The influence of maximum safe resection of glioblastoma on survival in 1229 patients: Can we do better than gross-total resection?

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OBJECT

Glioblastoma multiforme (GBM) is the most common and deadliest primary brain tumor. The value of extent of resection (EOR) in improving survival in patients with GBM has been repeatedly confirmed, with more extensive resections providing added advantages. The authors reviewed the survival of patients with significant EORs and assessed the relative benefit/risk of resecting 100% of the MRI region showing contrast-enhancement with or without additional resection of the surrounding FLAIR abnormality region, and they assessed the relative benefit/risk of performing this additional resection.

METHODS

The study cohort included 1229 patients with histologically verified GBM in whom ≥ 78% resection was achieved at The University of Texas MD Anderson Cancer Center between June 1993 and December 2012. Patients with > 1 tumor and those 80 years old or older were excluded. The survival of patients having 100% removal of the contrast-enhancing tumor, with or without additional resection of the surrounding FLAIR abnormality region, was compared with that of patients undergoing 78% to < 100% EOR of the enhancing mass. Within the first subgroup, the survival durations of patients with and without resection of the surrounding FLAIR abnormality were subsequently compared. The data on patients and their tumor characteristics were collected prospectively. The incidence of 30-day postoperative complications (overall and neurological) was noted.

RESULTS

Complete resection of the T1 contrast-enhancing tumor volume was achieved in 876 patients (71%). The median survival time for these patients (15.2 months) was significantly longer than that for patients undergoing less than complete resection (9.8 months; p < 0.001). This survival advantage was achieved without an increase in the risk of overall or neurological postoperative deficits and after correcting for established prognostic factors including age, Karnofsky Performance Scale score, preoperative contrast-enhancing tumor volume, presence of cyst, and prior treatment status (HR 1.53, 95% CI 1.33–1.77, p < 0.001). The effect remained essentially unchanged when data from previously treated and previously untreated groups of patients were analyzed separately. Additional analyses showed that the resection of ≥ 53.21% of the surrounding FLAIR abnormality beyond the 100% contrast-enhancing resection was associated with a significant prolongation of survival compared with that following less extensive resections (median survival times 20.7 and 15.5 months, respectively; p < 0.001). In the multivariate analysis, the previously treated group with < 53.21% resection had significantly shorter survival than the 3 other groups (that is, previously treated patients who underwent FLAIR resection ≥ 53.21%, previously untreated patients who underwent FLAIR resection < 53.21%, and previously untreated patients who underwent FLAIR resection ≥ 53.21%); the previously untreated group with ≥ 53.21% resection had the longest survival.

CONCLUSIONS

What is believed to be the largest single-center series of GBM patients with extensive tumor resections, this study supports the established association between EOR and survival and presents additional data that pushing the boundary of a conventional 100% resection by the additional removal of a significant portion of the FLAIR abnormality region, when safely feasible, may result in the prolongation of survival without significant increases in overall or neurological postoperative morbidity. Additional supportive evidence is warranted.

ABBREVIATIONSEOR = extent of resection; GBM = glioblastoma multiforme; KPS = Karnofsky Performance Scale; MD Anderson = The University of Texas MD Anderson Cancer Center; UCSF = University of California, San Francisco.

Glioblastoma multiforme (GBM) is the most common and deadliest primary brain tumor.14 The incidence of the disease is 5 to 10 cases per 100,000 persons per year, and more than 14,000 new cases of GBM are diagnosed in the United States each year.7 Although new treatment paradigms have had a significant impact on the outcomes of many other cancer types, the treatment of patients with GBM remains a challenge. Patients survive for an average of 14 months from diagnosis despite maximal treatment with surgery, chemotherapy, and radiation therapy,23 and the duration of survival has not changed significantly in decades.

The role of surgery in the management of GBM has been extensively investigated. Initial studies traditionally classified extent of resection (EOR) within the arbitrary categories of gross-total, subtotal, and partial resection. Our previous study on 416 patients with newly diagnosed and recurrent GBM shifted that paradigm of the 3 arbitrary categories into the concept of maximal, safely achievable volumetric resection, demonstrating an incremental increase in the duration of survival with each unit increase in the EOR, starting from 89%,15 with the strongest effect of resection on survival being achieved at the 98% threshold. Years later, these results were supported by investigators from the University of California, San Francisco (UCSF) in a retrospective review of 500 consecutive patients with newly diagnosed GBM, with minor differences in the EOR threshold, probably reflecting the distribution of EOR between the 2 study samples.20 The UCSF data showed a significant survival advantage starting at 78% EOR instead of the 89% reported in our series, and an EOR ≥ 95% had the greatest impact on overall survival instead of the ≥ 98% from our series. The median survival time among the 316 UCSF patients in the ≥ 95% EOR category was 14.5 months.20 Our group recently revisited data from 721 adult patients with GBM from 1993 to 2012 and provided further evidence supporting a maximum safe resection approach for GBM.19

Glioblastoma multiforme is regularly described as an invasive tumor.26 The motility of GBM cells has been demonstrated in vitro in cell cultures,2,12 in postmortem studies,3,4,27 and in stereotactic biopsy specimens,10,13 as well as in other studies.5,17,18,24 The area outside the contrast-enhancement region on a T1-weighted MR image is usually infiltrated by tumor cells.26 Fluid-attenuated inversion recovery (FLAIR) images are thought to represent these invasive cells,8,13 as well as cerebral edema, demyelination, and/or surgery-related injury.9,28 In a general review of GBM, Wilson points to the inadequacy of the current treatment paradigms for the patient presenting with GBM and links the probability of recurrence at any site to the number of cells left behind at or around the initial GBM site,26 supporting his theory by the fact that 80%–90% of patients who succumb to GBM die of local tumor recurrence,4,6,11,25 unlike those with other malignant tumors who die of metastasis.

If increasing the resection of the contrast-enhancing portion of a GBM leads to increased survival, based on the above 2 studies and other supportive literature, does 100% resection of the contrast-enhancing tumor confer a significant survival advantage relative to that obtained following the less expansive, though still extensive, resection? And would the additional removal of infiltrating tumor cells, as identified by FLAIR abnormality on T2-weighted MR images, have a significant impact? To answer these 2 questions, we identified patients undergoing an EOR ≥ 78% at our institution. We first compared the survival of patients with 78% to < 100% EOR with that of patients undergoing 100% EOR of the enhancing mass (with or without additional resection of the FLAIR abnormality). An EOR of 100% of the enhancing lesion is hereafter referred to as complete resection. The 78% cutoff was chosen because it was the lower of the 2 thresholds most significantly associated with survival in the prior MD Anderson and UCSF studies.20 In a secondary analysis, we reviewed the effect of the additional resection of the FLAIR abnormality region on survival within the group of patients undergoing complete resection of the enhancing lesion. The incidence of postoperative complications—overall and neurological—was also reviewed.

Methods

Patients and Treatment Characteristics

The study was conducted under the auspices of an institutional review board-approved protocol. In a search of the Brain and Spine Center Database at the University of Texas MD Anderson Cancer Center (MD Anderson), we identified all consecutive patients with GBM who had undergone tumor resection between June 1993 and December 2012. All cases had a diagnosis of GBM according to the Ringertz classification, Grade IV astrocytoma according to the WHO classification, and Grade 4 astrocytoma according to the St. Anne-Mayo classification.15 We excluded patients having more than 1 GBM, those aged 80 years or more at the time of surgery, and those with < 78% contrast-enhancing tumor resection. The final sample consisted of 1229 patients with GBM.

Demographic, clinical, and imaging data were obtained from the prospectively collected Brain and Spine Center Database. Each patient’s age, sex, and Karnofsky Performance Scale (KPS) score at the time of surgery was obtained. Previous neurosurgeries were recorded, including those undergone at another center, including cytoreductive surgery or a biopsy procedure with or without adjuvant chemotherapy or radiation therapy, which indicated that the patient had residual or recurrent tumor at the time of presentation at our institution. Such patients are referred to hereafter as the previously treated group. The MD Anderson Tumor Registry was used to identify each patient’s vital status at the time of data analysis. The tumor registry staff ascertain the vital status of all patients seen at our institution through sources such as the National Death Index and from letters or phone calls to patients and their families.

Imaging Studies

Preoperative and postoperative MR images (typically obtained within 48 hours after surgery) are routinely reviewed at our institution in a prospective fashion. Several tumor imaging characteristics are identified and entered into the Brain and Spine Center Database. Tumor location in regard to proximity to eloquent brain is characterized by functional grade, as described by Sawaya et al.21 The presence of mass effect, surrounding edema, and contrast-enhancement of the tumor mass are also assessed. Preoperative and postoperative tumor volumes are quantified. Tumor contrast-enhanced volume is defined as the area of increased signal intensity on contrast-enhancing T1-weighted MR images. The FLAIR abnormality volume is defined as the area of FLAIR hyperintensity signal seen on T2-weighted MR images beyond the contrast-enhanced T1-weighted images. The Vitrea software version 2 is currently used for these studies (the MedVision 1.41 computer software program from Technologies Inc. was used for older cases). This software allows calculation of the tumor area as outlined on selected axial or coronal images and then the estimation of tumor volume based on the known thickness of the slice.

Statistical Analyses

The primary objective of this study was to establish whether complete resection of the contrast-enhancing lesion (100%), as determined on the basis of objectively quantified preoperative and postoperative volume estimates, has prognostic value with regard to patient survival time after surgery, compared with resection < 100%. The secondary objectives were to examine whether additional resection of the region corresponding to the FLAIR abnormality beyond the contrast-enhancing area has a significant effect on survival time overall or within defined patient subgroups and to assess the incidence of overall and neurological complications associated with different EOR scenarios.

To achieve these objectives, frequencies and descriptive statistics of the variables under study were obtained. A recursive partitioning analysis was performed to identify a cutoff for continuous variables, if one existed. The cumulative survival duration measured from the time of surgery at our institution was computed using the Kaplan-Meier method. Survival curves for the various subgroups were compared using the log-rank test. The Cox proportional hazards model was used to identify factors associated with survival at the univariate and multivariate levels. Crude and adjusted hazard ratios and their 95% confidence intervals were calculated. All p values ranging from 0.0001 to 0.1 for categorized continuous variables were adjusted to achieve an approximate false-positive rate of 10%, based on the paper by Altman et al.1 All tests were 2-tailed. A p value ≤ 0.05 was considered significant. Statistical analyses were performed using the Statistical Package for the Social Sciences 21.0 (SPSS Inc.). The recursive partitioning analysis was performed using the R software (version 3.1.0).

Results

Patient and Tumor Characteristics

Table 1 summarizes the demographic, clinical, and tumor characteristics of the study patients. The median age was 55.7 years (range 4.6–80.0 years). Most patients were male (62%). The median KPS score was 90 (range 10–100), and 92% of patients had a score of at least 70. Most patients (91%) had symptoms before surgery. Previously untreated patients accounted for 61% of the group. Based on preoperative MR images, 14% of tumors were presumably located in noneloquent brain (Grade 1), 48% were located in near-eloquent brain (Grade 2), and 38% were within eloquent brain area (Grade 3).21 Necrosis was documented in 78% of tumors; a cystic component was found in 10% of tumors. The median preoperative contrast-enhancing tumor volume was 31.0 cm3 (range 0.3–186.3 cm3).

TABLE 1.

Characteristics of 1229 patients with GBM*

CharacteristicTotal No.100% Resection of T1 Contrast-Enhancing Vol78% to <100% Resection of T1 Contrast-Enhancing Volp Value
No. of patients1229876353
Median age at surgery in yrs (min, max)55.7 (4.6, 80.0)55.5 (4.6, 80.0)56.7 (6.0, 79.5)0.2
Sex (%)
 Male758 (62)539 (62)219 (62)
 Female471 (38)337 (38)134 (38)0.87
Median preop KPS score (min, max)90 (10, 100)90 (20, 100)80 (10, 100)<0.001
Preop KPS score (%)
 ≥701134 (92)819 (93)315 (89)
 <7095 (8)57 (7)38 (11)0.01
Tumor functional grade (%)
 1166 (14)151 (17)15 (4)
 2589 (48)409 (47)180 (51)
 3469 (38)313 (36)156 (44)<0.001
Symptoms before surgery (%)
 No105 (9)85 (10)20 (6)
 Yes1124 (91)791 (90)333 (94)0.02
Previously treated (%)
 No752 (61)539 (62)213 (60)
 Yes477 (39)337 (38)140 (40)0.70
Necrosis on imaging (%)
 No265 (22)225 (26)40 (11)
 Yes961 (78)648 (74)313 (89)<0.001
Cyst on imaging (%)
 No1108 (90)780 (89)328 (93)
 Yes118 (10)93 (11)25 (7)0.06
Median preop T1 contrast-enhancing vol in cm3 (min, max)§31.0 (0.3, 186.3)25.9 (0.3, 175.1)46.3 (3.9, 186.3)<0.001

Values represent numbers of patients (%) unless otherwise specified. Percentages may not add up to 100 due to rounding.

Percentages in first column to the right are based on a total of 1224; second column, 873; and third column, 351.

Percentages in first column to the right are based on a total of 1226; and second column, 873.

Values are based on 1206 tumors.

Complete resection (100%) of the T1 contrast-enhancing part of the tumor was achieved in 876 patients (71%). Less than complete resection (78% to < 100%) was achieved in 353 patients (29%). These 2 patient groups had different distributions with respect to preoperative KPS scores, tumor functional grade, preoperative contrast-enhancing tumor volume, and presence of necrosis, as well as preoperative symptoms (Table 1). They were comparable in terms of patient age, sex, presence of cysts on imaging, and prior treatment status. The median duration of follow-up among the 194 patients remaining alive at the end of the study was 19.9 months (range 0.1–190.1 months).

Analysis of Overall Survival

The Kaplan-Meier estimate of median postoperative survival time for the 1229 study patients was 13.4 months (95% CI 12.6–14.1 months; Table 2). Patients with complete resection (100% of contrast-enhancing region) had a median survival time of 15.2 months (95% CI 14.1–16.3 months), a duration significantly longer than the median survival of patients with less than complete resection (9.8 months, 95% CI 8.8–10.8 months; p < 0.001; Fig. 1). Patients without complete resection had a univariate HR of 1.87 (95% CI 1.63–2.14, p < 0.001) compared with patients undergoing complete resection (Table 3). This observed difference in survival between these 2 groups remained significant when other prognostic factors were adjusted for in a multivariate Cox model analysis: less than complete resection had an adjusted HR of 1.53 (95% CI 1.33–1.77, p < 0.001). Additional factors found to have a significant negative independent effect on survival duration in the multivariate analysis included an older age at surgery (HR 1.03, 95% CI 1.02–1.03; p < 0.001), a previously treated status (HR 1.67, 95% CI 1.46–1.90; p < 0.001), a preoperative KPS score less than 70 (HR 1.30, 95% CI 1.04–1.64; p = 0.02), and a larger preoperative contrast-enhancing tumor volume (HR 1.005, 95% CI 1.002–1.007; p < 0.001). The presence of a cyst had a positive impact on the duration of survival (HR 0.63, 95% CI 0.50–0.79; p < 0.001).

FIG. 1.
FIG. 1.

Kaplan-Meier plot of overall survival in a series of 1229 patients with GBM after different degrees of resection of the contrast-enhancing tumor volume. Compare the complete resection group (dashedline, 100%; black squares, 100%-censored) with the group that underwent less than complete resection (solid line, 78% to < 100%; black circles, 78% to < 100%-censored).

TABLE 2.

Outcomes in 1229 patients with GBM treated with resection of the T1 contrast-enhancing volume*

VariableTotal No.100% Resection78% to <100% Resectionp Value
No. of patients1229876353
EOR of T1 contrast-enhancing vol (%)
 100%876 (71)
 78% to <100%353 (29)
Vital status at last follow-up (%)
 Alive194 (16)154 (18)40 (11)
 Dead1035 (84)722 (82)313 (89)0.007
Median overall survival in mos (95% CI)13.4 (12.6, 14.1)15.2 (14.1, 16.3)9.8 (8.8, 10.8)<0.001
30-day postop complications (%)
 No950 (77)693 (79)257 (73)
 Yes279 (23)183 (21)96 (27)0.02
30-day postop neurological complications (%)
 No1002 (82)728 (83)274 (78)
 Yes227 (18)148 (17)79 (22)0.02
 Motor deficit115 (9)75 (9)40 (11)0.13
 Speech impairment77 (6)50 (6)27 (8)0.20
 Visual impairment33 (3)21 (2)12 (3)0.32
 Seizure30 (2)17 (2)13 (4)0.07
 Hemorrhage17 (1)12 (1)5 (1)1.00
 Intracranial hemorrhage14 (1)10 (1)4 (1)1.00
 Hydrocephalus12 (<1)7 (<1)5 (1)0.34
 Cognitive/memory/mental status problems12 (<1)8 (<1)4 (1)0.06
 Sensory deficit7 (<1)4 (<1)3 (<1)0.42
 Headache8 (<1)5 (<1)3 (<1)0.70
 Cranial nerve deficit6 (<1)5 (<1)1 (<1)0.68
 Other36 (3)24 (3)12 (3)0.54

Values represent numbers of patients (%) unless otherwise specified.

Other includes edema, cerebrospinal fluid leak, cerebral abscess, pneumocephalus, superior sagittal sinus thrombosis, fluid entrapment in resection cavity, left posterior cerebral artery infarct, nausea and vomiting, subdural empyema, bladder dysfunction, and gait abnormalities.

TABLE 3.

Overall survival analysis in 1229 patients with GBM

VariableKaplan-Meier AnalysisUnivariate AnalysisMultivariate Analysis
Total No. of PatientsEventsMedian Survival (mos)95% CIHR95% CIP ValueHR95% CIP Value
Age at surgery1.031.02–1.03<0.0011.031.02–1.03<0.001
Age at surgery in yrs
 ≤51.745634917.315.3–19.41.00
 >51.777368611.911.1–12.71.741.53–1.99<0.001
Sex (%)
 Male75863913.012.2–13.91.00
 Female47139613.712.0–15.40.880.78–1.000.04
Preop KPS score0.980.98–0.99<0.001
Preop KPS score
 ≥70113495113.612.9–14.31.001.00
 <7095849.97.6–12.21.491.19–1.86<0.0011.301.04–1.640.02
Tumor functional grade*
 116612517.815.7–19.81.00
 258950912.711.6–13.81.371.13–1.670.002
 346939613.212.2–14.21.291.06–1.580.013
Necrosis on imaging
 No26519517.815.4–20.31.00
 Yes96183712.711.9–13.51.601.37–1.88<0.001
Cyst on imaging
 No110894113.012.2–13.71.001.00
 Yes1189120.315.3–25.30.600.48–0.75<0.0010.630.50–0.79<0.001
Symptoms before surgery
 No1058713.511.6–15.51.00
 Yes112494813.412.6–14.21.050.84–1.310.65
Previously treated
 No75261314.913.7–16.11.001.00
 Yes47742210.89.9–11.71.421.26–1.62<0.0011.671.46–1.90<0.001
Preop T1 contrast-enhancing vol1.0041.002–1.006<0.0011.0051.002–1.007<0.001
EOR of T1 contrast-enhancing vol
  100%87672215.214.1–16.31.001.00
  78% to ≤100%3533139.88.8–10.81.871.63–2.14<0.0011.531.33–1.77<0.001

Values based on 1224 patients,

Values based on 1226 patients.

The 2 resection groups had significant differences in important characteristics, which could have impacted their effect on overall survival. Table 4 shows the effect of EOR within various categories of these characteristics (variables). The hazard ratio remained basically unaltered in terms of direction, and the p values remained significant in all categories except for an asymptomatic presentation. There were too few patients without symptoms in this series.

TABLE 4.

Survival relative to EOR within categories of prognostic variables in 1229 patients with GBM

Variables78% to ≤100% Resection100% ResectionUnivariate Cox Analysis*
Total No. of PatientsNo. of EventsMedian Survival (mos)95% CITotal No. of PatientsNo. of EventsMedian Survival (mos)95% CIHR95% CIp Value
Age at surgery in yrs
 ≤51.71191008.96.8–11.033724920.617.4–23.82.471.94–3.14<0.001
 >51.72342139.99.0–10.953947313.412.4–14.31.541.31–1.82<0.001
Sex
 Male2191949.88.5–11.253944514.713.6–15.71.861.57–2.21<0.001
 Female1341199.78.3–11.233727716.514.8–18.21.861.50–2.32<0.001
Preop KPS score
 ≥7031527810.08.9–11.181967315.514.5–16.61.851.60–2.13<0.001
 <7038357.64.8–10.4574913.08.6–17.51.811.14–2.860.01
Tumor functional grade
 115149.36.3–12.315111118.416.4–20.52.411.37–4.250.002
 21801619.18.2–10.040934814.813.4–16.11.731.43–2.09<0.001
 315613610.69.0–12.131326014.713.4–16.01.881.52–2.40<0.001
Necrosis on imaging
 No403311.99.2–14.622516219.917.4–22.32.011.38–2.94<0.001
 Yes3132809.78.8–10.664855714.413.5–15.41.741.50–2.01<0.001
Cyst on imaging
 No3282959.68.7–10.678064614.713.7–15.61.801.56–2.06<0.001
 Yes251811.58.6–14.4937323.215.7–30.62.361.37–4.070.001
Symptoms before surgery
 No20178.80.0–17.6857014.611.3–17.81.490.87–2.540.15
 Yes3332969.88.9–10.779165215.414.2–16.51.901.65–2.18<0.001
Previously treated
 No21318310.49.2–11.653943017.916.3–19.62.081.74–2.48<0.001
 Yes1401308.37.2–9.333729212.411.0–13.81.601.30–1.98<0.001
Preop T1 contrast-enhancing vol in cm3
  ≥31.024421714.212.9–15.536130011.410.4–12.41.811.51–2.16<0.001
  <31.01099616.114.5–17.749240014.613.3–15.91.721.37–2.16<0.001

100% resection is the referent group.

We performed a close and separate examination of previously untreated and previously treated patients and found similar negative prognostic effects for a less-than-complete resection in both groups (adjusted HR 1.69, 95% CI 1.41–2.04, p < 0.001, and adjusted HR 1.33, 95% CI 1.06–1.67, p = 0.02, respectively; data not shown).

To address one of the secondary objectives of the study—that is, whether additional resection of the FLAIR abnormality region beyond the enhancing area would have a significant effect on survival time overall or within defined patient subgroups—patients who underwent complete resection of the contrast-enhancing tumor volume were further examined. Of the 876 patients who had undergone complete resection, 643 underwent further resection of the T2 FLAIR abnormality region and had FLAIR data. The distribution of the EOR of the FLAIR abnormality area is presented in Fig. 2. Approximately 18% of the patients had a negative EOR, reflecting the development of postoperative edema. In the 643-patient subgroup, a FLAIR abnormality resection ≥ 53.21%, compared with one < 53.21%, was significantly associated with improved survival in the univariate analysis (median 20.7 months, compared with 15.5 months; crude HR 0.68, 95% CI 0.55–0.84, p < 0.001; Tables 5 and 6). In the multivariate analysis, the previously treated group with a FLAIR resection < 53.21% fared significantly worse than all others (that is, previously treated patients who underwent FLAIR resection ≥ 53.21%, previously untreated patients who underwent FLAIR resection < 53.21%, and previously untreated patients who underwent FLAIR resection ≥ 53.21%). The untreated group with at least 53.21% resection had the longest survival. Prior treatment in the 643-patient subgroup included prior resection in 100% of the patients, prior radiation in 189 (79%), and prior chemotherapy in 177 (74%; 61% of which received temozolomide; 72%, both radiation and chemotherapy; and 60%, both radiation and temozolomide). The median preoperative FLAIR abnormality volume was 57.3 cm3 in patients who had received prior radiation and/or chemo, compared with 33.3 cm3 in those who had not (p = 0.17). The median extent of FLAIR abnormality resection was 22% in patients who received prior radiation and/or chemo compared with 32% in those who did not (p = 0.02). Figure 3 shows the effect of EOR on survival according to treatment group. A younger age, a higher preoperative KPS score, a cystic tumor, and a smaller preoperative contrast-enhancing tumor on imaging were strong independent positive prognostic factors in this analysis. All categorized continuous variables had a p value < 0.001. Those p values remained significant after adjustment for an approximate true false-positive rate of 10% based on the method of Altman et al.1

FIG. 2.
FIG. 2.

Histogram showing percentages of 643 patients who underwent different EORs of the T2 FLAIR abnormality region for GBM. Figure is available in color online only.

FIG. 3.
FIG. 3.

Kaplan-Meier plot of overall survival in 643 patients with GBM who underwent resection of the T2 FLAIR abnormality region of the tumor after undergoing complete resection, in relation to previous treatment status, either previously treated (treated) or not treated. Represented are patients who underwent < 53.21% resection, not treated (dashed line; censored, black circles) and treated (dashed-dotted line; censored, black squares); ≥ 53.21% resection, not treated (solid line; censored, black triangles) and treated (dotted line; censored, black diamonds).

TABLE 5.

Survival in 643 patients with GBM whose entire T1 contrast-enhancing tumor portion was resected and who had EOR of T2 FLAIR abnormality data*

VariableNo. of Patients w/ Data AvailableNo. of Death EventsMedian Survival (mos)95% CIp Value (log-rank)Univariate AnalysisMultivariate Analysis
HR95% CIP ValueHR95% CIP Value
Overall survival643 (100)50216.815.4–18.2
Age at surgery1.031.02–1.04<0.0011.031.02–1.04<0.001
Sex
 Male399 (62)31515.213.8–16.71.00
 Female244 (38)18718.716.8–20.50.0030.760.63–0.910.004
Preop KPS score0.980.98–0.99<0.0010.9880.981–0.9950.001
Preop KPS score
 ≥70601 (93)46816.915.5–18.31.00
 <7042 (6)3414.79.6–19.90.141.300.92–1.840.14
Tumor functional grade
 1127 (20)8818.917.2–20.51.00
 2304 (47)24915.513.9–17.21.291.01–1.650.04
 3212 (33)16516.913.7–20.10.031.030.80–1.340.81
Necrosis on imaging
 No184 (29)12919.918.0–21.81.00
 Yes459 (71)37315.414.0–16.70.0031.351.10–1.650.004
Cyst on imaging
 No575 (89)44915.914.6–17.21.00
 Yes68 (10)5324.514.5–34.50.0070.680.51–0.900.0080.660.49–0.900.009
Symptoms before surgery
 No64 (10)5016.913.9–19.91.00
 Yes579 (90)45216.715.2–18.10.960.990.74–1.330.96
Previously treated
 No403 (63)30219.718.0–21.41.00
 Yes240 (37)20012.410.7–14.0<0.0011.691.41–2.02<0.001
Preop T1 contrast-enhancing vol1.0041.001–1.0070.021.0041.001–1.0080.03
Preop T2 FLAIR abnormality vol1.0000.999–1.0020.69
EOR of T2 FLAIR abnormality vol
  <53.21%484 (75)39015.514.1–17.01.00
  ≥53.21%159 (25)11220.718.2–23.1<0.0010.680.55–0.84<0.001
EOR of T2 FLAIR abnormality vol by previous treatment
  Treated, <53.21%199 (31)16611.29.8–12.61.001.00
  Treated, ≥53.21% or not treated, <53.21%327 (51)25818.717.0–20.40.620.51–0.75<0.0010.490.40–0.61<0.001
  Not treated, ≥53.21%117 (18)7823.017.6–28.4<0.0010.450.34–0.59<0.0010.430.33–0.57<0.001

Values represent numbers of patients (%) unless otherwise specified.

TABLE 6.

Survival relative to EOR of T2 FLAIR abnormality in 643 patients with GBM who had the entire contrast-enhancing portion of their tumor resected

EOR of T2 FLAIR Abnormality*Total No. of PatientsTotal No. of EventsMedian Survival (mos)95% CI
< −50%353215.911.2–20.1
 −50% to <−10%443716.210.1–22.3
 −10% to <0403710.58.0–12.9
  0 to <10%624716.112.2–20.1
 10% to <20%786114.69.3–19.9
 20% to <30%726514.612.2–16.9
 30% to <40%695516.013.1–18.9
 40% to <50%624116.210.7–21.8
 50% to <60%432626.49.9–42.8
 60% to <70%403219.511.4–27.7
 70% to <80%261922.511.4–33.5
 80% to <90%332320.216.5–23.9
 90% to 100%392720.215.7–24.7

Negative values indicate that the T2 FLAIR abnormality actually increased after surgery relative to the preoperative value; positive values, that it decreased.

Postoperative Complications

A review of postoperative outcomes revealed that 23% of the 1229 patients included in this study suffered from postoperative complications and 18% from neurological complications (Table 2). The most common neurological complications were motor deficits (9%), followed by speech impairments (6%) and visual deficits (3%). Seizures were observed in 2% of the patients.

The group with less than complete resection had a significantly higher rate of complications than the complete resection group (27% vs 21%, respectively, p = 0.02) and a significantly higher rate of neurological complications (22% vs 17%, p = 0.02).

In the complete resection group, we compared the overall and neurological postoperative complication rates between patients who also underwent ≥ 53.21% FLAIR resection with those who had < 53.21% resection. The rates of overall complications were significantly higher in patients with FLAIR resection < 53.21% (26% vs 18%, p = 0.04; Table 7). The rates of neurological complications were not significantly different between the 2 groups (p = 0.12).

TABLE 7.

Outcomes in 643 patients with GBM treated with additional resection of T2 FLAIR abnormality region*

VariableTotal No.≥53.21% Resection<53.21% Resectionp Value
No. of patients643159484
30-day postop complications (%)
 No490 (76)131 (82)359 (74)
 Yes153 (24)28 (18)125 (26)0.04
30-day postop neurological complications (%)
 No523 (81)136 (86)387 (80)
 Yes120 (19)23 (14)97 (20)0.12
 Motor deficit57 (9)8 (5)49 (10)0.05
 Speech impairment46 (7)9 (6)37 (8)0.40
 Visual impairment18 (3)4 (3)14 (3)1.00
 Seizure12 (2)1 (<1)11 (2)0.31
 Hemorrhage11 (2)1 (<1)10 (2)0.31
 Intracranial hemorrhage9 (1)1 (<1)8 (2)0.46
 Hydrocephalus7 (1)1 (<1)6 (1)1.00
 Cognitive/memory/mental status problems8 (1)3 (2)5 (1)0.42
 Sensory deficit4 (<1)1 (<1)3 (<1)1.00
 Headache3 (<1)1 (<1)2 (<1)0.57
Cranial nerve deficit4 (<1)1 (<1)3 (<1)1.00
Other22 (3)3 (2)19 (4)0.22

The value 53.21% comes from CART (classification and regression tree) analysis, also called recursive partitioning.

Other includes edema, cerebrospinal fluid leak, pneumocephalus, superior sagittal sinus thrombosis, fluid entrapment in resection cavity, posterior cerebral artery infarct, nausea and vomiting, subdural empyema, bladder dysfunction, and gait abnormalities.

Discussion

The current standard of care for patients with GBM is resection followed by adjuvant chemoradiotherapy. Several patient and tumor variables have been shown to affect the prognosis of patients with GBM, including age, preoperative functional status, and preoperative imaging characteristics of the tumor. Additionally, the prognostic value of EOR has been repeatedly confirmed,15,19,20 and authors of these studies and others have suggested that at least 78%–89% of the contrast-enhancing tumor volume needs to be resected for a significant survival advantage. In the current study, we first explored the influence of complete resection, that is, surgical removal of the entire contrast-enhancing region, on patient survival. Complete resection was achieved in 876 patients (71%). The 15.2-month median survival time among these patients was about 5.4 months longer than the median survival for patients undergoing less than complete resection (p < 0.001), a finding supported by our multivariate analysis (adjusted HR for the less than complete resection group 1.53, 95% CI 1.33–1.77, p < 0.001). The 2 resection groups had significant differences in important characteristics, which could have affected overall survival. We examined the effect of EOR within various categories of these characteristics. The hazard ratio remained basically unaltered in terms of direction, and the p values remained significant in all categories except for an asymptomatic presentation, alleviating concern that such a finding is attributable to a different distribution of prognostic variables between the 2 resection groups.

Therefore, the conclusion supported by the data and the one that should be emphasized to practicing neurosurgeons is that every attempt should be made to resect the totality of the contrast-enhancing portion of a GBM tumor, as this approach will lead to a maximal survival benefit. In addition, given that the contrast-enhancing portion of a tumor is entirely composed of tumor cells,16 the goal of complete resection should be achievable in most patients with GBM, even when the lesion is located within or near eloquent brain.

The incidence of complications was not higher in patients who underwent complete resection than in those who underwent less than complete resection. Rather, it was the other way around. This finding probably reflects the sicker status of the latter group, which we corrected for in the multivariate analysis of survival.

As noted previously, the invasiveness of GBM has been demonstrated in vitro, in vivo, and in postmortem and other studies. The majority of patients succumbing to GBM die of local tumor recurrence, presumably from re-growth of infiltrating tumors left behind in the vicinity of the original tumor. Cerebral edema, demyelination, and/or surgery-related injury represent an important component of the T2 FLAIR abnormality region.9,28 In cases in which edema is a significant component after resection of the enhancing mass, the FLAIR signal shrinks considerably. But the tumor component reflecting the invasive nature of GBM cannot be ignored.8,9,13,26,28 The area outside the contrast-enhancing region on T1-weighted MRI is usually infiltrated by tumor cells. These appear on T2 FLAIR images;8,13 therefore, we explored the effect of additional resection of the T2 FLAIR abnormality region in the subgroup that had undergone complete resection of their contrast-enhancing tumor.

We identified the subset of patients in whom some FLAIR abnormality region was resected. Of note, only around 30% of patients in our study had > 50% resection of the T2 FLAIR abnormality. When these cases were performed, there was no evidence in the literature to support a resected FLAIR region as a significant positive prognostic factor, nor was there evidence on the safety of additional FLAIR resection, hence the apparent reluctance of our surgeons to push the boundary of T2 FLAIR resection. To our knowledge, this study is the first to present data on the effect of T2 FLAIR resection in a large number of patients. The literature does support aggressive resection of the enhancing lesion, a practice rigorously followed at our center, as reflected in our study data on resecting the contrast-enhancing tumor volume. Resecting a portion of the T2 FLAIR abnormality region did confer an added survival benefit over complete resection at the univariate analysis level. The trend remained strong at the multivariate level. Such a benefit was observed in patients undergoing at least 53.21% resection of the FLAIR abnormality compared with those undergoing a less extensive resection. This advantage of the ≥ 53.21% EOR group over the < 53.21% EOR group was initially observed in the univariate analysis in both the previously untreated patient subset (median survival 23.2 months, 95% CI 17.8–28.6 months compared with 18.7 months, 95% CI 16.9–20.5 months, respectively) and in the previously treated patient subset (median survival 19.8 months, 95% CI 15.3–24.3 months compared with 11.2 months, 95% CI 9.8–12.6 months, respectively). In the multivariate analysis, after correcting for other independent prognostic factors, the previously treated group with < 53.21% resection had significantly shorter survival than the other 3 categories (that is, previously treated patients who underwent FLAIR resection ≥ 53.21%, previously untreated patients who underwent FLAIR resection < 53.21%, and previously untreated patients who underwent FLAIR resection ≥ 53.21%). The previously untreated group with ≥ 53.21% resection had the longest survival. (Of note, patients previously treated with radiation and/or chemotherapy had a significantly less extensive T2 FLAIR abnormality resection than those who had not been previously treated.) Therefore, resection of a significant portion of the T2 FLAIR abnormality region, if feasible and safely attempted, could have a beneficial impact on the survival of patients with GBM. We believe these results have significant value. Future reviews at our and other centers will hopefully shed more light on the issue, with confirmatory evidence and a better definition of the thresholds involved. Calls to maximize the EOR raise concerns about associated increases in patient morbidity.22 We reviewed the surgical morbidity associated with resection in our series. Complete resection was found to be relatively safe if it was feasible, as was removal of the T2 FLAIR abnormality region outside of the T1 contrast-enhancing GBM region. The decreased risk probably reflects the increased use of intraoperative neurophysiological monitoring; functional cortical, sub-cortical, and language mapping; awake craniotomy technique; neuronavigation overlapping with diffusion tensor imaging (DTI) and functional imaging; and intraoperative MRI. The focus of any GBM resection should be maximal tumor removal while protecting against postoperative neurological or other deficits. If complete (100%) resection of the contrast-enhancing tumor is not achievable, then less extensive resections (as dictated primarily by functional mapping) may still provide both symptomatic and survival benefits. Neurosurgeons should aim to perform the maximum resection possible without hurting the patient. Additional resection of the T2 FLAIR region appears to confer an added survival advantage without added risk.

This study has a number of limitations, the main one being that the compared cohorts may be inherently different. There were significant differences in baseline characteristics between patients undergoing 100% and less than 100% resection of the contrast-enhancing lesion. A closer examination showed that the findings remained basically unaltered when the effects of EOR on survival were compared within subgroups of these baseline characteristics. In addition to the known differences between the groups being compared, there are probably other inherent differences that are not necessarily easily controlled for within such a study design. In addition, although most of the data were collected prospectively, the study is a retrospective one. As a result, important information was not available to review—for example, the specific reason the neurosurgeon chose to resect the volume that he or she resected—as well as the unavailability of T2 FLAIR MRI studies for some of the earlier patients, which limited the power of the study in some of the subgroup analyses and possibly introduced bias. Despite these limitations, most of the data pointed in the same direction, lending support to the legitimacy of the conclusions derived from this study.

In the absence of better imaging techniques to distinguish between tumor and cerebral edema on FLAIR images, we retrospectively assessed the relation between resection of the FLAIR abnormality area and survival duration and concluded that a greater EOR of the FLAIR area is probably associated with longer patient survival.

Conclusions

Based on what is, to our knowledge, the largest single-center series of GBM patients with extensive tumor resections, this study supports the established association between EOR and survival. It also provides evidence that the maximum safe resection of contrast-enhancing GBM volume results in a significant survival advantage relative to less extensive resections. Such an outcome is achieved without a significant increase in postoperative neurological deficits or other complications. In addition, in the subgroup that underwent complete resection of the T1 contrast-enhancing region, additional resection of the T2 FLAIR abnormality region may confer a significant added survival advantage. We conclude that pushing the boundary to 100% resection and beyond, along with the removal of a significant amount of the FLAIR abnormality region, may result in longer survival without significant increases in postoperative morbidity and should be further investigated.

Acknowledgments

We thank David M. Wildrick, PhD, for editorial assistance and Stephanie Jenkins for assistance with manuscript preparation. Data for this work were compiled from a database partly funded by an institutional development grant from The University of Texas MD Anderson Cancer Center.

Author Contributions

Conception and design: Sawaya, Li, Suki. Acquisition of data: Sawaya Li, Suki. Analysis and interpretation of data: all authors. Drafting the article: Li, Suki. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Sawaya. Statistical analysis: Suki. Administrative/technical/material support: Sawaya. Study supervision: Sawaya, Suki.

References

  • 1

    Altman DGLausen BSauerbrei WSchumacher M: Dangers of using “optimal” cutpoints in the evaluation of prognostic factors. J Natl Cancer Inst 86:8298351994

  • 2

    Bernstein JJGoldberg WJLaws ER JrConger DMorreale VWood LR: C6 glioma cell invasion and migration of rat brain after neural homografting: ultrastructure. Neurosurgery 26:6226281990

  • 3

    Burger PCDubois PJSchold SC JrSmith KR JrOdom GLCrafts DC: Computerized tomographic and pathologic studies of the untreated, quiescent, and recurrent glioblastoma multiforme. J Neurosurg 58:1591691983

  • 4

    Burger PCHeinz ERShibata TKleihues P: Topographic anatomy and CT correlations in the untreated glioblastoma multiforme. J Neurosurg 68:6987041988

  • 5

    Cerame MAGuthikonda MKohli CM: Extraneural metastases in gliosarcoma: a case report and review of the literature. Neurosurgery 17:4134181985

  • 6

    Choucair AKLevin VAGutin PHDavis RLSilver PEdwards MS: Development of multiple lesions during radiation therapy and chemotherapy in patients with gliomas. J Neurosurg 65:6546581986

  • 7

    Dolecek TAPropp JMStroup NEKruchko C: CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005–2009. Neuro Oncol 14:Suppl 5v1v492012

  • 8

    Earnest FIVKelly PJScheithauer BWKall BACascino TLEhman RL: Cerebral astrocytomas: histopathologic correlation of MR and CT contrast enhancement with stereotactic biopsy. Radiology 166:8238271988

  • 9

    Ebos JMLee CRKerbel RS: Tumor and host-mediated pathways of resistance and disease progression in response to antiangiogenic therapy. Clin Cancer Res 15:502050252009

  • 10

    Greene GMHitchon PWSchelper RLYuh WDyste GN: Diagnostic yield in CT-guided stereotactic biopsy of gliomas. J Neurosurg 71:4944971989

  • 11

    Hochberg FHPruitt A: Assumptions in the radiotherapy of glioblastoma. Neurology 30:9079111980

  • 12

    Ibayashi NHerman MMBoyd JCRubinstein LJ: Relationship of invasiveness to proliferating activity and to cyto-skeletal protein production in human neuroepithelial tumors maintained in an organ culture system: use of human cortex and dura as supporting matrices. Neurosurgery 26:6296371990

  • 13

    Kelly PJDaumas-Duport CKispert DBKall BAScheithauer BWIllig JJ: Imaging-based stereotaxic serial biopsies in untreated intracranial glial neoplasms. J Neurosurg 66:8658741987

  • 14

    Kreisl TN: Chemotherapy for malignant gliomas. Semin Radiat Oncol 19:1501542009

  • 15

    Lacroix MAbi-Said DFourney DRGokaslan ZLShi WDeMonte F: A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg 95:1901982001

  • 16

    Lang FFSawaya RSuki DMcCutcheon IEHess KR: Glioblastoma resection. J Neurosurg 116:11661167

  • 17

    Leifer DMoore TUkena TWilner DThor AHedley-Whyte ET: Multifocal glioblastoma with liver metastases in the absence of surgery. Case report. J Neurosurg 71:7727761989

  • 18

    Liwnicz BHRubinstein LJ: The pathways of extraneural spread in metastasizing gliomas: a report of three cases and critical review of the literature. Hum Pathol 10:4534671979

  • 19

    Marko NFWeil RJSchroeder JLLang FFSuki DSawaya RE: Extent of resection of glioblastoma revisited: personalized survival modeling facilitates more accurate survival prediction and supports a maximum-safe-resection approach to surgery. J Clin Oncol 32:7747822014

  • 20

    Sanai NPolley MYMcDermott MWParsa ATBerger MS: An extent of resection threshold for newly diagnosed glioblastomas. J Neurosurg 115:382011

  • 21

    Sawaya RHammoud MSchoppa DHess KRWu SZShi WM: Neurosurgical outcomes in a modern series of 400 craniotomies for treatment of parenchymal tumors. Neurosurgery 42:104410561998

  • 22

    Stummer WTonn JCMehdorn HMNestler UFranz KGoetz C: Counterbalancing risks and gains from extended resections in malignant glioma surgery: a supplemental analysis from the randomized 5-aminolevulinic acid glioma resection study. Clinical article. J Neurosurg 114:6136232011

  • 23

    Van Meir EGHadjipanayis CGNorden ADShu HKWen PYOlson JJ: Exciting new advances in neuro-oncology: the avenue to a cure for malignant glioma. CA Cancer J Clin 60:1661932010

  • 24

    Vertosick FT JrSelker RG: Brain stem and spinal metastases of supratentorial glioblastoma multiforme: a clinical series. Neurosurgery 27:5165221990

  • 25

    Wallner KEGalicich JHKrol GArbit EMalkin MG: Patterns of failure following treatment for glioblastoma multiforme and anaplastic astrocytoma. Int J Radiat Oncol Biol Phys 16:140514091989

  • 26

    Wilson CB: Glioblastoma: the past, the present, and the future. Clin Neurosurg 38:32481992

  • 27

    Yung WAHorten BCShapiro WR: Meningeal gliomatosis: a review of 12 cases. Ann Neurol 8:6056081980

  • 28

    Zinn POMahajan BSathyan PSingh SKMajumder SJolesz FA: Radiogenomic mapping of edema/cellular invasion MRI-phenotypes in glioblastoma multiforme. PLoS One 6:e254512011. Erratum in PLoS One

Article Information

Correspondence Raymond Sawaya, Department of Neurosurgery, Unit 442, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas 77030. email: rsawaya@mdanderson.org.

* Drs. Li and Suki contributed equally to this work.

INCLUDE WHEN CITING Published online October 23, 2015; DOI: 10.3171/2015.5.JNS142087.

Disclosure This work was supported by a generous gift from the Apache Corporation.

© AANS, except where prohibited by US copyright law."

Headings

Figures

  • View in gallery

    Kaplan-Meier plot of overall survival in a series of 1229 patients with GBM after different degrees of resection of the contrast-enhancing tumor volume. Compare the complete resection group (dashedline, 100%; black squares, 100%-censored) with the group that underwent less than complete resection (solid line, 78% to < 100%; black circles, 78% to < 100%-censored).

  • View in gallery

    Histogram showing percentages of 643 patients who underwent different EORs of the T2 FLAIR abnormality region for GBM. Figure is available in color online only.

  • View in gallery

    Kaplan-Meier plot of overall survival in 643 patients with GBM who underwent resection of the T2 FLAIR abnormality region of the tumor after undergoing complete resection, in relation to previous treatment status, either previously treated (treated) or not treated. Represented are patients who underwent < 53.21% resection, not treated (dashed line; censored, black circles) and treated (dashed-dotted line; censored, black squares); ≥ 53.21% resection, not treated (solid line; censored, black triangles) and treated (dotted line; censored, black diamonds).

References

1

Altman DGLausen BSauerbrei WSchumacher M: Dangers of using “optimal” cutpoints in the evaluation of prognostic factors. J Natl Cancer Inst 86:8298351994

2

Bernstein JJGoldberg WJLaws ER JrConger DMorreale VWood LR: C6 glioma cell invasion and migration of rat brain after neural homografting: ultrastructure. Neurosurgery 26:6226281990

3

Burger PCDubois PJSchold SC JrSmith KR JrOdom GLCrafts DC: Computerized tomographic and pathologic studies of the untreated, quiescent, and recurrent glioblastoma multiforme. J Neurosurg 58:1591691983

4

Burger PCHeinz ERShibata TKleihues P: Topographic anatomy and CT correlations in the untreated glioblastoma multiforme. J Neurosurg 68:6987041988

5

Cerame MAGuthikonda MKohli CM: Extraneural metastases in gliosarcoma: a case report and review of the literature. Neurosurgery 17:4134181985

6

Choucair AKLevin VAGutin PHDavis RLSilver PEdwards MS: Development of multiple lesions during radiation therapy and chemotherapy in patients with gliomas. J Neurosurg 65:6546581986

7

Dolecek TAPropp JMStroup NEKruchko C: CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005–2009. Neuro Oncol 14:Suppl 5v1v492012

8

Earnest FIVKelly PJScheithauer BWKall BACascino TLEhman RL: Cerebral astrocytomas: histopathologic correlation of MR and CT contrast enhancement with stereotactic biopsy. Radiology 166:8238271988

9

Ebos JMLee CRKerbel RS: Tumor and host-mediated pathways of resistance and disease progression in response to antiangiogenic therapy. Clin Cancer Res 15:502050252009

10

Greene GMHitchon PWSchelper RLYuh WDyste GN: Diagnostic yield in CT-guided stereotactic biopsy of gliomas. J Neurosurg 71:4944971989

11

Hochberg FHPruitt A: Assumptions in the radiotherapy of glioblastoma. Neurology 30:9079111980

12

Ibayashi NHerman MMBoyd JCRubinstein LJ: Relationship of invasiveness to proliferating activity and to cyto-skeletal protein production in human neuroepithelial tumors maintained in an organ culture system: use of human cortex and dura as supporting matrices. Neurosurgery 26:6296371990

13

Kelly PJDaumas-Duport CKispert DBKall BAScheithauer BWIllig JJ: Imaging-based stereotaxic serial biopsies in untreated intracranial glial neoplasms. J Neurosurg 66:8658741987

14

Kreisl TN: Chemotherapy for malignant gliomas. Semin Radiat Oncol 19:1501542009

15

Lacroix MAbi-Said DFourney DRGokaslan ZLShi WDeMonte F: A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg 95:1901982001

16

Lang FFSawaya RSuki DMcCutcheon IEHess KR: Glioblastoma resection. J Neurosurg 116:11661167

17

Leifer DMoore TUkena TWilner DThor AHedley-Whyte ET: Multifocal glioblastoma with liver metastases in the absence of surgery. Case report. J Neurosurg 71:7727761989

18

Liwnicz BHRubinstein LJ: The pathways of extraneural spread in metastasizing gliomas: a report of three cases and critical review of the literature. Hum Pathol 10:4534671979

19

Marko NFWeil RJSchroeder JLLang FFSuki DSawaya RE: Extent of resection of glioblastoma revisited: personalized survival modeling facilitates more accurate survival prediction and supports a maximum-safe-resection approach to surgery. J Clin Oncol 32:7747822014

20

Sanai NPolley MYMcDermott MWParsa ATBerger MS: An extent of resection threshold for newly diagnosed glioblastomas. J Neurosurg 115:382011

21

Sawaya RHammoud MSchoppa DHess KRWu SZShi WM: Neurosurgical outcomes in a modern series of 400 craniotomies for treatment of parenchymal tumors. Neurosurgery 42:104410561998

22

Stummer WTonn JCMehdorn HMNestler UFranz KGoetz C: Counterbalancing risks and gains from extended resections in malignant glioma surgery: a supplemental analysis from the randomized 5-aminolevulinic acid glioma resection study. Clinical article. J Neurosurg 114:6136232011

23

Van Meir EGHadjipanayis CGNorden ADShu HKWen PYOlson JJ: Exciting new advances in neuro-oncology: the avenue to a cure for malignant glioma. CA Cancer J Clin 60:1661932010

24

Vertosick FT JrSelker RG: Brain stem and spinal metastases of supratentorial glioblastoma multiforme: a clinical series. Neurosurgery 27:5165221990

25

Wallner KEGalicich JHKrol GArbit EMalkin MG: Patterns of failure following treatment for glioblastoma multiforme and anaplastic astrocytoma. Int J Radiat Oncol Biol Phys 16:140514091989

26

Wilson CB: Glioblastoma: the past, the present, and the future. Clin Neurosurg 38:32481992

27

Yung WAHorten BCShapiro WR: Meningeal gliomatosis: a review of 12 cases. Ann Neurol 8:6056081980

28

Zinn POMahajan BSathyan PSingh SKMajumder SJolesz FA: Radiogenomic mapping of edema/cellular invasion MRI-phenotypes in glioblastoma multiforme. PLoS One 6:e254512011. Erratum in PLoS One

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