Accepted Manuscript

Extent of resection in glioma a review of the cutting edge

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

To appear in: World Neurosurgery

Received Date: 20 February 2017

Revised Date: 3 April 2017
Accepted Date: 6 April 2017

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.

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 ACCEPTED MANUSCRIPT

1 Extent of resection in glioma a review of the cutting edge.

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3 Randy S. DAmico, MD1, Zachary K. Englander, BA1, Peter Canoll, MD, PhD2, Jeffrey N.
4 Bruce, MD1
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6 Department of Neurological Surgery, and 2Pathology and Cell Biology, Columbia University
7 Medical Center, New York, NY 10032, USA.

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9 Corresponding Author: Randy S. DAmico
10 Phone: (212) 305-4118

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11 Fax: (212) 305-2026
12 Email: rd2398@cumc.columbia.edu
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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
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18 Running title: Extent of resection in gliomas
19
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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
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24 resection; STR = subtotal resection; FLAIR = fluid-attenuated inversion recovery; LITT = laser
25 interstitial thermotherapy; CED = convection-enhanced delivery.
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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,
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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
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32 manuscript be accepted for publication.

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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).

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39 However, in the absence of level I data, the overwhelming support for this idea is derived largely

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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

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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

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complex molecular profile. The neurosurgical community has put forth a large effort to define
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45 the clinical benefits of maximizing tumor resection, with particular attention paid to the ever-

46 evolving understanding of glioma molecular heterogeneity. Important new technologies have

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47 been developed concurrently to mitigate neurological risks related to the pursuit of maximizing
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48 EOR. These advances reflect the modern goal of glioma surgery to find the optimal balance
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49 between tumor removal and neurologic compromise. We review the current literature supporting

50 safe, maximal resection for gliomas.

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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

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58 comparison to established prognosticators in glioma such as patient age, tumor histology,

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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

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61 outcomes through safe and aggressive tumor resection.

62 However, the infiltrative nature of gliomas, with their propensity for microscopic

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dispersal through the brain and white matter, presents a unique challenge to achieving a complete
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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
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66 measuring T2/FLAIR-hyperintense regions.7-18 Given that tumor-infiltrated brain does not

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67 always enhance, reliance on contrast-enhancement underestimates the full extent of tumor

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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
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70 abnormalities.20 As a result, gross total resection (GTR), defined as the complete radiographic

71 resection of contrast-enhancing regions in HGG, and regions of T2/FLAIR hyperintensity in

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72 non-enhancing lesions, invariably fails to completely remove all microscopic residual,6 providing
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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

76 for patients, with serious prognostic implications.21,22

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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

79 resection on the efficacy of subsequent chemotherapy and radiotherapy, and ultimately

80 prognosis, remain inadequately defined within the literature, a commitment to ensure maximum

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81 tumor resection with minimum neurologic comorbidity has guided much of the recent progress

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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,

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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

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to assist with the real-time identification of tumor, its infiltrative boundaries, and its relationships
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87 with critical anatomic and eloquent structures. These intraoperative adjuncts including,

88 intraoperative magnetic resonance imaging (iMRI), fluorescence-guided resection, cortical

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89 stimulation mapping, and ultrasound, augment the surgeons ability to increase the EOR while
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90 simultaneously minimizing the risk to critical neurovascular structures and eloquent brain.
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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
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93 recent technological advances that facilitate safe, maximal resection, and consider the overall

94 implications for the future of glioma surgery.

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96

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97 HIGH-GRADE GLIOMAS

98 Standard treatment for HGGWorld Health Organization (WHO) Grade III and Grade

99 IV gliomasincludes microsurgical resection prior to concomitant chemotherapy and

100 radiation.26 Surgical resection establishes a histological diagnosis and reduces symptomatic mass

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101 effect with obvious benefit. However, the value of progressive cytoreduction is not definitively

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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,

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104 retrospective series examining heterogeneous populations of grade III anaplastic glioma

105 including astrocytoma, oligodendroglioma, and mixed oligoastrocytomaand grade IV

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glioblastoma (GBM), and a few large clinical trials studying only GBM.
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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-
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109 volumetric,22,37-51 as well as more precise volumetric imaging analyses of EOR,10-15,17 have
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110 largely supported increased EOR as a predictor of both, PFS, and OS. In fact, precise, volumetric
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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
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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
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115 the setting of tumor recurrence, where the clinical benefits of increasing EOR must be carefully
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116 balanced against an increased risk of transient neurological morbidity.13

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

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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)

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124 group, which discovered a higher rate of GTR in patients undergoing resection with

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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

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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
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identified a higher rate of GTR in the iMRI group as compared with the conventional surgery
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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
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132 remains complicated by the heterogeneity of the available data. Studies have utilized different
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133 imaging modalities, various methods of volume quantification, irregular timing of post-operative
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134 imaging, and heterogeneous treatment paradigms resulting in difficult-to-interpret outcomes.

135 Similarly, HGG is a widely heterogeneous group of diseases, which differentially respond to
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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
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138 progression at 6-months and 1-year, as well as decreased mortality at both, 1- and 2-years in the
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139 setting of GTR as compared with subtotal resection (STR), offering strong support for the

140 benefits of safely optimizing EOR.56

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142 LOW-GRADE GLIOMAS

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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

146 astrocytomas and oligodendrogliomas, that greater EOR of T2/FLAIR-hyperintense regions of

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147 tumor, portends better OS, PFS, and malignant progression-free survival (MPFS, Table 3).

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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

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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

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staging surgical resections for primary LGG to allow the patient to undergo chemotherapy
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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
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155 majority of data available reflects class III evidence.16,84

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156 The slow-growing nature of LGG prompts some unique considerations regarding the role
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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
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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
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161 delaying surgery until there was evidence of radiographic progression demonstrated no benefit in
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162 OS with either approach.74

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

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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

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170 hospital serving one area favored biopsy and watchful waiting, while the other hospital, serving a

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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

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173 with biopsied patients. Moreover, the authors reported 74% 5-year survival with upfront surgical

174 management versus 60% in biopsied patients.

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These data are further supported by evidence that resection of incidentally discovered
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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
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178 LGG.
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179 The influence of EOR on the inevitable malignant transformation, and thus the natural
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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
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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
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184 associated 5-year survival rates of 97% in patients receiving greater than 90% extent of resection
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185 of T2/FLAIR-hyperintense regions concerning for tumor on pre-operative MRI, as compared to

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

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188 showed no difference in malignant transformation following complete resection of the

189 T2/FLAIR abnormality seen on pre-operative MRI.75

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

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192 epilepsy is associated with cognitive deterioration and significant morbidity.89 As many patients

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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-

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195 related epilepsy yields a high rate of reduction in seizure frequency over STR, with many

196 patients even becoming seizure free after resection..89-92

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In light of the compelling evidence in support of EOR for LGG, current standard of care
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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
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200 prognostic implications (discussed below).93 Furthermore, the longevity associated with LGG
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201 requires serious consideration of the toxicities of classic oncologic treatments such as radiation
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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
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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
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206 radiation on quality-of-life.94,95 High-risk patients, defined as patients older than 40 years, or
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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

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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

214 foundation of its treatment.

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215

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216 RESIDUAL TUMOR VOLUME

217 Reports evaluating the benefits of increasing EORreported as percentage volume of

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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

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consistent among different tumor sizes and resection of 90% of a large tumor may result in a
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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
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223 with adjuvant therapies.

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224 Residual volume, defined as residual contrast-enhancing disease as determined on post-

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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
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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
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229 volume may be independent predictors of survival in addition to EOR, with residual contrast-
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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

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234 that reducing residual tumor volume may delay malignant transformation of LGG, with

235 associated survival benefits.97,99

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237 SUPRATOTAL RESECTION

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238 Even in the setting of a radiographically well-defined lesion, conventional MRI routinely

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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

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241 contralaterally in GBM.6,87 As a result, tumor recurrence frequently occurs in the immediate

242 vicinity of the initial tumor resection cavity.

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When amenable, removal of a margin around the tumor visible on FLAIR-weighted MRI,
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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
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246 controversial as a formal definition of supra-total resection remains undefined2,100 and the
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247 clinical effects potentially variable with tumor subtype.75

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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
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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
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252 after a complete resection (p = 0.037). Furthermore, supratotal resection was associated with a
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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

255 to malignant transformation in recurrent LGG.101

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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

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260 EOR in anisotropic and isotropic regions of diffusion tensor imaging (DTI) on MRI and reported

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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

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263 authors determined that more extensive resection of abnormal isotropic as well as contrast-

264 enhancing regions correlated with increased OS.103

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266 THE INFLUENCE OF MOLECULAR MARKERS ON EOR

267 In the last two decades, a number of recurring molecular alterations in both LGG and
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268 HGG have been identified that are changing the way gliomas are characterized in light of their
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269 prognostic implications.93 In particular, identification of 1p/19q co-deletions and IDH1/IDH2

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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
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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
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274 and III oligodendrogliomas and the majority of WHO grade II and III astrocytomas are now sub-
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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

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278 EOR remains poorly characterized. As a result, several studies have sought to establish the role

279 of resection in gliomas by controlling for these molecular features.

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

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282 prognosis than tumors with wildtype IDH1, even after controlling for histological grade.

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283 Furthermore, IDH-mutants may demonstrate survival benefits with aggressive resection as

284 compared with IDH-wildtype tumors.23

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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

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according to their IDH1/2 mutation status, and further stratified on the presence of 1p/19q co-
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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).
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290 GTR was not associated with OS in patients with IDH1/2 mutations and 1p/19q co-deletions, or
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291 in the IDH1/2 wildtype group. These data suggested that surgical resection was critical to
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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
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294 regarding the role of GTR for 1p/19q codeleted oligodendrogliomas.

295 In another study identifying WHO Grade II oligodendrogliomas prior to the 2016
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296 reclassification, both EOR and reduced postoperative tumor volume were found to be significant
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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

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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

304 depending on the presence of contrast-enhancement or FLAIR signal.25,75

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305 Reports also suggest that IDH1-mutants may be more likely to achieve GTR than IDH1

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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

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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

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suggests that maximizing surgical resection remains an important therapeutic factor to optimize
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311 prognosis in LGG, independent of the molecular pattern.24

312 Given the heterogeneity of available data, it remains difficult to draw significant
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313 conclusions on the effect of GTR on molecular subtypes of glioma. However, as the molecular
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314 and cytogenetic subtyping of LGG evolves, better-designed studies will be critical to developing
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315 appropriate treatment paradigms for these tumors. Based on the current data, particular focus is

316 needed on the role of EOR for treating oligodendrogliomas.

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318 SURGICAL ADJUNCTS

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319 Given the overwhelming support for maximizing EOR in the surgical treatment of
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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-

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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

326 patients remains to be determined.

327

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328 Cortical and subcortical stimulation mapping.

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329 The resection of lesions involving eloquent areas requires preservation of both cortical

330 and subcortical structures to maximize postoperative functional status. Electrostimulation

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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

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cortical areas to evoke motor movements or speech arrest permits real-time, intraoperative
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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
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336 guides the preservation of motor and language function while the surgeon works to maximize
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337 tumor resection.104-107 A recent meta-analysis found that intraoperative cortical stimulation
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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,
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340 and particularly in tumors arising in eloquent locations.108

341
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342 Intraoperative MRI.

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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

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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

350 additional morbidity.54

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351 While the clinical utility of iMRI has received strong support, the technology is yet to be

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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

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354 the universal implementation of iMRI.

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356 Functional neuronavigation.

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357 Multimodal, or functional neuronavigation refers to modern techniques co-registering

358 patient-specific functional and structural information with real-time intraoperative information to
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359 assist with the safe and complete resection of intracranial lesions occurring in eloquent cortical
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360 regions. In particular, functional MRI (fMRI) and diffusion tensor imaging (DTI) sequences
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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
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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
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365 neuronavigation in combination with intraoperative data such as cortical/subcortical mapping

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366 may further enhance surgical safety by reducing surgical time, identifying tracts for subcortical

367 stimulation, preserving function and facilitating maximal surgical resection.118-120

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368 Unfortunately, functional neuronavigation remains limited by the challenges facing

369 traditional navigation including inaccurate registration and brain shift with resultant loss of

370 anatomic accuracy.

371

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372 Navigable intraoperative ultrasound

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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

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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

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navigation systems may add additional benefits to its intraoperative use.114,121,122 Regardless, iUS
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378 is easily available, convenient, fast and easy to use and may provide a more practical alternative,

379 especially in resource-constrained settings.

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380
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381 Fluorescence-guided resection

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382 Fluorescence-guided resection has demonstrated great potential for maximizing EOR as it

383 permits real-time, intraoperative identification of residual tumor tissue.49,123-127 Although a

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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
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386 and increasing extent of resection in glioma.49

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387 Administration of 5-ALA results in preferential accumulation of fluorescent

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

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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

394 assistance of neuronavigation.124,126

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395 Sodium fluorescein is a green fluorescent compound that accumulates in areas of

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396 malignancy, vascular leaking defects, pooling defects and abnormal vasculature or

397 neovascularization. With the recent development of a surgical microscope fitted with fluorescent

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398 filter, several small studies have demonstrated increased rates of complete resection of contrast-

399 enhancing tumor regions using sodium fluorescein-guided resection.123,125

400
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Interestingly, evidence suggests that both 5-ALA,127-130 and fluorescein125 may also stain
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401 non-enhancing regions of glioma permitting intraoperative identification of anaplastic foci in

402 gliomas with non-significant contrast-enhancement. Identification of this higher-grade tissue is

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403 critical as treatment decisions vary with histopathological diagnosis. Further study is necessary
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404 to identify whether fluorescence-guidance can facilitate resection of tumor beyond the
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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
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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
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409 feature of fluorescence-guided resection.

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410

411 Laser ablation for glioma

412 Stereotactic laser ablation or laser interstitial thermotherapy (LITT) is an emerging

413 minimally invasive technique that leads to cell death via the administration of heat.131

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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

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418 both recurrent and newly diagnosed HGGs has demonstrated correlation with improved PFS

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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

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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
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maximizing cytoreduction when open resection is not safe.
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424

425 Convection-enhanced delivery

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426 Convection-enhanced delivery (CED) is a drug delivery technique in which one or more
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427 catheters are stereotactically-placed within target tissue for the direct infusion of therapeutic
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428 agents.137 Motorized pumps provide a continuous positive-pressure micro-infusion that

429 distributes therapeutic agents by principles of bulk flow, providing high local concentrations of
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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
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432 permit safe, targeted homogeneous delivery of high-concentration therapeutics to large brain
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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

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436 with poor infusate distribution and leakage into CSF spaces resulting in unwanted side effects

437 and sub-therapeutic drug concentrations within the target tissue.140-144

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

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440 regarding catheter position, rates and volumes of infusion, and the effects of tissue

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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

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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
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clinical utility of CED and ensuring that therapy is appropriately and completely targeting the
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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
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448 of gliomas and the importance of maximizing cytoreduction for the management of gliomas,
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449 CED promises a valuable technique for safely covering both the radiographically defined tumor
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450 as well as the surrounding infiltrated brain tissue with targeted therapeutics.
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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

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455 advances in our understanding of specific molecular alterations within gliomas that may

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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

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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
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patients individual pathology and anatomy. In addition, as studies further clarify the role of
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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
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463 prognosis while we pursue novel targeted therapies and innovative methods of drug delivery for
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464 the disease. In the meantime, the goal of the neurosurgeon remains to pursue the optimal balance
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465 between maximum tumor removal and maximal preservation of neurologic function.

466
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467
468
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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

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(%) 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

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50 -74 8 15.7
25 - 49 6 14.1
<25 3.5 8
Lacroix et al.12**

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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

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20-89 11.1
<20 27.4
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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
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>89 13.8
>79 12.8
>77 12.5
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Chaichana et al.52 2014 GBM 259 >70 9 14.4 0.0007 0.0006

<70 7.1 10.5
Grabowski et al.98 2014 GBM 128 >98 16 0.05 0.03
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<98 14
Oppenlander et
2014 r-GBM 170 >97 30 0.001 0.005
al.13****
>80 20
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*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
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mixed oligoastrocytoma.
****Patient population included only recurrent GBM.
GBM = glioblastoma; r-GBM = recurrent GBM; AA = anaplastic astrocytoma; AG = anaplastic glioma; EOR = extent of
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resection.

471
472

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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)

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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)

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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

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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)

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OS = overall survival; PFS = progression free survival; BCNU = 1,3-bis (2-chloroethyl)-1-nitrosourea.
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475

Table 3. Survival benefits with extent of resection in low-grade gliomas (WHO grade I & II) using volumetric analyses.
Extent

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No. of
Study Year Tumor type (No.) Conclusions
Patients resection
(%)
Patients who underwent subtotal resection
Oligodendroglioma (95) 100

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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

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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)

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90-99 OS was predicted by EOR, preoperative
and postoperative tumor volume on
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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.
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Mixed (32) 0-40 Improved outcome in adults with LGG

was predicted by greater EOR.
Snyder et A greater EOR was associated with
2014 Oligodendroglioma (93) 93 0-100
al.75
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improved OS, but did not prolong MPFS.

LGG = low grade glioma; EOR = extent of resection; PFS = progression free survival; MPFS = malignant progression free
survival; OS = overall survival.
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901 2014;13(3):276-282.
902

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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*

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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

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<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

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2005 GBM 110 100 22.1
significant significant
90-99 17.1
20-89 11.1
<20 27.4

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Not Not
AG 42 0-100 67
significant significant
Keles et al.50 Not Not
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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
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>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
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<98 14
Oppenlander et
2014 r-GBM 170 >97 30 0.001 0.005
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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
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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
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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)

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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)

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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

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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)

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OS = overall survival; PFS = progression free survival; BCNU = 1,3-bis (2-chloroethyl)-1-nitrosourea.
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Table 3. Survival benefits with extent of resection in low-grade gliomas (WHO grade I & II) using volumetric analyses.
Extent

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No. of
Study Year Tumor type (No.) Conclusions
Patients resection
(%)
Patients who underwent subtotal resection
Oligodendroglioma (95) 100

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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

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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)

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90-99 OS was predicted by EOR, preoperative
and postoperative tumor volume on
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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.
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Mixed (32) 0-40 Improved outcome in adults with LGG

was predicted by greater EOR.
Snyder et A greater EOR was associated with
2014 Oligodendroglioma (93) 93 0-100
al.103
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improved OS, but did not prolong MPFS.

LGG = low grade glioma; EOR = extent of resection; PFS = progression free survival; MPFS = malignant progression free
survival; OS = overall survival.
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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.

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8 Important new surgical adjuncts have been developed to mitigate operative risk while
9 augmenting surgical abilities.

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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

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manuscript be accepted for publication.

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