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. 2015 Jan 3;17(6):868–881. doi: 10.1093/neuonc/nou349

Biopsy versus partial versus gross total resection in older patients with high-grade glioma: a systematic review and meta-analysis

Saleh A Almenawer 1, Jetan H Badhiwala 1, Waleed Alhazzani 1, Jeffrey Greenspoon 1, Forough Farrokhyar 1, Blake Yarascavitch 1, Almunder Algird 1, Edward Kachur 1, Aleksa Cenic 1, Waseem Sharieff 1, Paula Klurfan 1, Thorsteinn Gunnarsson 1, Olufemi Ajani 1, Kesava Reddy 1, Sheila K Singh 1, Naresh K Murty 1
PMCID: PMC4483123  PMID: 25556920

Abstract

Background

Optimal extent of surgical resection (EOR) of high-grade gliomas (HGGs) remains uncertain in the elderly given the unclear benefits and potentially higher rates of mortality and morbidity associated with more extensive degrees of resection.

Methods

We undertook a meta-analysis according to a predefined protocol and systematically searched literature databases for reports about HGG EOR. Elderly patients (≥60 y) undergoing biopsy, subtotal resection (STR), and gross total resection (GTR) were compared for the outcome measures of overall survival (OS), postoperative karnofsky performance status (KPS), progression-free survival (PFS), mortality, and morbidity. Treatment effects as pooled estimates, mean differences (MDs), or risk ratios (RRs) with corresponding 95% confidence intervals (CIs) were determined using random effects modeling.

Results

A total of 12 607 participants from 34 studies met eligibility criteria, including our current cohort of 211 patients. When comparing overall resection (of any extent) with biopsy, in favor of the resection group were OS (MD 3.88 mo, 95% CI: 2.14–5.62, P < .001), postoperative KPS (MD 10.4, 95% CI: 6.58–14.22, P < .001), PFS (MD 2.44 mo, 95% CI: 1.45–3.43, P < .001), mortality (RR = 0.27, 95% CI: 0.12–0.61, P = .002), and morbidity (RR = 0.82, 95% CI: 0.46–1.46, P = .514) . GTR was significantly superior to STR in terms of OS (MD 3.77 mo, 95% CI: 2.26–5.29, P < .001), postoperative KPS (MD 4.91, 95% CI: 0.91–8.92, P = .016), and PFS (MD 2.21 mo, 95% CI: 1.13–3.3, P < .001) with no difference in mortality (RR = 0.53, 95% CI: 0.05–5.71, P = .600) or morbidity (RR = 0.52, 95% CI: 0.18–1.49, P = .223).

Conclusions

Our findings suggest an upward improvement in survival time, functional recovery, and tumor recurrence rate associated with increasing extents of safe resection. These benefits did not result in higher rates of mortality or morbidity if considered in conjunction with known established safety measures when managing elderly patients harboring HGGs.

Keywords: elderly, extent of resection, malignant glioma, meta-analysis, systematic review

In 2013, there were an estimated 69 720 newly diagnosed primary CNS tumors in the United States. Of these, 24 560 were malignant.1 High-grade gliomas (HGGs), World Health Organization (WHO) grades III and IV, are the most common primary malignant CNS tumors, accounting for nearly 80% of cases.2 The incidence of HGGs increases with advancing age, with a peak incidence between 65 and 84 years.3,4 In recent years, there has been a steep rise in the incidence of brain tumors, in particular HGGs, among the elderly.5–7 Despite the frequency of these tumors in older patients, the optimal management of HGGs in this population remains poorly defined.8,9

Treatment of HGGs generally consists of surgical resection, followed by radiotherapy and adjuvant chemotherapy with temozolomide.10–12 The prognosis of patients harboring HGGs remains poor, and these lesions are associated with substantial morbidity and mortality.13 Key prognostic factors include age, preoperative neurological function, extent of surgical resection (EOR), molecular subclass, and eloquent location.14–17 Although the infiltrative nature of HGGs represents an operative challenge, the existing evidence favors maximal tumor resection among the general population.18 Sanai and Berger19 in 2008 reviewed the literature regarding the impact of EOR on patients' survival outcome and found maximum resection to be associated with longer life expectancy for both low- and high-grade gliomas. Nonetheless, the value of optimal resection remains controversial in the elderly, given their existing medical comorbidities, poor physiological reserve, overall poorer prognosis, unclear benefits, and assumed higher rates of mortality and morbidity associated with maximum resections. Hence, these patients occasionally undergo biopsy or partial resection followed by adjuvant therapy. Given the aging nature of our population, together with the high incidence of HGGs among the elderly, critical appraisal of the literature and evaluation of current treatment strategies based on valid research methodologies is essential to improve the quality of care offered to this group of patients. The aim of this systematic review and meta-analysis is to compare clinical outcomes of elderly patients undergoing variable extents of resection and their impact on survival time, functional recovery, tumor progression rate, and associated morbidity and mortality. Moreover, we have included our institutional series with the published data to provide an evidence-based approach for the optimal surgical therapy.

Methods

We undertook a systematic review and meta-analysis based on a predefined protocol (see Supplementary material) and reported our findings in accordance with recommendations of the Meta-analysis of Observational Studies in Epidemiology (MOOSE),20 the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA),21 and the Cochrane Handbook.22

Search Strategy

Two independent reviewers (S.A.A. and J.H.B.) performed a detailed electronic search of MedLine (PubMed and Ovid), Embase, the Cumulative Index to Nursing and Allied Health Literature, Google Scholar, and the Cochrane Library for studies published between January 1, 1970 and January 1, 2014 on the EOR of HGGs among the elderly without language restriction. Keywords and terms in Medical Subject Headings pertaining to the condition (ie, high grade glioma, malignant astrocytoma/oligodendroglioma, glioblastoma multiforme, or anaplastic astrocytoma/oligodendroglioma) were cross-referenced with terms pertinent to the surgical management (ie, surgery, gross total/subtotal/partial resection, biopsy, extent of resection, therapy, or management) in relevant combinations. The full-text versions of all studies the reviewers considered relevant were obtained. References of studies with potential relevance and review studies were screened manually to identify any eligible resources that were not previously identified.

Selection Criteria

We included studies that compared 2 or more methods of EOR of HGGs among the elderly. Articles with a sample size of less than 10 consecutive patients were excluded. In addition, we excluded duplicate references, studies that did not specify the extent of tumor removal, and those that mixed the surgical outcomes of variable degrees of resection. Papers with more than one treatment were considered eligible if outcomes of management options were reported as events, means, or medians with measures of dispersion. We excluded reports that examined surgical outcomes only among younger patients and studies that mixed outcomes of HGGs with other tumors. In addition, we included studies that discussed outcomes of the elderly with younger patients if outcomes of the elderly were presented separately. Abstracts presented in conferences and letters to editors were excluded if studies were not published as full reports. Any disagreement between the 2 reviewers concerning the decision to include or exclude a study was resolved by discussion and consensus with a third reviewer (W.A.).

Data Extraction

Data were abstracted by 2 investigators (S.A.A. and J.H.B.) independently. Discrepancies were settled by consensus and discussion. We gathered information from eligible articles using data abstraction forms, including title, first author, year of publication, study design, number of cohorts, total number of managed patients, gender, mean age, presenting symptoms, tumor locations on imaging, tumor histology, definition of “elderly” within each study, mean neurological scores at presentation, types of postoperative adjuvant therapy, number of patients within each method of EOR, and the outcomes of mean survival time with measures of dispersion, mean postsurgical functional score, mean time to progression, postoperative mortality, and morbidity for each resection group.

Definition of Variables

HGGs included anaplastic astrocytoma or oligodendroglioma and glioblastoma multiforme (GBM), WHO grades III and IV glial tumors. While the definition of lesion biopsy was the use of surgical procedures exclusively for pathological diagnostic purposes, the definition of resection was the operative attempt of tumor removal. In this meta-analysis, resections were divided into gross total resection (GTR) and subtotal resection (STR) according to the complete removal of the lesion in the former and partial or incomplete results in the latter. Further classification of EOR into variable degrees and tumor removal percentages was not possible in our study design. The degree of resection was evaluated in eligible studies by comparing pre- with postoperative imaging volumetrically. The cutoff age defining the elderly patients varied from ≥60 to 75 years among eligible studies. The primary outcome of this study was mean overall survival (OS) time, in months, following operative procedures. Mean functional recovery among variable groups was considered as a secondary outcome. Variable assessment tools were used to report functional outcome. Karnofsky performance status (KPS)23,24 was the most commonly used measure. In addition, we examined the progression-free survival (PFS) time, in months, as an additional secondary outcome. This was achieved using the updated Macdonald25,26 criteria, which accounts for tumor recurrence according to true clinical and/or radiological features that may require medical attention. Postoperative mortality and morbidity were evaluated during the initial 30 days of hospital stay following the surgical intervention and calculated as tertiary outcomes. Morbidity included the surgical (eg, wound infection, hemorrhage, new deficit) and/or medical complications (eg, pneumonia, deep venous thrombosis, pulmonary embolus).

Quality Assessment

Methodological quality assessment was done by 2 reviewers (S.A.A. and W.A.). We used the Cochrane Collaboration' tool27 to assess the risk of selection, performance, detection, attrition, and reporting biases of randomized trials. The Newcastle-Ottawa Scale28 was used to measure comparability, selection of cohorts, and assessment of outcomes among observational studies.

Data Synthesis and Analysis

We performed detailed analyses to evaluate the value of EOR by conducting 4 separate comparisons (ie, biopsy vs STR, biopsy vs GTR, biopsy vs the overall resection group [regardless of extent], and STR vs GTR). Five outcomes were examined for each comparison: mean OS (primary outcome), mean postoperative KPS and PFS (secondary outcomes), and mortality and morbidity (tertiary outcomes). In addition, we calculated pooled weighted estimates of the 5 outcomes among the biopsy, STR, GTR, and overall resection groups. We used the extracted mean with standard deviation for analyses of continuous outcome measures and abstracted frequencies for categorical data. Measures of dispersion reported as standard error, range, or variance were converted to standard deviation. When the continuous outcome was reported only as a median, we assumed normal distribution and calculated the mean using the documented measure of dispersion.22 Individual studies contributed variably to these analyses based on data availability. Heterogeneity among studies was investigated using the Q test and quantified by the I2 statistic, which represents the percentage of total variation across studies with a predefined I2 > 50% as the cutoff point of statistical heterogeneity. We used the DerSimonian and Laird random effects model29 to calculate weighted pooled proportions due to variable studies with different designs being prone to inherent heterogeneity. Weights were calculated using the inverse variance method. Publication bias was evaluated visually by funnel plots, and quantified by Egger's regression30 and Begg–Mazumdar's tests.31 We examined the weighted mean differences for the continuous outcomes of OS, PFS, and postoperative KPS and analyzed relative risks (RRs) for the dichotomous outcomes of mortality and morbidity, with corresponding 95% CIs, and generated forest plots for all outcomes. An alpha error of <.05 was considered a criterion for statistical significance. We used Comprehensive Meta-Analysis version 2.2 for statistical analyses.

Results

Characteristics of Included Studies

Our search of the literature yielded 13 726 studies. By screening the articles' title, abstract, or both and removing duplicates, 13 602 records were excluded. After reviewing full-text versions of the remaining publications, we excluded 90 articles (Fig. 1). Resources that met our eligibility criteria numbered 34,32–64 totaling 12 607 participants, including the 211 patients from our current series. One of the eligible studies was a randomized trial,41 and the remaining 33 were observational. On the basis of methodology and reported data, 91% of included studies were of high quality as defined by a score of >4 points on quality assessment. Description of eligible studies is summarized in Table 1.

Fig. 1.

Fig. 1.

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Flow chart of study selection process.

Table 1.

Description of eligible studies

Author (y) Total N Elderly Definition Study Population Outcomes
Whittle et al32 (1991) 68 ≥60 y 68 HGGs. Tumor location: 33 right lobar, 31 left lobar, 6 callosal-diencephalic. Adjuvant therapy: 27 RT, 4 RT+CT. 29 underwent biopsy and 39 resection Biopsy: Median OS: 7.16. Mortality: 8. Morbidity: 2
Resection: Median OS: 15.23. Mortality: 0. Morbidity: 8
Ampil et al33 (1992) 19 ≥65 y 19 grade IV gliomas. 12 M and 7 F. Mean age 67.7 y. Mean preop KPS 46.1. Tumor location: 8 frontal, 5 temporal, 4 parietal, 1 temporoparietal, 1 cerebellum. Clinical presentation: progressive limb weakness, mental dysfunction. Adjuvant therapy: 12 RT, 1 RT+CT. 6 underwent biopsy and 13 resection (8 STR, 5 GTR) Biopsy: Mean OS: 4.17. Mean postop KPS: 40
Resection: Mean OS: 4.85. Mean postop KPS: 44
STR: Mean OS: 4. Mean postop KPS: 43.3
GTR: Mean OS: 6.2. Mean postop KPS: 45
Kelly et al34 (1994) 128 >65 y 128 grade IV gliomas. 67 M and 55 F. Mean age 71.1 y. Mean preop KPS 84.2. Tumor location: 12 frontal, 15 temporal, 35 parietal, 3 occipital, 14 frontoparietal, 3 frontotemporal, 11 temporoparietal, 5 parieto-occipital, 3 temporo-occipital, 6 basal ganglia, 8 thalamus, 11 corpus callosum, 2 brainstem. Clinical presentation: 36 seizure, 6 intracranial pressure symptom, 86 neurological deficit. Adjuvant therapy: 105 RT. 88 underwent biopsy and 40 resection Biopsy: Mean OS: 3.6. Mortality: 4. Morbidity: 6
Resection: Mean OS: 6.3. Mortality: 1. Morbidity: 2
Mohan et al35 (1998) 102 ≥70 y 102 grade IV gliomas. 62 M and 40 F. Mean age 74.5 y. Mean preop KPS 70.5. Tumor location: 19 frontal, 23 temporal, 19 parietal, 4 occipital, 8 frontoparietal, 1 frontotemporal, 10 temporoparietal, 7 parieto-occipital, 4 temporoparietal-occipital, 2 thalamic, 7 corpus callosum. Clinical presentation: 22 seizure, 48 motor deficit, 18 abnormal mental status. Adjuvant therapy: 77 RT, 16 CT. 53 underwent biopsy and 49 resection (42 STR, 7 GTR) Biopsy: Median OS: 3.4
Resection:
STR: Median OS: 7.2
GTR: Median OS: 17.3
Jeremic et al36 (1999) 44 ≥60 y 44 grade IV gliomas. 29 M and 15 F. 13 preop KPS ≥70. Tumor location: 16 frontal, 11 temporal, 13 parietal, 4 occipital Adjuvant therapy: 44 RT; 20 underwent biopsy and 24 resection Biopsy: Median OS: 6
Resection: Median OS: 14
Pierga et al37 (1999) 26 ≥70 y 30 HGGs. Tumor location: 30 supratentorial Adjuvant therapy: 26 RT. 14 underwent biopsy and 12 resection (7 STR, 5 GTR) Biopsy: Mean OS: 3.8
Resection: Mean OS: 6.7
Whittle et al38 (2002) 80 ≥60 y 64 grade IV and 16 grade III gliomas. Median age 68 y. 52 M and 28 F. Tumor location: 43 right lobar, 31 left lobar, 6 callosal-diencephalic. Clinical presentation: 40 headache, 20 seizure, 13 confusion, 50 sensorimotor deficit, 19 dysphasia, 14 psychomotor slowing. Adjuvant therapy: 38 RT. 40 underwent biopsy and 40 resection (26 STR, 14 GTR) Biopsy: Median OS: 7.38. Mortality: 9. Morbidity: 6
Resection: Median OS: 17.41. Mortality: 1. Morbidity: 3
Muacevic et al39 (2003) 123 ≥65 y 123 grade IV gliomas. 63 M and 60 F. Mean age 68.8 y. Tumor location: 44 lobar, 79 nonlobar. Clinical presentation: 27 seizure. Adjuvant therapy: 123 RT. 65 underwent biopsy and 58 resection Biopsy: Median OS: 8.5. Mortality: 1. Morbidity: 1
Resection: Median OS: 9. Mortality: 1. Morbidity: 3
Patwardhan et al40 (2003) 30 ≥60 y 30 grade IV gliomas. 16 M and 14 F. Mean preop KPS 67.9. Tumor location: 10 frontal, 10 parietal, 8 temporal, 7 occipital, 1 thalamus. Clinical presentation: 11 focal weakness, 8 headache, 6 seizures, 5 confusion, 5 aphasia, 5 aphasic-expressive speech. Adjuvant therapy: 6 RT, 9 RT+CT. 6 underwent biopsy and 22 resection Biopsy: Mean OS: 3.2
Resection: Mean OS: 2.2, 5.5, 13.6
Vuorinen et al41 (2003) 23 >65 y 19 grade IV and 4 grade III gliomas. 11 M and 12 F. Mean age 71.5 y. Mean preop KPS 73.5. Tumor location: 7 frontal, 7 temporal, 1 parietal, 2 occipital, 1 frontotemporal, 1 frontoparietal, 2 parieto-occipital, 1 temporoparietal, 1 temporo-occipital. Clinical presentation: 18 local neurological deficit, 5 intracranial pressure symptom, 1 epilepsy. Adjuvant therapy: 19 RT. 13 underwent biopsy and 10 resection (8 STR, 2 GTR) Biopsy: Mean OS: 3.9. Mean postop KPS: 69.2. Morbidity: 0. Mean PFS: 2.24
Resection: Mean OS: 7.7. Mean postop KPS: 77. Morbidity: 1. Mean PFS: 4.13
STR: Mean OS: 6.4. Mean postop KPS: 78.8. Morbidity: 1. Mean PFS: 3.83
GTR: Mean OS: 13.1. Mean postop KPS: 70. Morbidity: 0. Mean PFS: 5.35
Chinot et al42 (2004) 32 >70 y 32 grade IV gliomas. 15 M and 17 F. Median age 75 y. Tumor location: 6 frontal, 8 temporal, 4 parietal, 1 occipital, 6 bilobar, 4 midline, 2 multifocal. Clinical presentation: 20 altered mental status. Adjuvant therapy: 32 CT. 25 underwent biopsy and 7 resection (6 STR, 1 GTR) Biopsy: Median OS: 6.3
Resection: Median OS: 8.8
Kleinschmidt et al43 (2005) 18 ≥75 y 18 grade IV gliomas. 9 M and 9 F. Mean age 79.8 y. Tumor location: 5 frontal, 5 temporal, 1 parietal, 1 temporoparietal, 1 occipital, 1 cerebellum, 1 bifrontal, 3 not specified. Adjuvant therapy: 6 RT, 1 CT, 2 RT+CT. 6 underwent biopsy and 12 resection Biopsy: Mean OS: 3.08
Resection: Mean OS: 5.42
Combs et al44 (2008) 43 ≥65 y 43 grade IV gliomas. 29 M and 14 F. Median age 67 y. 26 preop KPS ≥70. Adjuvant therapy: 43 RT+CT. 14 underwent biopsy and 29 resection (17 STR, 12 GTR) Biopsy: Median OS: 6
Resection:
STR: Median OS: 16
GTR: Median OS: 18
Sijben et al45 (2008) 39 ≥65 y 39 grade IV gliomas. 25 M and 14 F. Tumor location: 39 supratentorial Adjuvant therapy: 20 RT, 19 RT+CT. 11 underwent biopsy and 28 resection Biopsy: Median OS: 5. Median PFS: 4.5
Resection: Median OS: 8.5. Median PFS: 5.2
Stummer et al46 (2008) 120 ≥60 y 120 HGGs. 120 underwent resection (70 STR, 50 GTR) Resection:
STR: Median OS: 11
GTR: Median OS: 13.8
Gerstein et al47 (2010) 51 ≥65 y 51 grade IV gliomas. 27 M and 24 F. Median age 70 y. 44 preop KPS ≥70. Adjuvant therapy: 51 RT+CT. 23 underwent biopsy and 28 resection (15 STR, 13 GTR) Biopsy: Median OS: 7.89. Median PFS: 4.73
Resection:
STR: Median OS: 15.5. Median PFS: 4.17
GTR: Median OS: 27.4. Median PFS: 9.53
Kimple et al48 (2010) 30 ≥70 y 30 grade IV gliomas. 17 M and 13 F. Mean age 76.9 y. Mean preop KPS 63.3. Clinical presentation: 19 altered mental status. Adjuvant therapy: 9 RT, 9 RT+CT. 14 underwent biopsy and 16 resection (7 STR, 9 GTR) Biopsy: Mean OS: 7
Resection: Mean OS: 6.8
STR: Mean OS: 4.6
GTR: Mean OS: 8.3
Lai et al49 (2010) 1,355 ≥65 y 1355 grade IV gliomas. Median age 72 y. Tumor location: 286 frontal, 377 temporal, 249 parietal, 92 occipital, 14 ventricle, brainstem or cerebellum, 273 bihemispheric, 84 not specified. Adjuvant therapy: 1005 RT, 370 RT+CT. 296 underwent biopsy and 1059 resection (485 STR, 574 GTR) Biopsy: Median OS: 5.6
Resection:
STR: Median OS: 8
GTR: Median OS: 9.3
Laigle-Donadey et al50 (2010) 39 ≥70 y 39 grade IV gliomas. 23 M and 16 F. Mean age 75.4 y. Mean preop KPS 73.6. Adjuvant therapy: 39 CT. 21 underwent biopsy and 18 resection (14 STR, 3 GTR) Biopsy: Mean OS: 8.4
Resection: Mean OS: 10.6
STR: Mean OS: 9.07
GTR: Mean OS: 16.0
Chaichana et al51 (2011) 80 ≥65 y 80 grade IV gliomas. 40 M and 40 F. Mean age 72.9 y. Median preop KPS 80. Tumor location: 35 frontal, 28 temporal, 14 parietal, 3 occipital. Clinical presentation: 17 seizure, 11 headache, 33 motor deficit, 10 sensory deficit, 21 language deficit, 11 gait deficit, 26 mental status change. Adjuvant therapy: 64 RT, 8 CT. 40 underwent biopsy and 40 resection (25 STR, 15 GTR) Biopsy: Median OS: 4. Mortality: 1. Morbidity: 4
Resection: Median OS: 5.7. Mortality: 0. Morbidity: 7
STR: Median OS: 5.4
GTR: Median OS: 5.8
Ewelt et al52 (2011) 103 >65 y 103 grade IV gliomas. 52 M and 51 F. Mean age 70.8 y. 66 preop KPS ≥70. Tumor location: 103 supratentorial. Adjuvant therapy: 37 RT, 35 RT+CT. 43 underwent biopsy and 60 resection (37 STR, 23 GTR) Biopsy: Median OS: 2.2. Median PFS: 2.1
Resection:
STR: Median OS: 7. Median PFS: 3.4
GTR: Median OS: 13.9. Median PFS: 6.4
Kushnir et al53 (2011) 68 ≥65 y 68 grade IV gliomas. 26 underwent biopsy and 42 resection Biopsy: Mean OS: 5.56
Resection: Mean OS: 11.83
Hashem et al54 (2012) 20 ≥60 y 20 grade IV gliomas. 14 M and 6 F. 13 preop KPS ≥70. Tumor location: 19 supratentorial Adjuvant therapy: 20 RT+CT. 10 underwent biopsy and 10 resection (8 STR, 2 GTR) Biopsy: Median OS: 8.26.
Resection:
STR: Median OS: 15.41
GTR: Median OS: 21.25
Oszvald et al55 (2012) 146 ≥65 y 146 grade IV gliomas. 77 M and 69 F. Mean age 71 y. Median preop KPS 70. Tumor location: 25 frontal, 43 temporal, 7 parietal, 6 occipital, 12 Wernicke area, 8 butterfly glioma, 13 Broca area, 7 gliomatosis, 6 basal ganglia, 4 trigonal, 15 central. Adjuvant therapy: 63 RT, 58 RT+CT. 66 underwent biopsy and 80 resection (61 STR, 19 GTR) Biopsy: Median OS: 4. Median postop KPS: 70. Median PFS: 3.9
Resection: Median OS: 13. Median postop KPS: 80. Median PFS: 7.9
STR: Median OS: 11.4, 16.1. Median PFS: 4.5, 10
GTR: Median OS: 17.7. Median PFS: 7.1
Scott et al56 (2012) 702 ≥70 y 702 HGGs. 404 M and 298 F. Median age 75 y. Median preop KPS 70. Tumor location: 165 frontal, 166 temporal, 154 parietal, 48 occipital, 24 corpus callosum, 1 cerebellum, 2 brainstem. Clinical presentation: 125 headache, 130 seizure, 117 hemiparesis, 123 language, 326 altered mental status, 51 visual, 23 general sensory, 19 cranial nerves, 24 increased intracranial pressure, 82 gait. Adjuvant therapy: 419 RT, 234 CT. 324 underwent biopsy and 378 resection Biopsy: Median OS: 2.3, 3.1, 4.3, 4.6
Resection: Median OS: 6.4, 7.7, 8.5, 9.3
Tanaka et al57 (2013) 105 ≥65 y 105 grade IV gliomas. 61 M and 44 F. Mean age 74.1 y. Mean preop KPS 74.9. Tumor location: 13 frontal, 60 temporal, 27 parietal, 12 occipital, 5 basal ganglia and thalamus, 14 corpus callosum, 2 cerebellum, 2 brainstem. Clinical presentation: 79 focal deficit, 45 seizure, 26 increased intracranial pressure. Adjuvant therapy: 23 RT, 1 CT, 41 RT+CT. 52 underwent biopsy and 53 resection Biopsy: Median OS: 1.5, 6.5. Mean postop KPS: 70.9. Mortality: 4. Morbidity: 16
Resection: Median OS: 0.5, 11.5. Mean postop KPS: 78.6. Mortality: 0. Morbidity: 10
Tanaka et al58 (2012) 42 ≥65 y 42 grade III gliomas. 22 M and 20 F. Mean age 74.2 y. Mean preop KPS 74.8. Tumor location: 4 frontal, 21 temporal, 10 parietal, 6 basal ganglia and thalamus, 5 corpus callosum, 5 cerebellum, 2 brainstem. Clinical presentation: 32 focal neurological deficit, 20 seizure, 3 increased intracranial pressure. Adjuvant therapy: 9 RT, 1 CT, 16 RT+CT. 33 underwent biopsy and 9 resection Biopsy: Median OS: 3.5. Mortality: 4. Morbidity: 7
Resection: Median OS: 12. Mortality: 0. Morbidity: 1
Fariselli et al59 (2013) 33 ≥70 y 33 grade IV gliomas. 20 M and 13 F. 33 preop KPS ≥70. Adjuvant therapy: 26 RT, 7 RT+CT. 4 underwent biopsy and 29 resection (13 STR, 16 GTR) Biopsy: Median OS: 7
Resection:
STR: Median OS: 8
GTR: Median OS: 11
Lee et al60 (2013) 20 ≥70 y 20 grade IV gliomas. 8 M and 12 F. Median age 73 y. Adjuvant therapy: 16 RT+CT. 9 underwent biopsy and 11 resection (3 STR, 8 GTR) Biopsy: Median OS: 11.8
Resection:
STR: Median OS: 5
GTR: Median OS: 28.9
Mukherjee et al61 (2013) 337 ≥70 y 337 HGGs. 196 underwent biopsy and 141 resection (46 STR, 38 GTR) Biopsy: Median OS: 4
Resection:
STR: Median OS: 5
GTR: Median OS: 7
Noorbaksh et al62 (2013) 8152 ≥60 y 8152 grade IV gliomas. 8152 underwent resection (5068 STR, 3084 GTR) Resection:
STR: Median OS: 7.4
GTR: Median OS: 10.6
Pichler et al63 (2013) 119 ≥60 y 119 grade IV gliomas. 77 M and 42 F. Mean age 69 y. Mean preop KPS 76. Adjuvant therapy: 5 RT, 85 RT+CT. 12 underwent biopsy and 107 resection (59 STR, 48 GTR) Biopsy: Median OS: 7.6. Mean PFS: 6.4
Resection:
STR: Median OS: 9.6. Mean PFS: 6
GTR: Median OS: 14.7. Mean PFS: 8
Uzuka et al64 (2013) 79 ≥75 y 79 grade IV gliomas. Median age 78 y. Median preop KPS 60. Tumor location: 33 frontal, 11 temporal, 22 parietal, 3 occipital, 3 basal ganglia, 2 thalamus, 2 corpus callosum, 1 lateral ventricle. Adjuvant therapy: 67 RT, 45 CT. 47 underwent biopsy and 31 resection (21 STR, 26 GTR) Biopsy: Median OS: 9.1
Resection:
GTR: Median OS: 13
Current series (2014) 211 ≥65 y 179 grade IV and 32 grade III gliomas. 119 M and 92 F. Mean age 72.3 y. Mean preop KPS 74.2. Tumor location: 96 frontal, 52 temporal, 33 parietal, 26 occipital, 4 cerebellum. Clinical presentation: 47 seizure, 41 headache, 45 motor deficit, 42 sensory deficit, 36 altered mental status. Adjuvant therapy: 101 RT, 72 RT+CT. 73 underwent biopsy and 138 resection (71 STR, 67 GTR) Biopsy: Mean OS: 5.4. Mean postop KPS: 62.1. Mortality: 4. Morbidity: 20. Mean PFS: 2
Resection: Mean OS: 9.7. Mean postop KPS: 76.2. Mortality: 3. Morbidity: 13. Mean PFS: 4.6
STR: Mean OS: 8.6. Mean postop KPS: 73.4. Mortality: 2. Morbidity: 9. Mean PFS: 3.9
GTR: Mean OS: 10.6. Mean postop KPS: 79.6. Mortality: 1. Morbidity: 4. Mean PFS: 5.6
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Abbreviations: CT, chemotherapy; F, females; M, males; postop, postoperative; preop, preoperative; RT, radiotherapy.

OS and PFS reported in months.

Outcome Measures Estimates

Pooled weighted estimates of study outcomes among the biopsy, STR, GTR, and overall resection groups are presented in Table 2. OS increased from 5.71 months (95% CI: 5.04–6.36) in patients undergoing biopsy and 8.68 months (95% CI: 7.87–9.48) in STR to 14.04 months (95% CI: 12.8–15.2) in the GTR group. Similarly, we found upward results in postoperative KPS and PFS with decreasing trends of mortality and morbidity rates in the order of biopsy, STR, and GTR, suggesting progressive improvement in clinical outcomes with greater degrees of resection.

Table 2.

Pooled estimates of included studies

EOR Degree Mean OS Mean Postoperative KPS Mean PFS Mortality Morbidity
Biopsy 5.71 mo (95% CI: 5.04–6.36) 62.46 (95% CI: 56.16–68.56) 3.68 mo (95% CI: 2.61–4.76) 8.1% (95% CI: 0.04–0.16) 13.3% (95% CI: 0.08–0.22)
Overall resection 9.34 mo (95% CI: 7.84–10.8) 71.16 (95% CI: 63.29–79.03) 5.47 mo (95% CI: 3.54–7.39) 2.1% (95% CI: 0.01–0.04) 12.3% (95% CI: 0.09–0.17)
STR 8.68 mo (95% CI: 7.87–9.48) 65.16 (95% CI: 47.12–83.2) 4.31 mo (95% CI: 3.48–5.14) 2.8% (95% CI: 0.01–0.11) 12.7% (95% CI: 0.07–0.22)
GTR 14.04 mo (95% CI: 12.8–15.2) 75.87 (95% CI: 61.18–89.55) 7.03 mo (95% CI: 5.85–8.23) 1.5% (95% CI: 0.01–0.09) 6.6% (95% CI: 0.03–0.16)
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Abbreviations: EOR, extent of surgical resection; GTR, gross-total resection; KPS, Karnofsky performance score; OS, overall survival; PFS, progression free survival; STR, subtotal resection.

Resection versus Biopsy

Upon comparing the group undergoing overall resection (of any extent) to patients undergoing biopsy, the overall results confirmed a significant benefit for the resection group. The mean difference in OS was 3.88 months (95% CI: 2.14–5.62, I2 = 67.6%, P < .001). Mean difference in postoperative KPS was 10.4 (95% CI: 6.58–14.22, I2 = 59.9%, P < .001) and mean difference in PFS was 2.44 months (95% CI: 1.45–3.43, I2 = 41.6%, P < .001). Mortality and morbidity results were RR = 0.27, 95% CI: 0.12–0.61, I2 = 0%, P = .002 and RR = 0.82, 95% CI: 0.46–1.46, I2 = 44.3%, P = .514, respectively (Fig. 2).

Fig. 2.

Fig. 2.

Fig. 2.

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Forest plots of the meta-analyses comparing overall resection (of any extent) vs biopsy. Outcomes evaluated are: (A) mean difference in OS time, in months, (B) mean difference in postoperative KPS, (C) mean difference in PFS, in months, (D) mortality, and (E) morbidity.

Subtotal Resection versus Biopsy

Patients undergoing STR compared with biopsy experienced a significant mean difference of 2.55 months in OS (95% CI: 0.91–4.19, I2 = 68.4%, P = .002) (Fig. 3A), in favor of patients undergoing STR. Similarly, the mean difference in postoperative KPS was increased by 11.1 (95% CI: 7.4–14.8, I2 = 0%, P < .001) and PFS was extended by 1.36 months (95% CI: 0.45–2.27, I2 = 29.1%, P = .003), with no statistical difference in mortality (RR = 0.51, 95% CI: 0.09–2.71, I2 = 0%, P = .434) or morbidity (RR = 0.88, 95% CI: 0.11–6.75, I2 = 51%, P = .905).

Fig. 3.

Fig. 3.

Open in a new tab

Forest plots of the meta-analyses evaluating the mean difference in OS time, in months, between: (A) STR and biopsy, (B) GTR and biopsy, and (C) GTR and STR.

Gross Total Resection versus Biopsy

When comparing the GTR group with patients undergoing biopsy, the pooled data showed statistical significance favoring GTR. The mean difference in OS was 7.05 months (95% CI: 4.17–9.93, I2 = 82.1%, P < .001) (Fig. 3B), postoperative KPS was 17.5 (95% CI: 13.81–21.18, I2 = 0%, P < .001), and PFS was 3.56 months (95% CI: 2.72–4.4, I2 = 0%, P < .001). Mortality and morbidity outcomes were RR = 0.27, 95% CI: 0.03–2.37, I2 = 0%, P = .239 and RR = 0.21, 95% CI: 0.07–0.6, I2 = 0%, P = .003, respectively.

Gross Total Resection versus Subtotal Resection

The comparison between the GTR group and patients undergoing STR confirmed the superiority of GTR. The mean differences in OS, postoperative KPS, and PFS were 3.77 months (95% CI: 2.26–5.29, I2 = 19.6%, P < .001) (Fig. 3C), 4.91 (95% CI: 0.91–8.92, I2 = 18.4%, P = .016), and 2.21 months (95% CI: 1.13–3.3, I2 = 13.3%, P < .001), respectively. Mortality and morbidity analyses did not result in a statistical difference between both groups of intervention (RR = 0.53, 95% CI: 0.05–5.71, I2 = 0%, P = .600 and RR = 0.52, 95% CI: 0.18–1.49, I2 = 0%, P = .223, respectively).

Discussion

Findings from our systematic review and meta-analysis suggest that surgical management paradigms of HGGs among elderly patients are in keeping with those for the younger adult population. In particular, our results indicate that maximum resections are safe and are associated with longer survival time, delayed tumor progression rate, and improved functional recovery.

Many clinical algorithms across diverse medical disciplines favor more conservative approaches in managing the elderly due to quality of life considerations. In accordance with this general principle, older patients with malignant gliomas frequently undergo biopsy, whereas the use of aggressive surgical resection methods is relatively limited.8–10,65 This is claimed to be due to multiple factors, including the poorer overall prognosis and the greater surgical risks among the elderly, together with unclear survival benefits and the potential for higher complication rates in this group of fragile patients. Further considerations include possible prolonged hospitalization and recovery times66 and greater medical costs34 associated with extensive resections compared with biopsy followed by adjuvant therapy.

In a population-based study, Iwamoto and colleagues9 found mean OS to be 4 months in GBM patients ≥65 years old compared with 12 to 14 months in younger patients. It is increasingly thought that poorer prognosis of HGGs among the elderly may be attributable to differences in underlying tumor biology, rather than the effect of age as a confounding factor. Lee et al67 suggested that the survival advantage of younger patients with GBM may be completely nullified once the proneural gene expression pattern has been taken into account, which occurs more frequently in younger than in older patients. In addition, the unfavorable impact of age in HGGs has been at least partly attributed to an age-related differential distribution of mutations in the isocitrate dehydrogenase 1 gene. Isocitrate dehydrogenase 1–mutant HGGs are associated with longer survival times; moreover, they occur predominantly in adults ≤60 years old.68,69 Noushmehr and colleagues70 reported a glioma cytosine–phosphate–guanine island methylator phenotype (G-CIMP) in GBM, where G-CIMP–positive patients have a survival benefit and are significantly younger relative to G-CIMP–negative patients. In 2013, Bozdag et al71 discovered major age-specific signatures in GBM at transcriptional, genetic, and epigenetic levels, including age-specific hypermethylation in polycomb group protein target genes and upregulation of angiogenesis-related genes in older patients. Greater angiogenic potential in GBM tumors has been correlated with lower survival rates.72,73 In summary, HGGs may be biologically more aggressive in older patients, accounting for the relatively shorter survival rates compared with younger populations.

The risks associated with operative resection may also influence the surgeons' decision to favor biopsy. Older patients often tolerate major surgeries poorly due to the presence of existing medical comorbidities, multiple medication use, and reduced physiological reserve. Evers et al74 proposed that the effects of aging on various organ systems usually do not affect their function in the normal state. Rather, during periods of stress, such as that posed by an operative procedure, the elderly patient may not be able to meet increased functional and metabolic demands, due to loss of reserve capacity. Accordingly, postoperative complications represent a significant source of morbidity and mortality in this population. Turrentine and colleagues75 found a progressive increase in postoperative mortality and morbidity, including wound, renal, cardiovascular, and respiratory complications with advancing age in adults undergoing general, thoracic, and vascular procedures. Other authors have made analogous conclusions in surgeries involving inflammatory bowel disease,76 aortic aneurysm repair,77 and craniotomy for brain tumor resection.78 Tomita and Raimondi79 reported a mortality rate of 3.8%, neurological deterioration in 16.3%, and medical complications in 28.8% of 80 patients over 65 years of age who underwent craniotomy for intra-axial tumor resection. These rates are higher than those seen in younger patients. Cabantog and Bernstein80 reported a complication rate of 25.1% among 207 consecutive patients undergoing craniotomy for brain tumor. Morbidity was 30.2% in 53 patients ≥65 years old and 50% in 20 patients >70 years of age. By contrast, reported mortality and morbidity from stereotactic biopsy does not appear to vary significantly with age. In a series of 300 patients undergoing biopsy of intra-axial lesions, Bernstein and Parrent81 reported a complication rate of 5.1% for patients older than 65 years, not significantly different from the 7% rate in those <65 years of age. Hence, it appears that the disparity in risk between resection and biopsy widens with increasing age.80,81 Nonetheless, more recent studies have indicated that the difference in risk between resection and biopsy in older patients may be smaller than previously thought.34,39,41 In our meta-analysis, more extensive degrees of resection were not associated with higher rates of mortality and morbidity. Indeed, lower rates were associated with the GTR group. This may be explained by the maximum relief of mass effect achieved with complete resection that improves functional recovery and, hence, decreases the mortality and morbidity associated with persisting neurological deficits in the minimal resection group.

The significance of a survival advantage conferred by higher degrees of HGG resection among the elderly, if any, has been disputed in the literature. In 1994, Kelly and Hunt34 reported only a modest prolongation of survival rate after resection, mean OS of 189 days, compared with biopsy, mean OS of 108 days, in a consecutive series of 128 patients >65 years of age with histologically proven grade IV astrocytomas. Laigle-Donadey et al50 found OS in older patients with GBM to be independent of the EOR. By contrast, in a randomized study involving 23 patients >65 years of age with HGGs, Vuorinen and colleagues41 reported a mean OS of 171 days after craniotomy compared with 85 days after biopsy; the estimated survival time was 2.76 times longer with surgical resection. Functional recovery and quality of life following variable levels of resections are essential factors for guiding surgical management of these patients. Hence, even if it were life prolonging, aggressive surgical resection would not be advised if associated with deterioration in quality of life. Contrarily, in our meta-analysis, more extensive degrees of resection were associated with longer survival times and improved functional outcomes, as expressed by improved postoperative KPS. In addition, a prolonged tumor recurrence rate correlated significantly with higher grades of resection.

There are key strengths, and also limitations, of the current series and meta-analysis. Our institutional experience represents a fair number of patients with multiple cohorts and variable outcomes relative to previously published reports in the literature. Nonetheless, it is an observational study. This study design is prone to data inaccuracy and missing information in addition to lack of randomization. All eligible studies, with the exception of one trial, were observational. This problem stems from the ethical dilemma of randomizing patients with such presentations into complete versus lesser degrees of EOR when a GTR can be achieved surgically, limiting the ability to conduct a randomized trial. Our systematic review is a critical assessment and comprehensive examination of 34 resources and more than 12 000 participants from the literature. As an expected limitation of including resources with variable qualities, definitions, follow-ups, and diagnostic criteria, inevitable heterogeneity was detected in some outcomes. Therefore, rigorous methodology was applied in investigating and examining resources for risk of bias30,31 and performing analyses in accordance with accepted methodological guidelines.20–22 In most included studies, the lesser degree of resection was not a planned goal but rather the best surgical choice considering patient-associated factors. However, regardless of the reasons behind attempting biopsy or partial resection, whether an aim or an undesirable option, these patients did poorer compared with the GTR group. Accordingly we based our conclusion that higher degrees of resection were associated with improved outcomes. Thus, the EOR is an essential factor for optimal management planning; however, it should be considered individually based on other patient factors and in conjunction with known established safety measures. Unfortunately, due to lack of information from included studies, we were not able to stratify our analyses based on different age groups or WHO grades of gliomas. Perhaps the greatest limitation in the current meta-analysis is the concern to account for similar distribution of patients' characteristics, including brain tumor location and size, presenting symptoms, adjuvant therapy, and preoperative baseline functional status among variable comparative resection groups. These variables were documented in the systematic review part of the study but were not accounted for in the meta-analysis given the nature of the study design. Nonetheless, findings from this study support the general principle of considering maximal degrees of tumor removal when the operative option is indicated and variable degrees of EORs are feasible, regardless of age. Although not without limitations, the current study is an attempt to provide a well-documented comprehensive review and critical appraisal of the data in the literature pertaining to the value of HGG EOR among the elderly.

In summary, our findings suggest that when multiple degrees of EOR are feasible within the limits of safety, favorable outcomes are associated with GTR of HGG among the elderly. These results are essential for optimal operative planning when the surgical option is indicated. The mean OS was significantly longer with maximum grades of resection. Moreover, patients undergoing complete resection experienced better functional recovery compared with participants with partial resection and individuals undergoing biopsy. With respect to tumor progression rate, elderly participants with GTR of HGG had longer PFS. The current meta-analysis did not result in a finding of higher rates of mortality or morbidity among older patients with higher grades of resection. Such findings are in keeping with the evidence obtained from the surgical outcomes of patients with glioma in the younger adult population.

Supplementary Material

Supplementary material is available online at Neuro-Oncology (http://neuro-oncology.oxfordjournals.org/).

Funding

None declared.

Conflict of interest statement. None declared.

Supplementary Material

Supplementary Data
supp_17_6_868__index.html (902B, html)

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