Glioblastoma; Extent of resection; Residual Volume; High-grade glioma; Low-
15 grade glioma; Intraoperative MRI; Fluorescence-guided resection; Sodium Fluorescein; 5-ALA;
16 Awake craniotomy; Cortical stimulation mapping
17
U
18 Running title: Extent of resection in gliomas
19
AN
20 Abbreviations: HGG = high-grade glioma; GBM = glioblastoma; LGG = low-grade glioma;
21 EOR = extent of resection; RCT = randomized controlled trial; MRI = magnetic resonance
22 imaging; CT = computed tomography; 5-ALA = 5-aminolevulinic acid; PFS = progression free
23 survival; OS = overall survival; MPFS = malignant progression free survival; GTR = gross total
M
24 resection; STR = subtotal resection; FLAIR = fluid-attenuated inversion recovery; LITT = laser
25 interstitial thermotherapy; CED = convection-enhanced delivery.
26
D
27 I, Randy S. DAmico, certify that this manuscript is a unique submission and has not been
28 previously published elsewhere, nor is it under consideration for publication, in part or in full,
TE
29 with any other source in any medium. All authors of this manuscript have contributed to, read,
30 and approved of the manuscript and its submission for publication. The authors have no conflicts
31 of interest, financial or otherwise, and will be happy to provide the required forms should the
EP
1
ACCEPTED MANUSCRIPT
35 ABSTRACT
36 Modern glioma surgery has evolved from the principle belief that safe, maximal tumor
37 resection improves symptom management, quality of life, progression-free survival (PFS), and
38 overall survival (OS) in both low- and high-grade glioma (LGG and HGG, respectively).
PT
39 However, in the absence of level I data, the overwhelming support for this idea is derived largely
RI
40 from retrospective series. As a result, the influence of increasing extent of resection (EOR) and
41 reducing tumor burden on the efficacy of postoperative chemotherapy and radiotherapy, and
SC
42 ultimately survival, remains inadequately defined. This is particularly true as gliomas represent a
43 widely heterogeneous group of tumors with varying behaviors and prognoses rooted in their
44
U
complex molecular profile. The neurosurgical community has put forth a large effort to define
AN
45 the clinical benefits of maximizing tumor resection, with particular attention paid to the ever-
47 been developed concurrently to mitigate neurological risks related to the pursuit of maximizing
D
48 EOR. These advances reflect the modern goal of glioma surgery to find the optimal balance
TE
49 between tumor removal and neurologic compromise. We review the current literature supporting
51
52
53
C
AC
2
ACCEPTED MANUSCRIPT
54 INTRODUCTION
55 Modern glioma surgery has evolved around the principle belief that safe, maximal tumor
56 resection improves symptoms, quality of life, progression-free survival (PFS), and overall
57 survival (OS) in both low- and high-grade gliomas (LGG and HGG, respectively).1-3 In
PT
58 comparison to established prognosticators in glioma such as patient age, tumor histology,
RI
59 functional status, and certain molecular markers, extent of resection (EOR) is unique in that it
60 represents a modifiable variable with which a surgeon has the ability to directly influence clinical
SC
61 outcomes through safe and aggressive tumor resection.
62 However, the infiltrative nature of gliomas, with their propensity for microscopic
63
U
dispersal through the brain and white matter, presents a unique challenge to achieving a complete
AN
64 resection.4-6 In particular, volumetric measurements of tumor size, EOR, and post-operative
65 residual tumor volume are typically performed on contrast-enhancing regions of tumor without
M
68 burden.19 This is particularly relevant in the setting of diffusely infiltrative non-enhancing LGG
69 where identification of the tumor volume relies primarily on the identification of T2/FLAIR
EP
70 abnormalities.20 As a result, gross total resection (GTR), defined as the complete radiographic
72 non-enhancing lesions, invariably fails to completely remove all microscopic residual,6 providing
AC
73 important context within which to evaluate the perceived benefits of GTR. Furthermore,
74 maximizing EOR requires caution as a failure to identify and preserve eloquent brain regions in
75 the pursuit of complete resection can significantly compromise performance and quality of life
3
ACCEPTED MANUSCRIPT
77 In the absence of level I data, the overwhelming support for maximizing EOR has been
78 derived largely from retrospective series. However, while the specific benefits of safe, maximal
80 prognosis, remain inadequately defined within the literature, a commitment to ensure maximum
PT
81 tumor resection with minimum neurologic comorbidity has guided much of the recent progress
RI
82 in glioma surgery. As a result, studies have identified molecular alterations with prognostic
83 implications in both LGG and HGG that are changing the way gliomas are being characterized,
SC
84 and which are providing valuable insights into the influence of maximizing EOR on prognosis
85 for distinct glioma subgroups.23-25 Similarly, a number of surgical adjuncts have been developed
86
U
to assist with the real-time identification of tumor, its infiltrative boundaries, and its relationships
AN
87 with critical anatomic and eloquent structures. These intraoperative adjuncts including,
89 stimulation mapping, and ultrasound, augment the surgeons ability to increase the EOR while
D
90 simultaneously minimizing the risk to critical neurovascular structures and eloquent brain.
TE
91 We review the body of evidence supporting safe, maximal resection in both LGG and
92 HGG, briefly discuss specific molecular markers that may influence resection in glioma, review
EP
93 recent technological advances that facilitate safe, maximal resection, and consider the overall
95
AC
96
4
ACCEPTED MANUSCRIPT
97 HIGH-GRADE GLIOMAS
98 Standard treatment for HGGWorld Health Organization (WHO) Grade III and Grade
100 radiation.26 Surgical resection establishes a histological diagnosis and reduces symptomatic mass
PT
101 effect with obvious benefit. However, the value of progressive cytoreduction is not definitively
RI
102 established. As a clinical trial randomizing patients to variable amounts of tumor resection is
103 unlikely, associations between outcomes and increasing EOR have been extrapolated from large,
SC
104 retrospective series examining heterogeneous populations of grade III anaplastic glioma
106
U
glioblastoma (GBM), and a few large clinical trials studying only GBM.
AN
107 While some early reports using non-volumetric imaging analyses of EOR failed to show
108 clear benefits of increasing EOR in HGG, 27-36 the majority of large series utilizing both non-
M
109 volumetric,22,37-51 as well as more precise volumetric imaging analyses of EOR,10-15,17 have
D
110 largely supported increased EOR as a predictor of both, PFS, and OS. In fact, precise, volumetric
TE
111 imaging analyses convincingly demonstrate a stepwise improvement in survival benefits with
112 increasing EOR (Table 1).10-13,15,17 These studies show that achieving at least 70-80% resection
EP
113 provides a measurable survival benefit in HGG, with incremental benefits in survival continuing
114 even at the highest levels of resection.17,52 Importantly, the benefits of increasing EOR persist in
C
115 the setting of tumor recurrence, where the clinical benefits of increasing EOR must be carefully
AC
117 Data supporting the benefits of EOR have also been extrapolated from randomized
118 controlled trials (RCT) studying HGG and GBM (Table 2). Of these, one prospective trial
119 comparing outcomes following tumor debulking versus stereotactic biopsy directly addressed
5
ACCEPTED MANUSCRIPT
120 EOR in HGG and demonstrated improved median survival for patients treated surgically as
121 compared with patients undergoing biopsy (171 days vs. 85 days, p = 0.035).53
122 Two additional randomized prospective trials indirectly examined the benefits of EOR in
123 GBM (Table 2). To date, the strongest evidence comes from the 5-aminolevulinic acid (5-ALA)
PT
124 group, which discovered a higher rate of GTR in patients undergoing resection with
RI
125 fluorescence-guidance (65% vs. 36%, p < 0.0001) that lead to improved 6-month PFS relative to
126 the conventional surgery group (41% vs. 21%, p = 0.0003), despite no difference in overall
SC
127 survival (15.2 months vs. 13.5 months, p = 0.1).49 Similarly, evidence from a prospective study
128 evaluating the capability of intraoperative MRI (iMRI) to enhance EOR in glioma patients
129
U
identified a higher rate of GTR in the iMRI group as compared with the conventional surgery
AN
130 group (96% vs. 68%, p = 0.0023) with increased 6-month PFS (67% vs. 36%, p = 0.046).54
131 Unfortunately, interpretation of results from studies examining the benefits of EOR
M
132 remains complicated by the heterogeneity of the available data. Studies have utilized different
D
133 imaging modalities, various methods of volume quantification, irregular timing of post-operative
TE
135 Similarly, HGG is a widely heterogeneous group of diseases, which differentially respond to
EP
136 both surgical and medical therapies.23,25,55 Despite this heterogeneity, a recent meta-analysis
137 reviewed 37 studies with 41,117 unique patients and found a decreased likelihood of disease
C
138 progression at 6-months and 1-year, as well as decreased mortality at both, 1- and 2-years in the
AC
139 setting of GTR as compared with subtotal resection (STR), offering strong support for the
141
6
ACCEPTED MANUSCRIPT
143 Compelling evidence in support of the benefits of EOR also exists for LGG. Here again,
144 the majority of studies utilizing non-volumetric imaging analyses,22,57-74 and all studies using
145 volumetric analyses7-9,16,18,75 have shown, both in hemispheric and insular WHO Grade I and II
PT
147 tumor, portends better OS, PFS, and malignant progression-free survival (MPFS, Table 3).
RI
148 Similar to HGG, persistent benefits of increased EOR in the setting of recurrent LGGwhere
149 repeat surgical intervention may be pursued with minimal risk to clinical performance status
SC
150 have resulted in reoperation being accepted as standard of care when a gross, or near-total
151 resection of the T2/FLAIR-hyperintense regions is expected.76-79 Some have even proposed
152
U
staging surgical resections for primary LGG to allow the patient to undergo chemotherapy
AN
153 between surgeries to both, fully maximize EOR and capitalize on the successes of adjuvant
154 therapy to optimize outcomes.80-83 Unfortunately as with HGG, class I evidence is scarce and the
M
156 The slow-growing nature of LGG prompts some unique considerations regarding the role
TE
157 of EOR. In particular, timing of the initial operative intervention has been debated. A watch and
158 wait approach was initially supported by evidence that conservative management resulted in a
EP
159 better quality-of-life as compared with surgical intervention.85 Furthermore, a study comparing
160 patients with LGG and epilepsy undergoing either immediate surgery and adjuvant therapy, or
C
161 delaying surgery until there was evidence of radiographic progression demonstrated no benefit in
AC
163 However, recent studies have better elucidated whether to pursue conservative
164 management or early surgical intervention.65,86 For example, evidence that prolonged seizure
165 history prior to surgical intervention adversely impacts OS provides support for upfront surgery
7
ACCEPTED MANUSCRIPT
166 in patients with seizures and imaging concerning for LGG.86 The strongest evidence to date
167 comes from a study of Norwegian patients treated in two hospitals in different geographical
168 regions that compared survival following two different treatment algorithms.65 While not a
169 randomized trial, treatment approach was essentially dependent on patient address as one
PT
170 hospital serving one area favored biopsy and watchful waiting, while the other hospital, serving a
RI
171 different area, favored upfront maximal safe resection at diagnosis. Interestingly, median
172 survival was significantly longer for patients treated with early maximal resection as compared
SC
173 with biopsied patients. Moreover, the authors reported 74% 5-year survival with upfront surgical
175
U
These data are further supported by evidence that resection of incidentally discovered
AN
176 LGG is safer and associated with better OS than resection of symptomatic LGG.87,88 As a result,
177 upfront maximal surgical resection is now supported for even asymptomatic, incidentally found
M
178 LGG.
D
179 The influence of EOR on the inevitable malignant transformation, and thus the natural
TE
180 history of these lesions is another unique consideration when pursuing resection for LGG.2,18,75
181 Evidence suggests that the median time to malignant transformation is improved with increasing
EP
182 EOR.2,18 In particular, Smith et al. reported on a mixed group of low-grade astrocytomas and
183 oligodendrogliomas and showed a median time to malignant transformation of 10.1 years, with
C
184 associated 5-year survival rates of 97% in patients receiving greater than 90% extent of resection
AC
186 5-year survival rates of 76% in patients with less than 90% extent of resection.18 However,
187 controversy exists as another study looking exclusively at WHO Grade II oligodendrogliomas
8
ACCEPTED MANUSCRIPT
190 Lastly, seizure management is critical to maintaining quality of life in glioma patients.
191 Seizures are the most frequent presenting symptom in patients with LGG and tumor-related
PT
192 epilepsy is associated with cognitive deterioration and significant morbidity.89 As many patients
RI
193 with low-grade tumors often survive many years, quality-of-life is thus a critical factor in
194 decisions regarding treatments. Evidence suggests that GTR of LGG in patients with tumor-
SC
195 related epilepsy yields a high rate of reduction in seizure frequency over STR, with many
197
U
In light of the compelling evidence in support of EOR for LGG, current standard of care
AN
198 is centered around maximal safe surgical resection. However, the treatment of LGG is evolving,
199 mainly because of increasingly important molecular and cytogenetic features with significant
M
200 prognostic implications (discussed below).93 Furthermore, the longevity associated with LGG
D
201 requires serious consideration of the toxicities of classic oncologic treatments such as radiation
TE
202 and chemotherapy. As a result, the risk-benefit ratio of observation or treatment with radiation
203 and chemotherapy must be weighed for each individual patient. Current trends in accepted
EP
204 practice suggest that young patients with LGG and favorable molecular profiles undergoing GTR
205 may be managed with surveillance in an effort to avoid the negative effects of chemotherapy and
C
206 radiation on quality-of-life.94,95 High-risk patients, defined as patients older than 40 years, or
AC
207 anyone undergoing STR are considered for further treatment with chemotherapy and radiation at
208 diagnosis.94,96 In particular, the management of young patients with lower-grade tumors and
209 unfavorable molecular markers remains unclear.94 These patients have a poor prognosis, and
210 observation may not be prudent. Notably, a subset of patients with prognostically favorable
9
ACCEPTED MANUSCRIPT
211 oligodendrogliomas may consider chemotherapy alone at initial diagnosis.94 Given the reliance
212 of targeted and personalized treatments on the identification of molecular and cytogenetic
213 prognosticators in acquired tissue, safe, maximal resection of LGG will likely remain at the
PT
215
RI
216 RESIDUAL TUMOR VOLUME
SC
218 total tumor resectedmay not fully capture the benefits of cytoreduction as compared with
219 studies evaluating the benefits of minimizing residual tumor volume.1 Specifically, EOR is not
220
U
consistent among different tumor sizes and resection of 90% of a large tumor may result in a
AN
221 greater actual volume of residual tumor than resection of 80% of a small tumor. As a result, a
222 discussion of EOR does not adequately depict the residual disease burden that must be addressed
M
225 operative MRI, has been evaluated in a number of retrospective analyses and evidence supports
226 that less residual volume is associated with improved PFS and OS.11,52,97-99 In particular, 5 cc has
EP
227 been defined as the maximum residual tumor volume significantly associated with prolonged
228 survival in HGG.52 Furthermore, residual contrast-enhancing volume and residual T2/FLAIR
C
229 volume may be independent predictors of survival in addition to EOR, with residual contrast-
AC
230 enhancing tumor volume being regarded as a significant radiological predictor of survival.98
231 Multivariate analyses of predictors of tumor progression in WHO Grade III lesions similarly
232 suggest that the volume of residual disease as measured on post-operative T2-weighted MRI is a
233 significant predictor of tumor progression.11 Of particular importance, some evidence suggests
10
ACCEPTED MANUSCRIPT
234 that reducing residual tumor volume may delay malignant transformation of LGG, with
236
PT
238 Even in the setting of a radiographically well-defined lesion, conventional MRI routinely
RI
239 underestimates the spatial extent of infiltrating gliomas. Tumor cells are found up to 20 mm
240 beyond imaging abnormalities in LGG, and throughout the involved hemisphere and even
SC
241 contralaterally in GBM.6,87 As a result, tumor recurrence frequently occurs in the immediate
243
U
When amenable, removal of a margin around the tumor visible on FLAIR-weighted MRI,
AN
244 i.e., a supratotal resection, might reduce the need for adjuvant therapy, improve outcomes in both
245 LGG and HGG, and delay malignant transformation in LGG.2,100 However, this remains
M
246 controversial as a formal definition of supra-total resection remains undefined2,100 and the
D
248 In one series comparing supratotal versus total resection for LGGs, and supported with
249 data from its own follow-up study, malignant transformation was not seen in any patients
EP
250 undergoing supratotal resection during a total of 11-years of follow-up.2,100 This was in
251 comparison to 24% of patients in the original control group undergoing malignant transformation
C
252 after a complete resection (p = 0.037). Furthermore, supratotal resection was associated with a
AC
253 reduction in the number of patients ultimately requiring adjuvant therapies.100 Minimizing the
254 need for adjuvant therapy is of particular relevance in LGG as TMZ-induced mutations may lead
11
ACCEPTED MANUSCRIPT
256 Supratotal resection may provide survival benefits in HGG as well. In a large study
257 reviewing 1229 patients with GBM over 19 years, prolonged survival was seen in patients that
258 underwent greater than 53% resection of the T2/FLAIR abnormality in addition to GTR of the
259 contrast-enhancing region (20.7 vs. 15.5 months, p < 0.001 ).102 In addition, Yan et al. analyzed
PT
260 EOR in anisotropic and isotropic regions of diffusion tensor imaging (DTI) on MRI and reported
RI
261 that increased resection of abnormal anisotropic and isotropic regions correlated with prolonged
262 PFS, while a larger residual anisotropic volume correlated with shorter time to progression. The
SC
263 authors determined that more extensive resection of abnormal isotropic as well as contrast-
265
U
AN
266 THE INFLUENCE OF MOLECULAR MARKERS ON EOR
267 In the last two decades, a number of recurring molecular alterations in both LGG and
M
268 HGG have been identified that are changing the way gliomas are characterized in light of their
D
270 mutations have strong associations with tumor type and therapeutic responses, and are associated
271 with prolonged survival.23,55 In fact, a recent restructuring of the WHO classification of diffuse
EP
272 gliomas incorporates these molecular parameters to better define specific tumor subtypes.93
273 Specifically, while in the past all astrocytic tumors had been grouped together, WHO grade II
C
274 and III oligodendrogliomas and the majority of WHO grade II and III astrocytomas are now sub-
AC
275 classified together based on the presence or absence of mutations in the IDH1 and IDH2 genes,
276 with oligodendroglioma being clearly distinguished through identification of the 1p/19q
277 codeletion.93 However, the relationships between specific molecular features of a tumor and
12
ACCEPTED MANUSCRIPT
278 EOR remains poorly characterized. As a result, several studies have sought to establish the role
280 IDH gene mutations identify tumors with different clinical presentations, genetic
281 alterations, and overall natural histories.55 IDH1 mutant gliomas are associated with better
PT
282 prognosis than tumors with wildtype IDH1, even after controlling for histological grade.
RI
283 Furthermore, IDH-mutants may demonstrate survival benefits with aggressive resection as
SC
285 Interestingly, the survival benefits of maximal resection may stratify within subgroups of
286 IDH-mutants. Recently, overall survival in patients with WHO Grade III gliomas, grouped
287
U
according to their IDH1/2 mutation status, and further stratified on the presence of 1p/19q co-
AN
288 deletions, was compared.25 Improved OS was noted in patients receiving GTR when tumors
289 contained IDH1/2 mutations but not 1p/19q co-deletions (77 months vs. undefined, p = 0.005).
M
290 GTR was not associated with OS in patients with IDH1/2 mutations and 1p/19q co-deletions, or
D
291 in the IDH1/2 wildtype group. These data suggested that surgical resection was critical to
TE
292 improving the prognosis of patients with grade III gliomas, especially in the setting of IDH1/2
293 mutations without associated 1p/19q codeletions. However, the study raised important questions
EP
295 In another study identifying WHO Grade II oligodendrogliomas prior to the 2016
C
296 reclassification, both EOR and reduced postoperative tumor volume were found to be significant
AC
297 predictors of OS and PFS, but not MPFS, after controlling for 1p/19q codeletion status.75 These
298 results suggested that the biologic effect of reducing tumor burden in oligodendrogliomas is
299 dissimilar to that for other LGG subtypes and that alterations of genetic and epigenetic
300 mechanisms by resection of LGG may vary uniquely by histological subtype. Of note, both
13
ACCEPTED MANUSCRIPT
301 studies were limited by small numbers and short follow-up times and do not address adjuvant
302 therapies. Furthermore, measurements of EOR and residual tumor volume in non-enhancing, or
303 minimally-enhancing, gliomas remains difficult to quantify with methods of evaluation varying
PT
305 Reports also suggest that IDH1-mutants may be more likely to achieve GTR than IDH1
RI
306 wild-type tumors (93% of IDH1 vs. 67% of IDH1 wildtype, p < 0.001), and multivariate
307 analyses has determined IDH1 mutation to be an independent factor associated with complete
SC
308 resection of enhancing disease, along with age and frontal lobe location.23 However, conflicting
309 evidence showing that improved EOR is not attributable to favorable genetic markers in LGG
310
U
suggests that maximizing surgical resection remains an important therapeutic factor to optimize
AN
311 prognosis in LGG, independent of the molecular pattern.24
312 Given the heterogeneity of available data, it remains difficult to draw significant
M
313 conclusions on the effect of GTR on molecular subtypes of glioma. However, as the molecular
D
314 and cytogenetic subtyping of LGG evolves, better-designed studies will be critical to developing
TE
315 appropriate treatment paradigms for these tumors. Based on the current data, particular focus is
317
319 Given the overwhelming support for maximizing EOR in the surgical treatment of
AC
320 glioma, a number of technological advances have been designed to enhance the surgeons ability
321 to better identify tumor and augment resection, while simultaneously minimize the risk to
322 eloquent brain. Technologies such as cortical and subcortical stimulation mapping, intraoperative
323 MRI (iMRI), functional neuronavigation, navigable intraoperative ultrasound, and fluorescence-
14
ACCEPTED MANUSCRIPT
324 guided resection all work to facilitate identification of tumor and preservation of brain anatomy
325 and function. However, whether these technologies offer additional long-term benefits to glioma
327
PT
328 Cortical and subcortical stimulation mapping.
RI
329 The resection of lesions involving eloquent areas requires preservation of both cortical
SC
331 interferes with neurologic function through temporary inactivation of brain regions and forms the
332 basis of cortical and subcortical stimulation mapping. Successive stimulation of neighboring
333
U
cortical areas to evoke motor movements or speech arrest permits real-time, intraoperative
AN
334 identification and monitoring of functionally critical regions. Subcortical stimulation mapping of
335 critical fiber tracts in combination with cortical stimulation mapping permits identification, and
M
336 guides the preservation of motor and language function while the surgeon works to maximize
D
337 tumor resection.104-107 A recent meta-analysis found that intraoperative cortical stimulation
TE
338 mapping reduces late, severe neurologic deficits without compromise of EOR, and suggests that
339 stimulation mapping should be implemented universally as standard of care for glioma surgery,
EP
341
C
343 Intraoperative MRI (iMRI) permits intraoperative correction of brain shift and
344 identification of tumor margins, adjusts surgical approaches, and monitors for complications, as
345 well as enables intraoperative detection and further resection of remaining tumor tissue.
346 Evidence suggests that iMRI increases EOR109-111 and OS in glioma patients.109,112,113 In a
15
ACCEPTED MANUSCRIPT
347 prospective, randomized trial comparing iMRI-guided resection to conventional microsurgery for
348 malignant gliomas, iMRI-guidance resulted in a higher rate of complete resection as compared
349 with controls (98% vs. 68%, respectively) and was associated with increased PFS, without
PT
351 While the clinical utility of iMRI has received strong support, the technology is yet to be
RI
352 considered standard of care for the management of gliomas. In particular, the installation and
353 cost of special equipment as well the additional operative time necessary for scans has limited
SC
354 the universal implementation of iMRI.
355
358 patient-specific functional and structural information with real-time intraoperative information to
M
359 assist with the safe and complete resection of intracranial lesions occurring in eloquent cortical
D
360 regions. In particular, functional MRI (fMRI) and diffusion tensor imaging (DTI) sequences
TE
361 appear promising as possible adjuncts to neuronavigation as they provide a means of identifying
362 eloquent cortical areas and the course of critical fiber tracts that may be at risk during tumor
EP
363 resection.114 Consequently, both fMRI and DTI have been shown to influence clinical decision-
364 making, surgical approach, and EOR.115-117 Additionally, some have suggested that multimodal
C
366 may further enhance surgical safety by reducing surgical time, identifying tracts for subcortical
16
ACCEPTED MANUSCRIPT
369 traditional navigation including inaccurate registration and brain shift with resultant loss of
371
PT
372 Navigable intraoperative ultrasound
RI
373 Intraoperative ultrasound (iUS) offers valuable real-time information about the location,
374 size, vascular relationships, and adjacent structures of brain tumors.121,122 As a result, iUS
SC
375 facilitates the identification of critical tumor margins during surgery and can help locate residual
376 tumor. Technologies such as contrast-enhanced iUS, or the ability to integrate iUS with
377
U
navigation systems may add additional benefits to its intraoperative use.114,121,122 Regardless, iUS
AN
378 is easily available, convenient, fast and easy to use and may provide a more practical alternative,
380
D
382 Fluorescence-guided resection has demonstrated great potential for maximizing EOR as it
384 number of fluorophores have been studied using various imaging techniques, 5-aminolevulinic
385 acid (5-ALA) and sodium fluorescein have shown the most promise for detecting residual tumor
C
388 protoporphyrin IX (PpIX) in malignant tissues compared with normal brain via the heme-
389 biosynthesis pathway.49 In a randomized controlled multicenter phase III trial, fluorescence-
390 guided resection using 5-ALA resulted in a 29% reduction in the proportion of patients with
17
ACCEPTED MANUSCRIPT
391 residual HGG on early MRI and an increase in PFS at 6 months compared to controls.49
392 Subsequent studies have further demonstrated the ability of 5-ALA to increase rates of safe
393 GTR, in particular when combined with mapping techniques in eloquent regions and the
PT
395 Sodium fluorescein is a green fluorescent compound that accumulates in areas of
RI
396 malignancy, vascular leaking defects, pooling defects and abnormal vasculature or
397 neovascularization. With the recent development of a surgical microscope fitted with fluorescent
SC
398 filter, several small studies have demonstrated increased rates of complete resection of contrast-
400
U
Interestingly, evidence suggests that both 5-ALA,127-130 and fluorescein125 may also stain
AN
401 non-enhancing regions of glioma permitting intraoperative identification of anaplastic foci in
403 critical as treatment decisions vary with histopathological diagnosis. Further study is necessary
D
404 to identify whether fluorescence-guidance can facilitate resection of tumor beyond the
TE
405 radiographically-defined margins in HGG and LGG. As future studies better clarify the
406 malignant potential of non-enhancing fluorescent tissue, further define the benefits of reducing
EP
407 residual tumor volume, and broaden our understanding of the role of supramaximal resection,
408 fluorescence-guided resection of non-enhancing tumor tissue may become an extremely valuable
C
410
413 minimally invasive technique that leads to cell death via the administration of heat.131
18
ACCEPTED MANUSCRIPT
414 Laser ablation of primary and recurrent HGGs that would formerly have undergone biopsies is
415 increasingly performed and reliably results in tumor cytoreduction.132 Multiple case series have
416 provided preliminary data supporting the safety and efficacy of laser ablation for recurrent
417 gliomas.133-136 Interestingly, a greater extent of tumor coverage with laser ablation treatment in
PT
418 both recurrent and newly diagnosed HGGs has demonstrated correlation with improved PFS
RI
419 suggesting that the extent of ablation may correlate with survival in a manner similar to extent of
420 resection achieved by traditional open surgery.135 Importantly, laser ablation provides the
SC
421 surgeon with the ability to treat deep seated tumors that might require traversing eloquent tissue
422 for conventional surgical resection and with future study may provide a valuable alternative to
423
U
maximizing cytoreduction when open resection is not safe.
AN
424
426 Convection-enhanced delivery (CED) is a drug delivery technique in which one or more
D
427 catheters are stereotactically-placed within target tissue for the direct infusion of therapeutic
TE
429 distributes therapeutic agents by principles of bulk flow, providing high local concentrations of
EP
430 drugs in the targeted tissue independent of the intrinsic diffusivity of the infusate. In the setting
431 of locally invasive gliomas, CED offers a method to bypass the blood-brain barrier (BBB) and
C
432 permit safe, targeted homogeneous delivery of high-concentration therapeutics to large brain
AC
433 volumes while simultaneously minimizing systemic toxicity. While a number of clinical trials
434 and small case series have attempted to characterize the clinical utility of CED in the
435 management of malignant glioma,138,139 these studies have suffered from ineffective delivery
19
ACCEPTED MANUSCRIPT
436 with poor infusate distribution and leakage into CSF spaces resulting in unwanted side effects
438 The efficacy of CED relies on both the ability of the technology to deliver therapy
439 effectively as well the ability of that therapy to elicit a valuable response. As a result, questions
PT
440 regarding catheter position, rates and volumes of infusion, and the effects of tissue
RI
441 cytoarchitecture and interstitial pressures in the setting of brain tumors remain unanswered.139,145-
148
442 Furthermore, although gadolinium co-infusion is routinely employed, the premise that CED
SC
443 enables targeting of large volumes is limited by the inability to visualize the distribution of the
444 infused therapy within the target tissue. Real-time tracking of infusions is critical to assessing the
445
U
clinical utility of CED and ensuring that therapy is appropriately and completely targeting the
AN
446 tissue of interest.149-152 Once technically optimized, the clinical success of CED will rely on the
447 identification of ideal therapeutics. With the evolving molecular and cytogenetic characterization
M
448 of gliomas and the importance of maximizing cytoreduction for the management of gliomas,
D
449 CED promises a valuable technique for safely covering both the radiographically defined tumor
TE
450 as well as the surrounding infiltrated brain tissue with targeted therapeutics.
C EP
AC
20
ACCEPTED MANUSCRIPT
451 CONCLUSION
452 Despite the absence of level I evidence clarifying the benefits of EOR on prognosis, the
453 consistency of available data supports the long-held principle that safe, maximal tumor resection
454 improves symptom management, quality of life, PFS, and OS in glioma patients. Recent
PT
455 advances in our understanding of specific molecular alterations within gliomas that may
RI
456 predispose certain tumor subtypes to improved outcomes with increasing resection, as well as
457 technological advances augmenting the ability of surgeons to optimize removal of pathological
SC
458 tissue while identifying and preserving functional brain, have the potential to further optimize the
459 surgical management of gliomas and permit personalized treatment approaches based on a
460
U
patients individual pathology and anatomy. In addition, as studies further clarify the role of
AN
461 supratotal resection for gliomas, real-time intraoperative technologies such as fluorescence-
462 guidance and its ability to identify non-enhancing residual tumor tissue may similarly improve
M
463 prognosis while we pursue novel targeted therapies and innovative methods of drug delivery for
D
464 the disease. In the meantime, the goal of the neurosurgeon remains to pursue the optimal balance
TE
465 between maximum tumor removal and maximal preservation of neurologic function.
466
EP
467
468
C
AC
21
ACCEPTED MANUSCRIPT
469 TABLES
470
Table 1. Stepwise improvement in survival benefits with extent of resection in high-grade glioma (WHO grades III
and IV).
Median
Median
Extent of progression Univariate Multivariate
Tumor No. overall
Study Year resection free analysis p analysis p
type patients survival
PT
(%) survival value value
(months)
(months)
Keles et al.10* 1999 GBM 107 100 13.3 23.3 <0.0005
75 - 99 11.5 22.1
RI
50 -74 8 15.7
25 - 49 6 14.1
<25 3.5 8
Lacroix et al.12**
SC
2001 GBM 416 >98 13 <0.0001 <0.0001
<98 8.8
Pope et al.15*** Not Not
2005 GBM 110 100 22.1
significant significant
90-99 17.1
U
20-89 11.1
<20 27.4
AN
Not Not
AG 42 0-100 67
significant significant
Keles et al.11 Not Not
2006 AA 102 0-100 25.5 41
significant significant
17
Sanai et al. 2011 GBM 500 100 16 <0.0001 0.004
M
>89 13.8
>79 12.8
>77 12.5
D
<98 14
Oppenlander et
2014 r-GBM 170 >97 30 0.001 0.005
al.13****
>80 20
EP
*Used CT and MR for volumetric measurements and had irregular post-operative imaging.
**Patient population included primary and recurrent GBM.
***Unclear method of volumetric measurements. No statistically significant improvement in outcomes for GBM. Data for
43 AGs not shown and EOR reported as not significant. AG comprised of anaplastic astrocytoma, oligodendroglioma, or
C
mixed oligoastrocytoma.
****Patient population included only recurrent GBM.
GBM = glioblastoma; r-GBM = recurrent GBM; AA = anaplastic astrocytoma; AG = anaplastic glioma; EOR = extent of
AC
resection.
471
472
22
ACCEPTED MANUSCRIPT
473
474
Table 2. Data from randomized trials supporting the role for surgery in HGG.
Media
No. Median P-
Tumor types n OS
Study Year Patien Study Groups (n) PFS value P -value
(n) (mont
ts (months)
hs)
PT
Vuorinen et
2003 30 Grade IV (19) Open Resection (10) vs. 5.7 0.035
al.53
Grade III (4) Stereotactic biopsy (13) 2.8
Other (7)
RI
Stummer et Fluorescence-guided resection
2006 270 Grade IV (260) 5.1 0.0003 15.2 0.1
al.49 (161) vs.
Conventional white-light
Grade III (9) 3.6 13.5
SC
microsurgery (161)
54
Senft et al. 2011 49 Grade IV (46) Intraoperative MRI (24) vs. 7.5 0.083
Grade III (2) Conventional treatment (25) 5.1
Other (1)
Patients who underwent complete resection had a longer PFS (7.5 vs. 3.3, p = 0.003)
U
OS = overall survival; PFS = progression free survival; BCNU = 1,3-bis (2-chloroethyl)-1-nitrosourea.
AN
M
D
TE
C EP
AC
23
ACCEPTED MANUSCRIPT
475
Table 3. Survival benefits with extent of resection in low-grade gliomas (WHO grade I & II) using volumetric analyses.
Extent
PT
No. of
Study Year Tumor type (No.) Conclusions
Patients resection
(%)
Patients who underwent subtotal resection
Oligodendroglioma (95) 100
RI
were at 1.4x the risk of disease recurrence
and 4.9x the risk of death relative to
Claus et
2005 Astrocytoma (35) 156 <100 patients undergoing gross total resection
al.7
There is a possible association between
SC
resection and survival for LGG using
Mixed (26)
intraoperative MRI.
100 Patients with at least 90% EOR had 5- and
8-year OS of 97% and 91%, respectively.
Astrocytoma (93)
U
90-99 OS was predicted by EOR, preoperative
and postoperative tumor volume on
AN
multivariate analysis.
Smith et 70-89
18 2008 216 PFS was predicted by preoperative and
al. Oligodendroglioma (91) postoperative tumor volume.
41-69 MPFS was predicted by EOR and
preoperative tumor volume.
M
24
ACCEPTED MANUSCRIPT
476 REFERENCES
477
478 1. Almeida JP, Chaichana KL, Rincon-Torroella J, Quinones-Hinojosa A. The value of extent
479 of resection of glioblastomas: clinical evidence and current approach. Curr Neurol
480 Neurosci Rep. 2015;15(2):517.
481 2. Duffau H. Long-term outcomes after supratotal resection of diffuse low-grade gliomas: a
482 consecutive series with 11-year follow-up. Acta Neurochir (Wien). 2016;158(1):51-58.
PT
483 3. Hervey-Jumper SL, Berger MS. Maximizing safe resection of low- and high-grade glioma.
484 J Neurooncol. 2016;130(2):269-282.
485 4. Albert FK, Forsting M, Sartor K, Adams HP, Kunze S. Early postoperative magnetic
RI
486 resonance imaging after resection of malignant glioma: objective evaluation of residual
487 tumor and its influence on regrowth and prognosis. Neurosurgery. 1994;34(1):45-60;
488 discussion 60-41.
SC
489 5. Berger MS. Malignant astrocytomas: surgical aspects. Semin Oncol. 1994;21(2):172-185.
490 6. Kelly PJ, Daumas-Duport C, Kispert DB, Kall BA, Scheithauer BW, Illig JJ. Imaging-based
491 stereotaxic serial biopsies in untreated intracranial glial neoplasms. J Neurosurg.
U
492 1987;66(6):865-874.
493 7. Claus EB, Horlacher A, Hsu L, et al. Survival rates in patients with low-grade glioma after
AN
494 intraoperative magnetic resonance image guidance. Cancer. 2005;103(6):1227-1233.
495 8. Hollon T, Nguyen V, Smith BW, Lewis S, Junck L, Orringer DA. Supratentorial hemispheric
496 ependymomas: an analysis of 109 adults for survival and prognostic factors. J
M
502 progression and survival in patients with glioblastoma multiforme of the cerebral
503 hemisphere. Surg Neurol. 1999;52(4):371-379.
504 11. Keles GE, Chang EF, Lamborn KR, et al. Volumetric extent of resection and residual
505 contrast enhancement on initial surgery as predictors of outcome in adult patients with
EP
509 2001;95(2):190-198.
510 13. Oppenlander ME, Wolf AB, Snyder LA, et al. An extent of resection threshold for
AC
511 recurrent glioblastoma and its risk for neurological morbidity. J Neurosurg.
512 2014;120(4):846-853.
513 14. Orringer D, Lau D, Khatri S, et al. Extent of resection in patients with glioblastoma:
514 limiting factors, perception of resectability, and effect on survival. J Neurosurg.
515 2012;117(5):851-859.
516 15. Pope WB, Sayre J, Perlina A, Villablanca JP, Mischel PS, Cloughesy TF. MR imaging
517 correlates of survival in patients with high-grade gliomas. AJNR Am J Neuroradiol.
518 2005;26(10):2466-2474.
25
ACCEPTED MANUSCRIPT
519 16. Sanai N, Berger MS. Glioma extent of resection and its impact on patient outcome.
520 Neurosurgery. 2008;62(4):753-764; discussion 264-756.
521 17. Sanai N, Polley MY, McDermott MW, Parsa AT, Berger MS. An extent of resection
522 threshold for newly diagnosed glioblastomas. J Neurosurg. 2011;115(1):3-8.
523 18. Smith JS, Chang EF, Lamborn KR, et al. Role of extent of resection in the long-term
524 outcome of low-grade hemispheric gliomas. J Clin Oncol. 2008;26(8):1338-1345.
PT
525 19. Wallner KE, Galicich JH, Krol G, Arbit E, Malkin MG. Patterns of failure following
526 treatment for glioblastoma multiforme and anaplastic astrocytoma. Int J Radiat Oncol
527 Biol Phys. 1989;16(6):1405-1409.
528 20. Gerin C, Pallud J, Deroulers C, et al. Quantitative characterization of the imaging limits of
RI
529 diffuse low-grade oligodendrogliomas. Neuro Oncol. 2013;15(10):1379-1388.
530 21. Gulati S, Jakola AS, Nerland US, Weber C, Solheim O. The risk of getting worse: surgically
SC
531 acquired deficits, perioperative complications, and functional outcomes after primary
532 resection of glioblastoma. World Neurosurg. 2011;76(6):572-579.
533 22. McGirt MJ, Chaichana KL, Gathinji M, et al. Independent association of extent of
534 resection with survival in patients with malignant brain astrocytoma. J Neurosurg.
U
535 2009;110(1):156-162.
536 23. Beiko J, Suki D, Hess KR, et al. IDH1 mutant malignant astrocytomas are more amenable
AN
537 to surgical resection and have a survival benefit associated with maximal surgical
538 resection. Neuro Oncol. 2014;16(1):81-91.
539 24. Cordier D, Goze C, Schadelin S, Rigau V, Mariani L, Duffau H. A better surgical
M
543 WHO grade III glioma harboring the IDH 1/2 mutation without the 1p/19q co-deletion. J
544 Neurooncol. 2016;129(3):505-514.
TE
545 26. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and
546 adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987-996.
547 27. Duncan GG, Goodman GB, Ludgate CM, Rheaume DE. The treatment of adult
548 supratentorial high grade astrocytomas. J Neurooncol. 1992;13(1):63-72.
EP
549 28. Hollerhage HG, Zumkeller M, Becker M, Dietz H. Influence of type and extent of surgery
550 on early results and survival time in glioblastoma multiforme. Acta Neurochir (Wien).
551 1991;113(1-2):31-37.
C
552 29. Huber A, Beran H, Becherer A, Prosenc N, Witzmann A. [Supratentorial glioma: analysis
553 of clinical and temporal parameters in 163 cases]. Neurochirurgia (Stuttg).
AC
554 1993;36(6):189-193.
555 30. Kowalczuk A, Macdonald RL, Amidei C, et al. Quantitative imaging study of extent of
556 surgical resection and prognosis of malignant astrocytomas. Neurosurgery.
557 1997;41(5):1028-1036; discussion 1036-1028.
558 31. Levin VA, Yung WK, Bruner J, et al. Phase II study of accelerated fractionation radiation
559 therapy with carboplatin followed by PCV chemotherapy for the treatment of anaplastic
560 gliomas. Int J Radiat Oncol Biol Phys. 2002;53(1):58-66.
26
ACCEPTED MANUSCRIPT
561 32. Phillips TL, Levin VA, Ahn DK, et al. Evaluation of bromodeoxyuridine in glioblastoma
562 multiforme: a Northern California Cancer Center Phase II study. Int J Radiat Oncol Biol
563 Phys. 1991;21(3):709-714.
564 33. Prados MD, Gutin PH, Phillips TL, et al. Highly anaplastic astrocytoma: a review of 357
565 patients treated between 1977 and 1989. Int J Radiat Oncol Biol Phys. 1992;23(1):3-8.
566 34. Puduvalli VK, Hashmi M, McAllister LD, et al. Anaplastic oligodendrogliomas: prognostic
PT
567 factors for tumor recurrence and survival. Oncology. 2003;65(3):259-266.
568 35. Sandberg-Wollheim M, Malmstrom P, Stromblad LG, et al. A randomized study of
569 chemotherapy with procarbazine, vincristine, and lomustine with and without radiation
570 therapy for astrocytoma grades 3 and/or 4. Cancer. 1991;68(1):22-29.
RI
571 36. Tortosa A, Vinolas N, Villa S, et al. Prognostic implication of clinical, radiologic, and
572 pathologic features in patients with anaplastic gliomas. Cancer. 2003;97(4):1063-1071.
SC
573 37. Barker FG, 2nd, Prados MD, Chang SM, et al. Radiation response and survival time in
574 patients with glioblastoma multiforme. J Neurosurg. 1996;84(3):442-448.
575 38. Buckner JC, Schomberg PJ, McGinnis WL, et al. A phase III study of radiation therapy plus
576 carmustine with or without recombinant interferon-alpha in the treatment of patients
U
577 with newly diagnosed high-grade glioma. Cancer. 2001;92(2):420-433.
578 39. Curran WJ, Jr., Scott CB, Horton J, et al. Does extent of surgery influence outcome for
AN
579 astrocytoma with atypical or anaplastic foci (AAF)? A report from three Radiation
580 Therapy Oncology Group (RTOG) trials. J Neurooncol. 1992;12(3):219-227.
581 40. Dinapoli RP, Brown LD, Arusell RM, et al. Phase III comparative evaluation of PCNU and
M
582 carmustine combined with radiation therapy for high-grade glioma. J Clin Oncol.
583 1993;11(7):1316-1321.
584 41. Jeremic B, Grujicic D, Antunovic V, Djuric L, Stojanovic M, Shibamoto Y. Influence of
D
585 extent of surgery and tumor location on treatment outcome of patients with
586 glioblastoma multiforme treated with combined modality approach. J Neurooncol.
TE
587 1994;21(2):177-185.
588 42. Lamborn KR, Chang SM, Prados MD. Prognostic factors for survival of patients with
589 glioblastoma: recursive partitioning analysis. Neuro Oncol. 2004;6(3):227-235.
590 43. Nitta T, Sato K. Prognostic implications of the extent of surgical resection in patients
EP
27
ACCEPTED MANUSCRIPT
605 48. Stark AM, Nabavi A, Mehdorn HM, Blomer U. Glioblastoma multiforme-report of 267
606 cases treated at a single institution. Surg Neurol. 2005;63(2):162-169; discussion 169.
607 49. Stummer W, Pichlmeier U, Meinel T, et al. Fluorescence-guided surgery with 5-
608 aminolevulinic acid for resection of malignant glioma: a randomised controlled
609 multicentre phase III trial. Lancet Oncol. 2006;7(5):392-401.
610 50. Ushio Y, Kochi M, Hamada J, Kai Y, Nakamura H. Effect of surgical removal on survival
PT
611 and quality of life in patients with supratentorial glioblastoma. Neurol Med Chir (Tokyo).
612 2005;45(9):454-460; discussion 460-451.
613 51. Vecht CJ, Avezaat CJ, van Putten WL, Eijkenboom WM, Stefanko SZ. The influence of the
614 extent of surgery on the neurological function and survival in malignant glioma. A
RI
615 retrospective analysis in 243 patients. J Neurol Neurosurg Psychiatry. 1990;53(6):466-
616 471.
SC
617 52. Chaichana KL, Jusue-Torres I, Navarro-Ramirez R, et al. Establishing percent resection
618 and residual volume thresholds affecting survival and recurrence for patients with newly
619 diagnosed intracranial glioblastoma. Neuro Oncol. 2014;16(1):113-122.
620 53. Vuorinen V, Hinkka S, Farkkila M, Jaaskelainen J. Debulking or biopsy of malignant
U
621 glioma in elderly people - a randomised study. Acta Neurochir (Wien). 2003;145(1):5-10.
622 54. Senft C, Bink A, Franz K, Vatter H, Gasser T, Seifert V. Intraoperative MRI guidance and
AN
623 extent of resection in glioma surgery: a randomised, controlled trial. Lancet Oncol.
624 2011;12(11):997-1003.
625 55. Bush NA, Butowski N. The Effect of Molecular Diagnostics on the Treatment of Glioma.
M
629 57. North CA, North RB, Epstein JA, Piantadosi S, Wharam MD. Low-grade cerebral
630 astrocytomas. Survival and quality of life after radiation therapy. Cancer. 1990;66(1):6-
TE
631 14.
632 58. Philippon JH, Clemenceau SH, Fauchon FH, Foncin JF. Supratentorial low-grade
633 astrocytomas in adults. Neurosurgery. 1993;32(4):554-559.
634 59. Rajan B, Pickuth D, Ashley S, et al. The management of histologically unverified
EP
635 presumed cerebral gliomas with radiotherapy. Int J Radiat Oncol Biol Phys.
636 1994;28(2):405-413.
637 60. Leighton C, Fisher B, Bauman G, et al. Supratentorial low-grade glioma in adults: an
C
638 analysis of prognostic factors and timing of radiation. J Clin Oncol. 1997;15(4):1294-
639 1301.
AC
640 61. Nakamura M, Konishi N, Tsunoda S, et al. Analysis of prognostic and survival factors
641 related to treatment of low-grade astrocytomas in adults. Oncology. 2000;58(2):108-
642 116.
643 62. Yeh SA, Ho JT, Lui CC, Huang YJ, Hsiung CY, Huang EY. Treatment outcomes and
644 prognostic factors in patients with supratentorial low-grade gliomas. Br J Radiol.
645 2005;78(927):230-235.
646 63. Ahmadi R, Dictus C, Hartmann C, et al. Long-term outcome and survival of surgically
647 treated supratentorial low-grade glioma in adult patients. Acta Neurochir (Wien).
648 2009;151(11):1359-1365.
28
ACCEPTED MANUSCRIPT
649 64. Chaichana KL, Zadnik P, Weingart JD, et al. Multiple resections for patients with
650 glioblastoma: prolonging survival. J Neurosurg. 2013;118(4):812-820.
651 65. Jakola AS, Myrmel KS, Kloster R, et al. Comparison of a strategy favoring early surgical
652 resection vs a strategy favoring watchful waiting in low-grade gliomas. JAMA.
653 2012;308(18):1881-1888.
654 66. Lote K, Egeland T, Hager B, et al. Survival, prognostic factors, and therapeutic efficacy in
PT
655 low-grade glioma: a retrospective study in 379 patients. J Clin Oncol. 1997;15(9):3129-
656 3140.
657 67. Nicolato A, Gerosa MA, Fina P, Iuzzolino P, Giorgiutti F, Bricolo A. Prognostic factors in
658 low-grade supratentorial astrocytomas: a uni-multivariate statistical analysis in 76
RI
659 surgically treated adult patients. Surg Neurol. 1995;44(3):208-221; discussion 221-203.
660 68. Scerrati M, Roselli R, Iacoangeli M, Pompucci A, Rossi GF. Prognostic factors in low grade
SC
661 (WHO grade II) gliomas of the cerebral hemispheres: the role of surgery. J Neurol
662 Neurosurg Psychiatry. 1996;61(3):291-296.
663 69. Ito S, Chandler KL, Prados MD, et al. Proliferative potential and prognostic evaluation of
664 low-grade astrocytomas. J Neurooncol. 1994;19(1):1-9.
U
665 70. Karim AB, Maat B, Hatlevoll R, et al. A randomized trial on dose-response in radiation
666 therapy of low-grade cerebral glioma: European Organization for Research and
AN
667 Treatment of Cancer (EORTC) Study 22844. Int J Radiat Oncol Biol Phys. 1996;36(3):549-
668 556.
669 71. Peraud A, Ansari H, Bise K, Reulen HJ. Clinical outcome of supratentorial astrocytoma
M
679 astrocytoma: prognostic factors, dedifferentiation, and the issue of early versus late
680 surgery. J Neurol Neurosurg Psychiatry. 1998;64(5):581-587.
681 75. Snyder LA, Wolf AB, Oppenlander ME, et al. The impact of extent of resection on
C
684 76. Uppstrom TJ, Singh R, Hadjigeorgiou GF, Magge R, Ramakrishna R. Repeat surgery for
685 recurrent low-grade gliomas should be standard of care. Clin Neurol Neurosurg.
686 2016;151:18-23.
687 77. Nahed BV, Redjal N, Brat DJ, et al. Management of patients with recurrence of diffuse
688 low grade glioma: A systematic review and evidence-based clinical practice guideline. J
689 Neurooncol. 2015;125(3):609-630.
690 78. Kaspera W, Majchrzak K, Bobek-Billewicz B, et al. Reoperations of patients with low-
691 grade gliomas in eloquent or near eloquent brain areas. Neurol Neurochir Pol.
692 2013;47(2):116-125.
29
ACCEPTED MANUSCRIPT
PT
699 followed by surgical resection as a new strategy for WHO grade II gliomas: a study of
700 cognitive status and quality of life. J Neurooncol. 2012;106(2):353-366.
701 82. Blonski M, Pallud J, Goze C, et al. Neoadjuvant chemotherapy may optimize the extent
702 of resection of World Health Organization grade II gliomas: a case series of 17 patients. J
RI
703 Neurooncol. 2013;113(2):267-275.
704 83. van den Bent MJ. Practice changing mature results of RTOG study 9802: another positive
SC
705 PCV trial makes adjuvant chemotherapy part of standard of care in low-grade glioma.
706 Neuro Oncol. 2014;16(12):1570-1574.
707 84. Aghi MK, Nahed BV, Sloan AE, Ryken TC, Kalkanis SN, Olson JJ. The role of surgery in the
708 management of patients with diffuse low grade glioma: A systematic review and
U
709 evidence-based clinical practice guideline. J Neurooncol. 2015;125(3):503-530.
710 85. Reijneveld JC, Sitskoorn MM, Klein M, Nuyen J, Taphoorn MJ. Cognitive status and
AN
711 quality of life in patients with suspected versus proven low-grade gliomas. Neurology.
712 2001;56(5):618-623.
713 86. Afra D, Osztie E, Sipos L, Vitanovics D. Preoperative history and postoperative survival of
M
717 88. Potts MB, Smith JS, Molinaro AM, Berger MS. Natural history and surgical management
718 of incidentally discovered low-grade gliomas. J Neurosurg. 2012;116(2):365-372.
TE
719 89. Englot DJ, Han SJ, Berger MS, Barbaro NM, Chang EF. Extent of surgical resection
720 predicts seizure freedom in low-grade temporal lobe brain tumors. Neurosurgery.
721 2012;70(4):921-928; discussion 928.
722 90. Chang EF, Potts MB, Keles GE, et al. Seizure characteristics and control following
EP
728 with low-grade astrocytomas and medically intractable seizures. Acta Neurol Scand.
729 2002;105(4):289-292.
730 93. Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization
731 Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol.
732 2016;131(6):803-820.
733 94. Bush NA, Chang SM, Berger MS. Current and future strategies for treatment of glioma.
734 Neurosurg Rev. 2017;40(1):1-14.
30
ACCEPTED MANUSCRIPT
735 95. Shaw EG, Berkey B, Coons SW, et al. Recurrence following neurosurgeon-determined
736 gross-total resection of adult supratentorial low-grade glioma: results of a prospective
737 clinical trial. J Neurosurg. 2008;109(5):835-841.
738 96. Buckner JC, Shaw EG, Pugh SL, et al. Radiation plus Procarbazine, CCNU, and Vincristine
739 in Low-Grade Glioma. N Engl J Med. 2016;374(14):1344-1355.
740 97. Capelle L, Fontaine D, Mandonnet E, et al. Spontaneous and therapeutic prognostic
PT
741 factors in adult hemispheric World Health Organization Grade II gliomas: a series of
742 1097 cases: clinical article. J Neurosurg. 2013;118(6):1157-1168.
743 98. Grabowski MM, Recinos PF, Nowacki AS, et al. Residual tumor volume versus extent of
744 resection: predictors of survival after surgery for glioblastoma. J Neurosurg.
RI
745 2014;121(5):1115-1123.
746 99. Roelz R, Strohmaier D, Jabbarli R, et al. Residual Tumor Volume as Best Outcome
SC
747 Predictor in Low Grade Glioma - A Nine-Years Near-Randomized Survey of Surgery vs.
748 Biopsy. Sci Rep. 2016;6:32286.
749 100. Yordanova YN, Moritz-Gasser S, Duffau H. Awake surgery for WHO Grade II gliomas
750 within "noneloquent" areas in the left dominant hemisphere: toward a "supratotal"
U
751 resection. Clinical article. J Neurosurg. 2011;115(2):232-239.
752 101. Johnson BE, Mazor T, Hong C, et al. Mutational analysis reveals the origin and therapy-
AN
753 driven evolution of recurrent glioma. Science. 2014;343(6167):189-193.
754 102. Li YM, Suki D, Hess K, Sawaya R. The influence of maximum safe resection of
755 glioblastoma on survival in 1229 patients: Can we do better than gross-total resection? J
M
765 2008;109(3):461-471.
766 106. Eisner W, Burtscher J, Bale R, et al. Use of neuronavigation and electrophysiology in
767 surgery of subcortically located lesions in the sensorimotor strip. J Neurol Neurosurg
C
770 subcortical stimulation mapping for hemispherical perirolandic gliomas located within or
771 adjacent to the descending motor pathways: evaluation of morbidity and assessment of
772 functional outcome in 294 patients. J Neurosurg. 2004;100(3):369-375.
773 108. De Witt Hamer PC, Robles SG, Zwinderman AH, Duffau H, Berger MS. Impact of
774 intraoperative stimulation brain mapping on glioma surgery outcome: a meta-analysis. J
775 Clin Oncol. 2012;30(20):2559-2565.
776 109. Schneider JP, Trantakis C, Rubach M, et al. Intraoperative MRI to guide the resection of
777 primary supratentorial glioblastoma multiforme--a quantitative radiological analysis.
778 Neuroradiology. 2005;47(7):489-500.
31
ACCEPTED MANUSCRIPT
779 110. Hatiboglu MA, Weinberg JS, Suki D, et al. Impact of intraoperative high-field magnetic
780 resonance imaging guidance on glioma surgery: a prospective volumetric analysis.
781 Neurosurgery. 2009;64(6):1073-1081; discussion 1081.
782 111. Senft C, Seifert V, Hermann E, Franz K, Gasser T. Usefulness of intraoperative ultra low-
783 field magnetic resonance imaging in glioma surgery. Neurosurgery. 2008;63(4 Suppl
784 2):257-266; discussion 266-257.
PT
785 112. Senft C, Franz K, Ulrich CT, et al. Low field intraoperative MRI-guided surgery of gliomas:
786 a single center experience. Clin Neurol Neurosurg. 2010;112(3):237-243.
787 113. Wirtz CR, Knauth M, Staubert A, et al. Clinical evaluation and follow-up results for
788 intraoperative magnetic resonance imaging in neurosurgery. Neurosurgery.
RI
789 2000;46(5):1112-1120; discussion 1120-1112.
790 114. D'Amico RS, Kennedy BC, Bruce JN. Neurosurgical oncology: advances in operative
SC
791 technologies and adjuncts. J Neurooncol. 2014;119(3):451-463.
792 115. Berntsen EM, Gulati S, Solheim O, et al. Functional magnetic resonance imaging and
793 diffusion tensor tractography incorporated into an intraoperative 3-dimensional
794 ultrasound-based neuronavigation system: impact on therapeutic strategies, extent of
U
795 resection, and clinical outcome. Neurosurgery. 2010;67(2):251-264.
796 116. Romano A, D'Andrea G, Minniti G, et al. Pre-surgical planning and MR-tractography
AN
797 utility in brain tumour resection. Eur Radiol. 2009;19(12):2798-2808.
798 117. Romano A, Ferrante M, Cipriani V, et al. Role of magnetic resonance tractography in the
799 preoperative planning and intraoperative assessment of patients with intra-axial brain
M
805 tractography and subcortical mapping for resection of gliomas: technical considerations.
806 Neurosurg Focus. 2010;28(2):E6.
807 120. Mikuni N, Okada T, Enatsu R, et al. Clinical impact of integrated functional
808 neuronavigation and subcortical electrical stimulation to preserve motor function during
EP
814 high-grade gliomas--overall results, impact of image quality and patient selection. Acta
815 Neurochir (Wien). 2010;152(11):1873-1886.
816 123. Acerbi F, Broggi M, Eoli M, et al. Is fluorescein-guided technique able to help in resection
817 of high-grade gliomas? Neurosurg Focus. 2014;36(2):E5.
818 124. Della Puppa A, De Pellegrin S, d'Avella E, et al. 5-aminolevulinic acid (5-ALA)
819 fluorescence guided surgery of high-grade gliomas in eloquent areas assisted by
820 functional mapping. Our experience and review of the literature. Acta Neurochir (Wien).
821 2013;155(6):965-972; discussion 972.
32
ACCEPTED MANUSCRIPT
822 125. Neira JA, Ung TH, Sims JS, et al. Aggressive resection at the infiltrative margins of
823 glioblastoma facilitated by intraoperative fluorescein guidance. J Neurosurg. 2016:1-12.
824 126. Schucht P, Beck J, Abu-Isa J, et al. Gross total resection rates in contemporary
825 glioblastoma surgery: results of an institutional protocol combining 5-aminolevulinic
826 acid intraoperative fluorescence imaging and brain mapping. Neurosurgery.
827 2012;71(5):927-935; discussion 935-926.
PT
828 127. Schucht P, Knittel S, Slotboom J, et al. 5-ALA complete resections go beyond MR
829 contrast enhancement: shift corrected volumetric analysis of the extent of resection in
830 surgery for glioblastoma. Acta Neurochir (Wien). 2014;156(2):305-312; discussion 312.
831 128. Aldave G, Tejada S, Pay E, et al. Prognostic value of residual fluorescent tissue in
RI
832 glioblastoma patients after gross total resection in 5-aminolevulinic Acid-guided surgery.
833 Neurosurgery. 2013;72(6):915-920; discussion 920-911.
SC
834 129. Roessler K, Becherer A, Donat M, Cejna M, Zachenhofer I. Intraoperative tissue
835 fluorescence using 5-aminolevolinic acid (5-ALA) is more sensitive than contrast MRI or
836 amino acid positron emission tomography ((18)F-FET PET) in glioblastoma surgery.
837 Neurol Res. 2012;34(3):314-317.
U
838 130. Widhalm G, Kiesel B, Woehrer A, et al. 5-Aminolevulinic acid induced fluorescence is a
839 powerful intraoperative marker for precise histopathological grading of gliomas with
AN
840 non-significant contrast-enhancement. PLoS One. 2013;8(10):e76988.
841 131. Hurwitz MD. Today's thermal therapy: not your father's hyperthermia: challenges and
842 opportunities in application of hyperthermia for the 21st century cancer patient. Am J
M
846 133. Schwarzmaier HJ, Eickmeyer F, von Tempelhoff W, et al. MR-guided laser-induced
847 interstitial thermotherapy of recurrent glioblastoma multiforme: preliminary results in
TE
852 135. Mohammadi AM, Hawasli AH, Rodriguez A, et al. The role of laser interstitial thermal
853 therapy in enhancing progression-free survival of difficult-to-access high-grade gliomas:
854 a multicenter study. Cancer Med. 2014;3(4):971-979.
C
855 136. Carpentier A, Chauvet D, Reina V, et al. MR-guided laser-induced thermal therapy (LITT)
856 for recurrent glioblastomas. Lasers Surg Med. 2012;44(5):361-368.
AC
857 137. Bobo RH, Laske DW, Akbasak A, Morrison PF, Dedrick RL, Oldfield EH. Convection-
858 enhanced delivery of macromolecules in the brain. Proc Natl Acad Sci U S A.
859 1994;91(6):2076-2080.
860 138. Juratli TA, Schackert G, Krex D. Current status of local therapy in malignant gliomas--a
861 clinical review of three selected approaches. Pharmacol Ther. 2013;139(3):341-358.
862 139. Bruce JN, Fine RL, Canoll P, et al. Regression of recurrent malignant gliomas with
863 convection-enhanced delivery of topotecan. Neurosurgery. 2011;69(6):1272-1279;
864 discussion 1279-1280.
33
ACCEPTED MANUSCRIPT
865 140. Lidar Z, Mardor Y, Jonas T, et al. Convection-enhanced delivery of paclitaxel for the
866 treatment of recurrent malignant glioma: a phase I/II clinical study. J Neurosurg.
867 2004;100(3):472-479.
868 141. Sampson JH, Akabani G, Archer GE, et al. Intracerebral infusion of an EGFR-targeted
869 toxin in recurrent malignant brain tumors. Neuro Oncol. 2008;10(3):320-329.
870 142. Kunwar S, Chang S, Westphal M, et al. Phase III randomized trial of CED of IL13-
PT
871 PE38QQR vs Gliadel wafers for recurrent glioblastoma. Neuro Oncol. 2010;12(8):871-
872 881.
873 143. Sampson JH, Archer G, Pedain C, et al. Poor drug distribution as a possible explanation
874 for the results of the PRECISE trial. J Neurosurg. 2010;113(2):301-309.
RI
875 144. Mueller S, Polley MY, Lee B, et al. Effect of imaging and catheter characteristics on
876 clinical outcome for patients in the PRECISE study. J Neurooncol. 2011;101(2):267-277.
SC
877 145. Anderson RC, Kennedy B, Yanes CL, et al. Convection-enhanced delivery of topotecan
878 into diffuse intrinsic brainstem tumors in children. J Neurosurg Pediatr. 2013;11(3):289-
879 295.
880 146. Kunwar S, Chang SM, Prados MD, et al. Safety of intraparenchymal convection-
U
881 enhanced delivery of cintredekin besudotox in early-phase studies. Neurosurg Focus.
882 2006;20(4):E15.
AN
883 147. Parney IF, Kunwar S, McDermott M, et al. Neuroradiographic changes following
884 convection-enhanced delivery of the recombinant cytotoxin interleukin 13-PE38QQR for
885 recurrent malignant glioma. J Neurosurg. 2005;102(2):267-275.
M
886 148. Vogelbaum MA, Sampson JH, Kunwar S, et al. Convection-enhanced delivery of
887 cintredekin besudotox (interleukin-13-PE38QQR) followed by radiation therapy with and
888 without temozolomide in newly diagnosed malignant gliomas: phase 1 study of final
D
898 197.
899 152. Chittiboina P, Heiss JD, Warren KE, Lonser RR. Magnetic resonance imaging properties of
AC
34
ACCEPTED MANUSCRIPT
Table 1. Stepwise improvement in survival benefits with extent of resection in high-grade glioma (WHO grades III
and IV).
Median
Median
Extent of progression Univariate Multivariate
Tumor No. overall
Study Year resection free analysis p analysis p
type patients survival
(%) survival value value
(months)
(months)
Keles et al.49*
PT
1999 GBM 107 100 13.3 23.3 <0.0005
75 - 99 11.5 22.1
50 -74 8 15.7
25 - 49 6 14.1
RI
<25 3.5 8
Lacroix et al.55** 2001 GBM 416 >98 13 <0.0001 <0.0001
<98 8.8
Pope et al.79*** Not Not
SC
2005 GBM 110 100 22.1
significant significant
90-99 17.1
20-89 11.1
<20 27.4
U
Not Not
AG 42 0-100 67
significant significant
Keles et al.50 Not Not
AN
2006 AA 102 0-100 25.5 41
significant significant
89
Sanai et al. 2011 GBM 500 100 16 <0.0001 0.004
>89 13.8
>79 12.8
M
>77 12.5
Chaichana et al.15 2014 GBM 259 >70 9 14.4 0.0007 0.0006
<70 7.1 10.5
Grabowski et al.33 2014 GBM 128 >98 16 0.05 0.03
D
<98 14
Oppenlander et
2014 r-GBM 170 >97 30 0.001 0.005
TE
al.72****
>80 20
*Used CT and MR for volumetric measurements and had irregular post-operative imaging.
**Patient population included primary and recurrent GBM.
***Unclear method of volumetric measurements. No statistically significant improvement in outcomes for GBM. Data for
EP
43 AGs not shown and EOR reported as not significant. AG comprised of anaplastic astrocytoma, oligodendroglioma, or
mixed oligoastrocytoma.
****Patient population included only recurrent GBM.
GBM = glioblastoma; r-GBM = recurrent GBM; AA = anaplastic astrocytoma; AG = anaplastic glioma; EOR = extent of
C
resection.
AC
ACCEPTED MANUSCRIPT
Table 2. Data from randomized trials supporting the role for surgery in HGG.
Media
No. Median P-
Tumor types n OS
Study Year Patien Study Groups (n) PFS value P -value
(n) (mont
ts (months)
hs)
PT
Vuorinen et
2003 30 Grade IV (19) Open Resection (10) vs. 5.7 0.035
al.114
Grade III (4) Stereotactic biopsy (13) 2.8
Other (7)
RI
Stummer et Fluorescence-guided resection
2006 270 Grade IV (260) 5.1 0.0003 15.2 0.1
al.106 (161) vs.
Conventional white-light
Grade III (9) 3.6 13.5
SC
microsurgery (161)
95
Senft et al. 2011 49 Grade IV (46) Intraoperative MRI (24) vs. 7.5 0.083
Grade III (2) Conventional treatment (25) 5.1
Other (1)
Patients who underwent complete resection had a longer PFS (7.5 vs. 3.3, p = 0.003)
U
OS = overall survival; PFS = progression free survival; BCNU = 1,3-bis (2-chloroethyl)-1-nitrosourea.
AN
M
D
TE
C EP
AC
ACCEPTED MANUSCRIPT
PT
RI
U SC
AN
M
D
TE
EP
C
AC
ACCEPTED MANUSCRIPT
Table 3. Survival benefits with extent of resection in low-grade gliomas (WHO grade I & II) using volumetric analyses.
Extent
PT
No. of
Study Year Tumor type (No.) Conclusions
Patients resection
(%)
Patients who underwent subtotal resection
Oligodendroglioma (95) 100
RI
were at 1.4x the risk of disease recurrence
and 4.9x the risk of death relative to
Claus et
2005 Astrocytoma (35) 156 <100 patients undergoing gross total resection
al.18
There is a possible association between
SC
resection and survival for LGG using
Mixed (26)
intraoperative MRI.
100 Patients with at least 90% EOR had 5- and
8-year OS of 97% and 91%, respectively.
Astrocytoma (93)
U
90-99 OS was predicted by EOR, preoperative
and postoperative tumor volume on
AN
multivariate analysis.
Smith et 70-89
102 2008 216 PFS was predicted by preoperative and
al. Oligodendroglioma (91) postoperative tumor volume.
41-69 MPFS was predicted by EOR and
preoperative tumor volume.
M
PT
RI
U SC
AN
M
D
TE
EP
C
AC
ACCEPTED MANUSCRIPT
1 HIGHLIGHTS
2
3 Safe, complete resection improves symptom management, quality of life, progression-
4 free survival, and overall survival in both low- and high-grade gliomas.
5 The benefits of safe, supratotal resection warrants further exploration.
6 Differential surgical efficacy may exist among the heterogeneous molecular subgroups
7 that comprise glioma.
PT
8 Important new surgical adjuncts have been developed to mitigate operative risk while
9 augmenting surgical abilities.
RI
U SC
AN
M
D
TE
C EP
AC
1
ACCEPTED MANUSCRIPT
DISCLAIMER
I, Randy DAmico, certify that this manuscript is a unique submission and has not been
previously published elsewhere, nor is it under consideration for publication, in part or in full,
with any other source in any medium. All authors of this manuscript have contributed to, read,
and approved of the manuscript and its submission for publication. The authors have no conflicts
of interest, financial or otherwise, and will be happy to provide the required forms should the
PT
manuscript be accepted for publication.
RI
U SC
AN
M
D
TE
C EP
AC