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Review

Impact of Extent of Resection on Overall Survival in Glioblastomas: An Umbrella Review of Meta-Analyses

by
Pemla Jagtiani
1,
Mert Karabacak
2,
Alejandro Carrasquilla
2,
Raymund Yong
2 and
Konstantinos Margetis
2,*
1
School of Medicine, SUNY Downstate Health Sciences University, New York, NY 11203, USA
2
Department of Neurosurgery, Mount Sinai Health System, New York, NY 10029, USA
*
Author to whom correspondence should be addressed.
Onco 2024, 4(4), 359-368; https://doi.org/10.3390/onco4040025
Submission received: 21 August 2024 / Revised: 21 October 2024 / Accepted: 24 October 2024 / Published: 25 October 2024
Browse Figure
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Simple Summary

Glioblastoma is the most common and aggressive type of brain tumor in adults, and deciding how much of the tumor to remove during surgery is crucial for patient survival. However, there is no clear agreement on whether removing all visible parts of the tumor is better than leaving some parts behind. This study aims to bring together and analyze existing research to better understand how the extent of tumor removal affects survival in patients with glioblastoma. By examining and summarizing the findings from multiple studies, we hope to provide clearer guidance for surgeons and improve outcomes for patients.

Abstract

(1) Background: Glioblastoma (GBM) is the most common malignant brain tumor in adults. Due to a lack of level 1 evidence, there is no clear consensus on the optimal extent of resection to improve overall survival. This umbrella review aggregates existing meta-analyses (MAs) to assess overall survival in patients undergoing subtotal resection (STR) versus gross total resection (GTR). (2) Methods: A systematic search of PubMed, Scopus, and Web of Science identified 441 studies, with four MAs meeting inclusion criteria. Data were analyzed using the metaumbrella R package, focusing on overall survival. Quality was assessed using AMSTAR2, with scores ranging from 0 to 11. The Ioannidis criteria were applied to evaluate the credibility of the evidence. (3) Results: The quality assessment rated all four studies highly, with a mean AMSTAR2 score of 10.25. The pooled analysis revealed a significant survival advantage for GTR over STR. However, the Ioannidis classification graded the evidence as Class III, indicating weak credibility. (4) Conclusions: GTR offers a slight survival benefit over STR in GBM patients, but the credibility of the evidence is weak, highlighting the need for further research.

1. Introduction

Glioblastoma (GBM) is acknowledged as the most prevalent malignant primary tumor of the brain and the central nervous system (CNS) [1]. With its origin traced to astrocytic glial cells, GBM is classified as a WHO grade 4 primary CNS malignancy, constituting 14.5% of all CNS tumors and 48.6% of malignant CNS tumors [2]. Despite significant advancements in GBM diagnosis and treatment modalities, it remains a terminal condition with a median overall survival ranging from 1.9 months in those who receive only supportive care to 11 months for those undergoing resection and radiotherapy [3]. Notably, the extent of resection goals in GBM varies among neurosurgeons, even for the same patient, primarily because of differing assessments of disease prognosis, patient risk factors for surgery, and tumor resectability based on anatomic characteristics [4]. The frequent occurrence of bilateral and multifocal GBMs and the expanding landscape of less invasive surgical options further exacerbates the debate concerning the most suitable extent of resection to achieve optimal survival and functional outcomes.
An umbrella review, colloquially known as an overview of reviews or a meta-review, exemplifies a unique form of systematic review that consolidates and critically appraises the data derived from previously published meta-analyses (MAs) on a research question or topic. Essentially serving as a “review of reviews”, an umbrella review endeavors to offer a broad, in-depth perspective of the extant literature on a specific subject, condition, or intervention. Within the realm of medical research, where the number of interventions is substantial, and the accompanying literature is abundant, an umbrella review can distill a comprehensive, informative, and coherent narrative [5]. For instance, it can aggregate all the available data regarding the impact of resection extent on patients’ overall survival across diverse types of cancers or assorted surgical procedures. This integrative analysis can facilitate a clearer comprehension of the varied benefits, risks, and effectiveness of interventions, potentially guiding clinical decisions and protocols [6].
The rationale for umbrella reviews is rooted in the exponential proliferation of scientific research [7,8,9]. A plethora of systematic reviews and MAs, published to address intricate medical questions and often presenting divergent conclusions, makes it increasingly demanding for clinicians, researchers, and policymakers to stay up to date on the evolving evidence base and effectively interpret it. While controlling for all confounding variables, the core question remains whether the extent of resection independently predicts survival. The current literature provides an inconsistent and imprecise methodology for defining the extent of resection. In fact, Albert et al. showed a disparity between a surgeon’s estimate of the extent of resection and a radiologically determined extent of resection [10]. Similarly, Orringer et al. emphasize that even when surgeons are guided by the idea of achieving safe, maximal resection, depending on a qualitative assessment of tissue margins, it is surprising that optimal surgical results are not achieved in more patients [11]. This contributes to the current state of mixed results from meta-analyses. Through this umbrella review, we aim to collect and compare existing MAs to explore the role of the extent of resection on overall survival, thereby providing a comprehensive overview of the topic.

2. Materials and Methods

This umbrella review was structured in adherence to the Preferred Reporting Items for Overviews of Reviews (PRIOR) methodology guidelines (Supplementary File S1) [5]. The design of this review also followed the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines (Supplementary File S2) [12]. The study was registered in the Open Science Foundation database (osf.io/hkb9a). However, a protocol paper was not prepared.

2.1. Search Strategy

We conducted a literature search in PubMed, Scopus, and Web of Science databases, aimed at identifying MAs probing the impact of resection extent on the overall survival of patients with GBM. The keywords used for the search strategy were “glioblastoma”, “resection”, and “meta-analysis”. Detailed search strategies are presented in Supplementary File S3. The search was last updated on 4 April 2023 and did not employ any time-bound restrictions.

2.2. Inclusion Criteria

Inclusion criteria were delineated using the PICOS format. The population (P) encompassed patients of any age diagnosed with GBM. The intervention (I) was the surgical resection of GBM, and comparators (C) were STR and GTR. The primary outcome of interest (O) was overall survival. Specific outcomes, such as postoperative intracranial hemorrhage, were excluded due to the insufficient number of MAs reporting them. The study design (S) included only MAs. Exclusion criteria encompassed studies that (1) lacked a quantitative MA, (2) reported outcomes not of interest for the present study, (3) focused on a specific patient subgroup, (4) blended STR and GTR with other extents of resections, (5) did not compare STR and GTR, (6) comprised an editorial, commentary, or conference paper, and (7) did not provide retrievable full texts.

2.3. Study Selection

A literature search was executed using the defined search strategy, covering the three databases. The Covidence systematic review software was used to import all identified articles, with duplicates being automatically removed [13]. Two independent reviewers (Author 1 and Author 2) conducted an initial screening of titles and abstracts according to the inclusion criteria. This was followed by a full-text review of the selected articles to confirm their eligibility. Articles that met the criteria during the full-text review were included in the umbrella review. Any conflicts during the selection process were resolved with input from a third reviewer (Author 5).

2.4. Data Extraction

Data from the MAs were independently extracted by two reviewers (Author 1 and Author 2). Any disagreements during this process were resolved through discussion until consensus was reached, with assistance from a third reviewer (Author 5) if needed. The extracted data included the following: first author and year of publication, last search date, data sources, range of publication date of primary studies, study design of primary studies, number of primary studies, total number of patients (including numbers of STR and GTR patients), effect measure, effect size with 95% confidence intervals (CIs), p-value for the effect size, and I2 value for heterogeneity.

2.5. Quality Assessment

Each included MA underwent a quality assessment via the AMSTAR2 (A Measurement Tool to Assess Systematic Reviews) instrument [14]. This tool assigns each article a total score ranging from 0 to 11, with a higher score indicating superior quality. It comprises 11 criteria, each given a score of 1 if met or 0 if unmet. Articles scoring 0–4 were designated as low quality, 5–8 as medium quality, and 9–11 as high quality [6,15]. Quality assessment was performed by one author (Author 1), with any uncertainties resolved through discussion with another author (Author 2).

2.6. Data Analysis and Credibility of the Evidence

A descriptive analysis was employed to synthesize the characteristics, results, and quality of MAs. Data from primary studies included in the MAs were pooled, and the effect size with 95% CI, p-value for effect size, I2 value of heterogeneity, and p-value for excess significance bias were calculated for outcomes of interest. The Ioannidis classification was utilized to ascertain the credibility of the evidence concerning the associations between GTR and STR and the outcome of interest. This classification system categorizes evidence into five ordered classes based on the criteria outlined by Fusar-Poli and Radua [16]. The five classes are “Class I”, “Class II”, “Class III”, “Class IV”, and “Class ns” (Table 1) [17]. The R package metaumbrella was used to interpret pooled effect sizes employing equivalent Hedges’ g values (eG) [18]. eG corrects for potential biases, which is particularly beneficial in studies with small sample sizes. Calculations depended on numerous parameters, including but not limited to the number of cases, p-value of random-effects models, presence of heterogeneity, small study effects, and excess significance bias [19].

3. Results

3.1. Literature Search

Our literature search yielded a total of 441 studies. After removing 208 duplicates and excluding 215 studies based on their titles and abstracts, 18 studies remained. Upon full-text screening, an additional 14 studies were excluded, leaving 4 for inclusion in this umbrella review (Figure 1).

3.2. Meta-Analysis Characteristics

The four MAs included in this review compared overall survival between STR and GTR in patients with GBM [1,4,20,21]. Published between 2015 and 2023, these MAs incorporated between 8 and 25 primary studies, with total sample sizes ranging from 552 to 20,769. The characteristics of these studies are summarized in Table 2.

3.3. Quality Assessment

The quality of the four included studies was evaluated using the AMSTAR2 assessment tool, with results provided in Table 3. All included studies scored either 10 or 11, classifying them as high quality. The mean AMSTAR2 score across the studies was 10.25.

3.4. Overall Survival

Each of the four MAs provided data comparing the overall survival between STR and GTR. AbdelFatah et al. [4] detected negligible differences in overall survival between GTR and STR, whereas Almenawer et al. [1], Brown et al. [20], and Jusue-Torres et al. [21] unveiled a significant increase in overall survival post-GTR. A summary of the extracted data, which includes effect measures and sizes, along with corresponding p-values, is detailed in Table 4. Two studies reported statistically significant differences in their effect. The I2 values, indicating heterogeneity, ranged from 0 to 99%. When pooled, the MAs revealed a statistically significant difference in overall survival favoring GTR over STR [eG = −0.356 (95% CI −0.554, −0.158), p = 0.000425]. The credibility of the evidence supporting this difference was found to be “Class III” according to the Ioannidis classification. High heterogeneity (I2 = 91.87%) and excess significance bias (p < 10−6) were found.

4. Discussion

4.1. Background

At present, no screening tests are available for GBM. Diagnosis is primarily symptom-based, and magnetic resonance imaging (MRI) serves as the gold-standard imaging method for GBM [22]. Computed tomography (CT) imaging may also provide valuable adjunctive information. Furthermore, histopathological and molecular analysis plays a pivotal role in GBM diagnosis and treatment planning. Treatment for GBM typically involves a combination of surgical resection, chemotherapy, and radiation. Initial treatment aims at surgical resection to decrease tumor burden and allow for histopathological and molecular analysis. Numerous studies indicate a survival benefit with gross total resection (GTR) over subtotal resection (STR) [20], with postoperative residual tumor volume (RTV) being a strong predictor of outcome [23]. Emerging research suggests that in some tumor locations, supra-total or supra-maximal resection may provide a survival advantage [24,25]. However, the extent of resection must be balanced against the functional outcome, particularly when the tumor involves eloquent brain regions. Evidence suggests that postoperative neurological deficits may negatively impact survival [26,27]. Hence, the objective of surgical resection is to safely remove as much of the tumor as possible, a concept referred to as safe maximal resection. Tumors located in eloquent areas that are not amenable to safe resection may be biopsied to guide further management.
GTR of a GBM is intended to maximize the extent of resection while preserving a good quality of life for patients. This largely depends on the tumor’s spread and the provider’s judgment when detecting the tumor on T1+C or T2WI or FLAIR imaging [4]. Given the infiltrative nature of GBM on surrounding brain tissue, recurrence is inevitable even after GTR [28]. Neurosurgeons aim to achieve complete resection of the contrast-enhancing portion of the tumor on MRI. Recent studies suggest that extending the resection to include the non-contrast-enhancing portion of the tumor may further improve outcomes, particularly in two groups: (1) patients with IDH wildtype tumors, regardless of their MGMT methylation status, and (2) younger patients, regardless of IDH status [29]. Several surgical adjuncts have also been developed to improve resection outcomes, including intraoperative neuromonitoring with asleep or awake cortical mapping, intraoperative MRI (iMRI), fluorescence-guided surgery (FGS), intraoperative ultrasound (iUS), tractography or diffuse tensor imaging (DTI), and neuronavigation. A 2022 MA suggested that iMRI, cortical mapping (asleep or awake), FGS, and a combination of these modalities enhance the extent of resection [30]. An ongoing randomized controlled trial is investigating whether the use of iUS and DTI affects disease-free survival (DFS) [31]. Despite the availability of several intraoperative techniques that provide real-time visualization of the brain and tumor borders, differentiating between tissues remains a challenge. The location and depth of the GBM invasion add to this complexity.
Emerging treatments for GBM are being actively developed to improve outcomes beyond the traditional methods of surgical resection, radiation, and chemotherapy. One promising approach involves targeting programmed cell death protein-1 (PD-1) or its ligand (PD-L1) to prevent GBM tumor cells from evading immune system detection and destruction [32]. Recent studies have also highlighted the potential of personalized vaccine-based therapies that utilize tumor-associated antigens to activate the patient’s immune system and target residual tumor cells. Dendritic cell-based vaccines, which use autologous cells primed in vivo with tumor antigens, and peptide-based vaccines, which deliver tumor-specific antigens to stimulate T-cell responses, have shown encouraging results [33]. Peptide vaccines target multiple antigens, including Wilms tumor 1, survivin, cytomegalovirus, neoantigen, and TAS0313 (a multipeptide vaccine targeting EGFR, LCK, KUA, PTHRP, MRP3, WHSC2, SART2, and SART3) [33]. Additionally, several proteins commonly altered in GBM, such as IDH1, EGFR, TERT, TP53, PTEN, NF1, PDGFRA, and RB1, are being targeted for therapy [34]. Although these novel treatments offer significant promise, their long-term efficacy requires further validation in large clinical trials.

4.2. Main Findings

Our umbrella review summarizes the impact of resection extent on overall survival in GBM, compiling the findings of numerous primary studies included in each MA. This approach addresses inconsistencies in the literature and provides a more comprehensive evaluation [35]. Medicine is continuously evolving, and umbrella reviews are crucial in delivering to clinicians, researchers, and policymakers an overview of existing evidence while also identifying areas for future research.
While there are many MAs comparing STR and GTR, our umbrella review is the most extensive study to date, pooling data from four MAs and 43 unique primary studies. The use of Hedges’ g values facilitated the analysis of the pooled MA data. A positive value signifies higher odds for the first group (in this case, STR), and a negative value suggests higher odds for the second group (GTR). Hence, the negative Hedges’ g value we found indicates that GTR significantly improves overall survival compared to STR. While three MAs pooled primary studies and reported better overall survival with statistical significance for GTR compared to STR, AbdelFatah et al. reported no statistical difference [4]. This highlights the utility of umbrella reviews to reconcile discrepancies among studies through an expanded pooled analysis.
Almenawer et al. defined GTR by comparing the degree of resection amongst preoperative and postoperative imaging volumetrically [1]. Brown et al. included primary studies that defined GTR as no residual enhancement or >90% resection of enhancing tissue [20]. AbdelFatah et al. defined GTR using postoperative imaging but emphasized that the definitions of GTR across the primary studies varied. They varied from additional resection of fluorescing tumor tissue to total resection of T2-weighted or FLAIR hyperintensity [4]. Jusue-Torres et al. defined GTR strictly by the absence of residual contrast-enhancing tumor on MRI within 48 h, considering even minor enhancing remnants as incomplete resection [21].
While a survival advantage of GTR was detected, the credibility of the evidence was classified as Class III when evaluated using the Ioannidis classification system. This indicates that the evidence is suggestive, but only has mild strength. Several factors contributed to this weak credibility. Firstly, high statistical heterogeneity was found when pooling the meta-analyses (I2 = 91.87%), implying inconsistency across the included studies. Differences in how primary studies and/or MAs defined GTR and STR in terms of percentage resection could have contributed to the weak credibility of the evidence. Secondly, there was significant excess significance bias detected (p < 10−6), meaning the observed number of studies with statistically significant results exceeded the expected number. Taken together, these quantitative assessments indicate low robustness of the evidence. However, the included MAs themselves were rated as high quality per the AMSTAR2 tool, lending some strength to the evidence. Additional factors that may impact credibility include the small sample size, with only four eligible meta-analyses identified despite an extensive literature search. Furthermore, the umbrella review could not account for potential differences amongst specific patient subgroups. Given these limitations, while a survival benefit of GTR over STR was found, the current evidence supporting this difference is weak. Higher-quality and more consistent primary studies are imperative to strengthen the evidence base and reach definitive conclusions on the impact of resection extent on survival.

4.3. Limitations

This umbrella review comparing STR and GTR in patients with GBM exhibits high statistical power. Our methodological rigor is demonstrated by the fact that all the MAs included were rated as high quality using AMSTAR2, and we employed the Ioannidis criteria to assess the credibility of the evidence. However, several limitations of our study should be acknowledged. During the screening process, we excluded MAs focusing on specific patient subgroups, such as those solely examining obese patients or young patients. Therefore, our results may not capture the nuances that might exist in these populations, which could potentially have different outcomes for GTR versus STR. Another limitation relates to the limited sample size; we found only four MAs that directly compared overall survival in STR versus GTR. This could potentially limit the robustness of our findings. Additionally, we had to exclude certain outcomes (e.g., postoperative intracranial hemorrhage) from our review due to insufficient MAs reporting them. The inclusion of multiple outcomes would have allowed for a more comprehensive comparison and understanding of the pros and cons associated with each resection method. Another important limitation is that our review primarily focused on overall survival without an assessment of quality of life. Although GTR might be associated with greater overall survival in GBM patients, the impact on quality of life remains unclear. Future research should investigate not only survival but also the potential negative impacts of STR and GTR, such as the occurrence of new neurological deficits.

5. Conclusions

Our umbrella review provides a comprehensive and up-to-date understanding of the influence of the extent of GBM resection on overall survival. It highlights the strengths and weaknesses of GTR and STR, acknowledges inconsistencies within the literature, and emphasizes the need for careful consideration of the marginal superiority of GTR over STR. Surgeons should balance the pursuit of maximal resection against the risk of surgical complications and the potential impact on quality of life. Our findings underscore that GTR has a slightly higher overall survival compared to STR, but the significance of this is very weak. Despite significant advances in the management of GBM, it remains an incurable cancer that warrants continued research and collaborative effort.

Supplementary Materials

The following are available online at https://www.mdpi.com/article/10.3390/onco4040025/s1, Supplementary File S1: PRIOR Checklist, Supplementary File S2: PRISMA Checklist, Supplementary File S3: Search strategies.

Author Contributions

Conceptualization, P.J., M.K., A.C., R.Y. and K.M.; Methodology, M.K. and K.M.; Software, M.K.; Formal Analysis, M.K.; Data Curation, P.J. and M.K.; Writing—Original Draft Preparation, P.J., M.K. and A.C.; Writing—Review and Editing, R.Y. and K.M.; Visualization, M.K.; Supervision, R.Y. and K.M.; Project Administration, M.K. and K.M. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflicts of interest.

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Onco 04 00025 g001
Figure 1. PRISMA flow diagram.
Figure 1. PRISMA flow diagram.
Onco 04 00025 g001
Table 1. Classes of the credibility of the evidence by Ioannidis classification.
Table 1. Classes of the credibility of the evidence by Ioannidis classification.
ClassCriteria
Class INumber of cases > 1000, p-value of the meta-analysis < 10−6, I2 < 0.5, 95% prediction interval excluding the null, p-value of the Egger test > 0.05, and p-value of the excess of statistical significance test > 0.05.
Class IINumber of cases > 1000, p-value of the meta-analysis < 10−6, largest study with a statistically significant effect, and class I criteria not met.
Class IIINumber of cases > 1000, p-value of the meta-analysis < 10−3, and class I-II criteria not met.
Class IVp-value of the meta-analysis < 0.05 and class I–III criteria not met.
Class nsp-value of the meta-analysis ≥ 0.05.
Table 2. Study characteristics.
Table 2. Study characteristics.
Author (Year)Last SearchData SourcesRange of Publication Date of Primary StudiesDesign of Primary StudiesNumber of Primary StudiesTotal Number of Patients
(STR + GTR)
Almenawer et al. (2015) [1]1 January 2014Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, Embase, Google Scholar, Medline1992–2014Observational, Randomized Control Trial10552
(314 + 238)
Brown et al. (2016) [20]12 January 2015Cumulative Index to Nursing and Allied Health Literature, PubMed, Web of Science1987–2016Retrospective2520,769
(12,472 + 8297)
AbdelFatah et al. (2022) [4]2 January 2020Embase, Google Scholar, Medline, PubMed, Science Direct2010–2019Retrospective, Prospective82249
(1002 + 1247)
Jusue-Torres et al. (2023) [21]9 January 2021ClinicalTrials.gov, Cochrane Central Register of Controlled Trials, Cochrane Database, PubMed, Web of Science2014–2022Retrospective, Prospective91699
(911 + 788)
Table 3. AMSTAR2 quality assessment.
Table 3. AMSTAR2 quality assessment.
Almenawer et al. (2015) [1]Brown et al. (2016) [20]AbdelFatah et al. (2022) [4]Jusue-Torres et al. (2023) [21]Total
Uses elements of PICOXXXX4
Explained selection of the study designsXXXX4
Comprehensive literature searchXXXX4
Study selection in duplicateXXXX4
Excluded study list providedXXXX4
Included studies describedXXXX4
Funding sources reportedX X 2
Quality assessedXXXX4
Quality used appropriatelyXXXX4
Satisfactory discussion of heterogeneityXXXX4
Conflicts of interest reportedXX X3
AMSTAR211101010Mean = 10.25
Table 4. Summary of the overall survival outcome for each included meta-analysis.
Table 4. Summary of the overall survival outcome for each included meta-analysis.
Author
(Year)		No. of Primary StudiesTotal Number of Patients
(STR + GTR)		Effect MeasureEffect Size
(95% CI)		p-Value for EffectI2 (%)p-Value for Heterogeneity
Almenawer et al. (2015) [1]11552
(314 + 238)		MD3.77
[2.255, 5.294]		<0.00019.60.020
Brown et al. (2016) [20]2520,769
(12,472 + 8297)		RR0.62
[0.56, 0.69]		<0.00167.0<0.001
AbdelFatah et al. (2022) [4]82249
(1002 + 1247)		OR0.61
[0.16, 2.32]		0.47099NR
Jusue-Torres et al. (2023) [21]41699
(911 + 788)		HR0.49
[0.36, 0.65]		NR0.00.460
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Jagtiani, P.; Karabacak, M.; Carrasquilla, A.; Yong, R.; Margetis, K. Impact of Extent of Resection on Overall Survival in Glioblastomas: An Umbrella Review of Meta-Analyses. Onco 2024, 4, 359-368. https://doi.org/10.3390/onco4040025

AMA Style

Jagtiani P, Karabacak M, Carrasquilla A, Yong R, Margetis K. Impact of Extent of Resection on Overall Survival in Glioblastomas: An Umbrella Review of Meta-Analyses. Onco. 2024; 4(4):359-368. https://doi.org/10.3390/onco4040025

Chicago/Turabian Style

Jagtiani, Pemla, Mert Karabacak, Alejandro Carrasquilla, Raymund Yong, and Konstantinos Margetis. 2024. "Impact of Extent of Resection on Overall Survival in Glioblastomas: An Umbrella Review of Meta-Analyses" Onco 4, no. 4: 359-368. https://doi.org/10.3390/onco4040025

APA Style

Jagtiani, P., Karabacak, M., Carrasquilla, A., Yong, R., & Margetis, K. (2024). Impact of Extent of Resection on Overall Survival in Glioblastomas: An Umbrella Review of Meta-Analyses. Onco, 4(4), 359-368. https://doi.org/10.3390/onco4040025

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