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SUPRATOTAL RESECTION - AN EMERGING CONCEPT OF GLIOMABLASTOMA
MULTIFORME SURGERY - SYSTEMATIC REVIEW AND META-ANALYSIS
Peer Asad Aziz, Salma Farrukh Memon, Mubarak Hussain, A. Rauf Memon, Kiran
Abbas, Shurjeel Uddin Qazi, Riaz A.R. Memon, Kanwal Ali Qambrani, Osama Taj,
Shamas Ghazanfar, Aayat Ellahi, Moiz Ahmed
PII:
S1878-8750(23)00950-6
DOI:
https://doi.org/10.1016/j.wneu.2023.07.020
Reference:
WNEU 20830
To appear in:
World Neurosurgery
Received Date: 21 March 2023
Revised Date:
4 July 2023
Accepted Date: 5 July 2023
Please cite this article as: Aziz PA, Memon SF, Hussain M, Memon AR, Abbas K, Qazi SU, Memon
RAR, Qambrani KA, Taj O, Ghazanfar S, Ellahi A, Ahmed M, SUPRATOTAL RESECTION - AN
EMERGING CONCEPT OF GLIOMABLASTOMA MULTIFORME SURGERY - SYSTEMATIC REVIEW
AND META-ANALYSIS, World Neurosurgery (2023), doi: https://doi.org/10.1016/j.wneu.2023.07.020.
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Title Page
Title:
SUPRATOTAL RESECTION - AN EMERGING CONCEPT OF GLIOMABLASTOMA MULTIFORME SURGERY SYSTEMATIC REVIEW AND META-ANALYSIS
Peer Asad Aziza,*, Salma Farrukh Memon a, Mubarak Hussain a, A. Rauf Memona , Kiran Abbasb,
Shurjeel Uddin Qazic, Riaz A. R. Memona, Kanwal Ali Qambrania, Osama Tajd, Shamas
Ghazanfarc, Aayat Ellahie, Moiz Ahmedf
ro
of
Affiliations
a
re
Aga Khan University, Karachi, Pakistan
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b
-p
Liaquat University of Medical Health Sciences, Jamshoro, Pakistan
c
e
Creek General Hospital, Karachi, Pakistan
ur
d
na
Dow University of Health Sciences, Karachi, Pakistan
f
Jo
Jinnah Sindh Medical University, Karachi, Pakistan
National Institute of Cardiovascular Diseases
Corresponding author*
Tel.: +92-3332760161
E-mail: azizpirasad@gmail.com
Aziz
Title Page
SUPRATOTAL RESECTION - AN EMERGING CONCEPT OF
GLIOMABLASTOMA MULTIFORME SURGERY - SYSTEMATIC REVIEW AND
META-ANALYSIS
oo
f
Peer Asad Aziza,*, Salma Farrukh Memon a, Mubarak Hussain a, A. Rauf Memona , Kiran
Abbasb, Shurjeel Uddin Qazic, Riaz A. R. Memona, Kanwal Ali Qambrania, Osama Tajd,
lP
re
-p
r
Shamas Ghazanfarc, Aayat Ellahie, Moiz Ahmedf
a
ur
na
Liaquat University of Medical Health Sciences, Jamshoro, Pakistan
b
Aga Khan University, Karachi, Pakistan
c
Jo
Dow University of Health Sciences, Karachi, Pakistan
d
Creek General Hospital, Karachi, Pakistan
e
Jinnah Sindh Medical University, Karachi, Pakistan
f
National Institute of Cardiovascular Diseases
Corresponding author*
Peer Asad Aziz
Tel.: +92-3332760161
E-mail: azizpirasad@gmail.com
1
Aziz
SUPRATOTAL RESECTION - AN EMERGING CONCEPT OF
GLIOMABLASTOMA MULTIFORME SURGERY - SYSTEMATIC REVIEW AND
META-ANALYSIS
Abstract
The severe neurological tumor known as glioblastoma (GBM), also referred to as a
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grade IV astrocytoma, is rapidly progressive and debilitating. Supratotal resection (SpTR) is
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an emerging concept within glioma surgery, which aims to achieve a more extensive
resection of the tumor than is possible with conventional techniques. We performed a
language-independent search of PubMed, Scopus, and Cochrane CENTRAL to identify all
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available literature up to August 2022 of patients undergoing SpTR assessing survival
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outcomes in comparison to other surgical modalities. After screening for exclusion, a total of
13 studies, all retrospective in design, were identified and included in our meta-analysis.
SpTR was associated with significantly increased overall survival (HR=0.77, [0.71-0.84];
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p<0.01, I2=96%) and progression-free survival (HR=0.2, [0.07-0.56]; p=0.002, I2=88%).
Keywords: Glioblastoma; Supratotal resection; Supramarginal resection; Astrocytoma;
Supra complete
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1. Introduction
Glioblastoma Multiforme (GBM) is the most common malignant primary brain
tumor, accounting for approximately 15% of all brain tumors.1 The severe neurological
tumor, also referred to as a grade IV astrocytoma, is rapidly progressive and generally fatal.
Brain GBMs can form on their own or grow from lower grade astrocytoma. Although it
colonizes the nearby brain tissue, it generally does not metastasize to other organs. 2 The
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main form of treatment for this type of glioma is surgical resection or excision, which is
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subsequently complemented by adjuvant radiation and chemotherapy.2
Supratotal resection (SpTR) is an emerging concept within GBM surgery, which aims to
achieve a more extensive resection of the tumor than is possible with conventional
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techniques.3 This technique involves the removal of more than 100% of the visible tumor
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tissue, which means that the surgeon removes not only the tumor itself but also some
surrounding healthy brain tissue.3-4
True SpTR is defined as excision past all discernible and visible magnetic resonance
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imaging (MRI) abnormalities, including fluid attenuated inversion recovery (FLAIR) borders.
This may be accomplished with 5-ALA-guided tumor tissue elimination, using intraoperative
MRI for non-enhancing residual tumors, or resection until improvement in clinical outcome
is achieved.5 SpTR is therefore more extensive than gross total resection (GTR), which
involves removal of the visible tumor only. 6,7 This raises the probability of progression-free
recession and, eventually, survival while lowering the likelihood of recurrence. The
procedure has been shown to be safe and effective in multiple studies, and its use is
increasing in clinical practice. 6,7
In a meta-analysis of glioblastoma patients, Brown et al. found a correlation between
the size of the resection and survival. Patients who had more tissue removed after surgery did
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better than those who had less extensive resections, according to a study of 37 studies. These
findings suggest that maximal safe surgical resection should be considered in the treatment of
glioblastoma.8
However, SpTR is not without its challenges.9 The procedure requires a high degree
of technical expertise and specialized equipment, which may not be available at all medical
centers. Additionally, the procedure carries a higher risk of surgical complications such as
neurological deficits, which can have a significant impact on patient outcomes.9 Several
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studies suggest that the potential benefits of SpTR could be insignificant and that other
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factors, such as the patient's age, general health, and the location and size of the tumor might
be more important survival predictors. 9,10
The decision to perform SpTR should generally be based on a thorough evaluation of
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the patient's particular circumstances, including the risks and advantages of the treatment, as
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well as the patient's overall wellbeing and expectations. This decision should be made in
consultation with a team of medical professionals, including neurosurgeons, oncologists, and
other specialists, who can provide the best possible care for the patient.9,10
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This meta-analysis performed to determine the patient survival rates and the progression-free
survival rates of glioblastoma patients who underwent SpTR.
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2. Methods
Protocol and registration:
We adhered to the established standards of the Preferred Reporting Items for Systematic
Reviews and Meta-analyses (PRISMA) to correctly report this systematic review and metaanalysis.11 The protocol has been tentatively registered and published in PROSPERO.
(www.crd.york.ac.uk/PROSPERO,CRD 42022366204)
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Search Strategy:
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Six databases, including PubMed, EMBASE, The Cochrane Library, Web of Science,
Scopus, and ClinicalTrials.gov, were thoroughly searched for relevant literature from their
inception through August 20, 2022. The following search string was utilized to obtain
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pertinent articles: (supra total resection OR glioma resection OR supra marginal OR supra
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complete) AND (glioma OR glioblastoma OR GBM OR glioblastoma multiforme OR
astrocytoma OR ependymoma OR oligodendroma) AND (resections OR margin resections
OR tumor-free margins OR FLAIR region). Furthermore, the reference lists of the retrieved
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trials, meta-analyses, research papers, and review articles were manually browsed to identify
any published literature on this topic.
Study Selection:
All the studies included in this meta-analysis satisfied the following eligibility criteria: (a)
published case-control or prospective/retrospective cohort studies; (b) patients which were
diagnosed with glioblastoma multiforme; (c) glioblastoma patients who underwent SpTR;
(d) supra-total resection being compared with other surgery options such as subtotal, partial
and gross total resection.
SpTR was defined as complete resection of contrast enhanced region of the tumor with
additional resection of different percentages of FLAIR region.
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Data Extraction and Quality assessment:
The output of the systematic search was exported to the EndNote Reference Library
program and any duplicate entries were eliminated. Two independent reviewers (SUQ and
MA) thoroughly assessed all the articles and only the trials that satisfied the predetermined
criteria were included. A third investigator (KA) rectified any discrepancies. The initial
author's name, the year of publication, the study's location, its design, its sampling
procedures, the number of patients who got SpTR, and the number of patients handled with
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other surgical techniques were all extracted from the trials. The overall survival of SpTR was
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the main endpoint of interest. The secondary outcomes of interest were surgical risk of
complications and focal impairments. Two separate researchers evaluated the caliber of the
qualifying studies using an observational variation of the Newcastle-Ottawa Scale. Any
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Statistical Analysis:
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disputes were resolved via dialogue and effective communication.
Review Manager (version 5.3; Copenhagen: The Nordic Cochrane Centre, The Cochrane
Collaboration, 2014) was employed to conduct the statistical evaluation. A general inverse
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variance function was used to aggregate the overall survival hazard ratios and the 95%
confidence intervals, which was then assessed using a random effects model. For continuous
outcomes, mean differences along with their standard deviations were meta-analyzed using
the random effects model. We analyzed statistical heterogeneity using Cochrane Q and I2
statistics.12 The Egger asymmetry test and a visual inspection of the funnel plot were used to
assess the publication bias. A p-value of <0.05 was regarded as significant in all cases.
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3. Results:
Literature review:
The process for choosing and searching for studies is outlined in the PRISMA chart
(Figure 1). 12,141 results were produced by the initial search. A total of 92 articles were
selected for screening and approved. Thirty papers were excluded because they did not
include patients with SpTR, as well as forty studies where the variable of interest was not
Study characteristics:
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total of 13 papers in our meta-analysis.12-24
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mentioned. Fifteen articles written in other languages were not included. We considered a
All of the studies were retrospective in design. A total of 20,726 patients were
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included in the analysis with a male dominant patient population (n=11,820, 57%). The mean
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age in our population ranged from 38 to 63 years. 212 individuals underwent SpTR, 473
underwent GTR, 300 underwent subtotal resection, and 165 underwent partial resection. The
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baseline characteristics of the included studies and their individuals are compiled in Table 1.
Overall survival with SpTR:
All studies reported overall survival with SpTR. SpTR was associated with a
significant increase in overall survival (HR=0.78, [0.72-0.85]; p<0.01, I2=96%). A high
heterogeneity was observed as shown in Figure 2.
Progression free survival with Supra-total Resection:
Four studies reported progression free survival. SpTR was associated with a
significantly increased progression free survival (HR=0.2, [0.07-0.56]; p=0.002, I2=88%) as
7
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shown in Figure 3. In addition, we observed that duration of progression free survival was
significantly increased with SpTR as compared to other surgical subtypes. (Figure 4)
Assessment of heterogeneity:
The assessment of study quality revealed that the included studies had scores in the
medium range and a high risk of bias. (Supplementary Table). Among them, three studies
did not select patients that were true representatives of the cohort.15,22,24 All studies matched
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the experimental and control groups based on baseline demographics and the presence of
glioblastoma; however only four studies reported the IDH1 mutation status of GBM. Four
Publication Bias:
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studies used record linkage to determine outcomes.15,16,22,24
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Publication bias was assessed by visual inspection of funnel plots. We observed a
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high asymmetry in the outcome progression free survival (Supplementary Figure 1).
Moderate level asymmetry was observed with overall survival benefit of SpTR
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(Supplementary Figure 2).
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4. Discussion
Our meta-analysis revealed that SpTR was associated with a significant improvement
in overall survival when compared to other surgical techniques. Other resection subtypes
were associated with a significantly decreased progression free survival as compared to
SpTR.
Four studies have reported varying findings on the effectiveness of SpTR in
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glioblastoma, with some suggesting that the procedure can lead to improved survival rates
and others suggesting that the benefits may be limited. It's important to note that the decision
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to pursue SpTR should be made on an individual basis, considering a range of patient- and
tumor-specific factors, and being overseen by a group of medical experts with expertise in the
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field.26-29
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SpTR in glioblastoma was the subject of a thorough literature review in the 2019
Neuro-oncology paper by de Leeuw and Vogelbaum. The authors set out to summarize the
benefits and drawbacks of doing glioma surgery with less than a complete removal of the
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projected tumor volume.30 The authors determined that 11 trials, totaling 548 patients,
satisfied their inclusion requirements. The studies were all retrospective and included both
high- and low-grade gliomas. The majority of studies relied on intraoperative imaging
methods like MRI to gauge the extent of resection.
The main finding of the review was that SpTR of gliomas is related with improved
overall survival and progression-free survival when compared to subtotal resection. Similar
results were also seen when SpTR was compared to subtotal resection. The main difference
between the two types of resections is that the subtotal resection removes all the tumors,
while the partial resection removes only the major tumors. Although the extent of resection
varied between studies, some reported a maximum extent of resection of 110% and others
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reported up to 160% of the predicted tumor volume being removed. The researchers also
discovered that SpTR was associated with a higher likelihood of neurological impairments
and postoperative problems, such wound infections.30
We found that different aspects of the disease were studied in affiliated literature on
the subject, and provided distinct insights on how to potentially navigate therapeutic
intervention. The effects of supramarginal resection on survival outcomes following gross-
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total resection of IDH-wild-type glioblastoma, for instance, were investigated in the study by
Vivas-Buitrago et al.12. The study looked at 219 people who underwent surgery for IDH-
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wild-type glioblastoma, and it found a correlation between supramarginal resection and
longer overall survival and progression-free survival. The investigators' conclusion is that
supramarginal resection may improve survival outcomes for individuals with IDH-wild-type
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glioblastoma. On the other hand, the study by Anselmo et al.31 aimed to clinically
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characterize glioblastoma patients living longer than 2 years. The study analyzed the medical
records of 68 patients from two Italian institutions who survived for more than 2 years after
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the initial diagnosis of glioblastoma. The authors found that patients who survived for longer
than 2 years were more likely to be younger, have a lower Karnofsky Performance Status,
and receive a combination of temozolomide and radiotherapy as the initial treatment.
Additionally, patients who underwent a second surgery for disease progression had a longer
survival than those who did not.
While both studies provide insights into glioblastoma survival outcomes, they focus
on different aspects of the disease. Vivas-Buitrago et al. emphasize the importance of surgical
technique and suggest that supramarginal resection could improve survival outcomes in IDHwild-type glioblastoma patients. 12 Anselmo et al. characterize the clinical features of
glioblastoma patients who survived for more than 2 years and highlight the potential benefits
of a combined treatment approach and re-surgery for disease progression. 31
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The thorough study by Motomura et al. (2021)13 used awake brain imaging to analyze
the impact of resection size on survival in patients with grade II and grade III gliomas. The
study included 57 patients who underwent SpTR, which was defined as resection of more
than 100% of the estimated tumor volume. The extent of resection was found to be a
significant predictor of overall survival by the researchers, with patients receiving SpTR
living longer overall than those getting partial resection.. In addition, the study found that
awake brain mapping was safe and effective for identifying functional areas and achieving
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SpTR. The researchers postulated that SpTR using awake brain mapping may be an
grade III gliomas.13
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advantageous surgical technique for improving the prognosis for survival with grade II and
The surgical approach and its impact on survival outcomes for patients with different
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types of gliomas are described in the studies by Moiraghi et al.14 and Rossi et al.15 The
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possibility, effectiveness, and effect on overall survival of awake resection in patients with
recently diagnosed supratentorial IDH-wildtype glioblastomas were examined by Moiraghi et
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al. in 2021. The study found that awake surgery was feasible and safe, with a low rate of
complications, and suggested that it could be a valid option for selected patients.
In contrast, the Rossi et al (2021) study investigated the relationship between SpTR
and survival from lower-grade gliomas, survival without progression, malignant
transformation, and overall survival.15 SpTR was connected to better overall survival rates,
including PFS and OS, after surgery for 341 individuals with low-grade gliomas, but it had
no impact on how quickly tumors developed into malignancies.
Overall, both studies highlight the importance of surgical technique in improving
survival outcomes in patients with gliomas. However, they focus on different types of
gliomas and different surgical approaches. Lower-grade glioma patients who get SpTR may
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have a better chance of surviving. Nevertheless, as demonstrated by Moiraghi et al., awake
surgery may be a possibility for some patients with IDH-wildtype glioblastomas.14 .
Using selective cortical mapping and the subpial technique, Esquenazi et al. (2017)
assessed the effect of supratotal resection on the survival of glioblastoma patients.19 The
scientists conducted a retrospective study of 103 patients who underwent surgery for
glioblastoma and found that those who underwent supratotal resection had a significantly
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longer median overall survival time than those who underwent less severe resection. The
experts found that patients who received supratotal resection had a lower risk of tumor
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recurrence than those who got less extensive resection. According to the study's findings,
glioblastoma patients may have a selective advantage when undergoing supratotal resection
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using the subpial technique and selective cortical mapping.
The results and findings of our study should be interpreted with caution due to its
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limitations.. The included studies in our meta-analysis were underpowered which could have
introduced biases in the results. A particular location of GBM was not resected and compared
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across studies which could have impacted the survival of patients. There was under
representation of females in the cohorts which may have led to gender disparity in the results.
In addition, the studies did not compare the outcomes of SpTR with each individual surgery
subtype due to which it may have overestimated or underestimated the results.
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5. Conclusion
In conclusion, we found that SpTR is associated with greater overall and progressionfree survival when compared to other glioblastoma surgeries like GTR or SubTR. The present
study suggests that SpTR can be a useful strategy for improving outcomes in glioma surgery,
but it should be balanced against the potential risks and individual patient factors. Further
research is required to determine the benefits and downsides of this treatment and to specify
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the ideal level of resection for the different subtypes of glioma. The present study
underscores the complex and multifaceted nature of glioblastoma and the need for a
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personalized and multidisciplinary approach to treatment.
13
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Figure 1: Prisma chart summarizing the literature search.
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Figure 2: Overall survival with SpTR
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Figure 3: Progression free survival with SpTR
Figure 4: Duration of progression free survival with SpTR
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Table 1: Baseline characteristics of included studies
Age
No.
Study
mean
Population
Tumor Location
IDH 1 status
Surgery type
52
73
Buitrago
68
(67%)
34
(33%)
± 17
(9.5%)
13
(10.3%)
14
(13.9%)
47
26
(46.5%)
(25.7%)
(45.5%)
59
71
et al.
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59.8
1 (0.8%)
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(58.7%) (41.3%) (57.9%)
Vivas2
12
42.8
et al.
Wild
Parietal Occipital Temporal Insular/deep
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74
Frontal
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Motomura
1
Females
27 (21.4%)
Mutation Supratotal
GTR
Partial
Subtotal
15
(11.9%)
32
(25.4%)
52
(41.3%)
27
(21.4%)
Type
21
(16.7%)
105
(83.3%)
37
367
127
166
96
15
(9.2%)
(90.8%)
(31.4%)
(41.1%)
(23.7%)
(3.7%)
150
98
(33.1%)
(21.6%)
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Males
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± SD
46
51 (50.5%)
38.9
Rossi et
3
195
124
188
±
al.
86 (21.3%)
(61.1%)
(38.9%)
(46.5%)
(14.6%)
251
202
170
89
(17.6%)
11.8
Moiraghi
4
et al.
63 ±
12.6
17 (3.8%)
(55.4%)
(44.6%)
(37.5%)
(19.7%)
137
(30.2%)
21 (4.6%)
16 (3.5%)
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8
9
10
11
Li et al.
149
96
(39%)
758
471
(62%)
(38%)
60
45
16
(57.1%)
(42.9%)
25
7
Glen et al
54.9
±
14.6
De Bonis
et al.
57.5
±
14.7
84
161
(34%)
(66%)
9
16
(28.1%)
(50%)
f
(61%)
53 ±
56 ±
15
(22.5%)
11 (5%)
Eyupogolu
et al.
Esquenaizi
et al.
(77.5%)
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7
55.7
±
18.8
(61.9%)
18
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et al.
(43.4%)
62
re
6
59.9±
13.48
(56.6%)
33 (29.2%)
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Mampre
48 ±
16
70
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Rho et al.
49
21
3 (9.4%)
7 (21.9%)
(78.1%)
(21.9%)
(65.6%)
57
29
28
(66%)
(34%)
(33%)
47
41
36
52
(53.4%)
(46.6%)
(40.9%)
(59.1%)
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5
64
19
36 (42%)
3 (3%)
(22%)
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16 (27
4 (24%)
12 (55%)
4 (51%)
%)
9581
7782
2907
2451
4879
(55.8%)
(44.2%)
(16.5%)
(13.9%)
(27.6%)
-p
r
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(73%)
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73 ±
2.5
43
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Rivera et al
48.57
±
15.3
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Hamada et
al
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12
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Supplemental Table: Quality Assessment of included studies using Newcastle Ottawa
Scale
Selection
Comparability
C
S1
S2
S3
O2
O3
*
*
7
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f
Study/Score
Outcome
S4
O1
Total
*
*
5
*
*
6
*
*
5
*
*
7
*
*
5
VivasBuitrago et
*
*
*
*
*
*
*
al, 2020
De Bonis et
Esquenazi et
*
*
*
*
*
*
*
Jo
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Eyupogolu
et al, 2016
*
lP
*
al, 2017
*
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r
*
al, 2013
*
*
Glen et al,
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
6
*
*
*
*
*
*
*
7
2018
Hamada et
al, 2013
*
*
Rho et al,
2019
Li et al, 2016
1
Aziz
Mampre et
*
*
*
*
*
*
*
7
*
*
*
*
*
*
*
7
*
*
*
*
*
*
*
5
*
*
*
*
*
*
*
5
al, 2018
Motomura et
al, 2021
Rivera et al,
2021
Rossi et al,
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2021
2
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Supplementary Figure 3: Funnel plot for progression free survival with SpTR
Supplementary Figure 3: Funnel plot for overall survival with SpTR
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4
Abbreviations List
Definition
Supra Total Resection
Sub Total Resection
Gross Total Resection
Glioblastoma
Fluid-attenuated inversion recovery
Magnetic Resonance Imaging
Isocitrate Dehydrogenase
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Abbreviation
SupTR
SubTR
GTR
GBM
FLAIR
MRI
IDH
We have no conflicts of interest to disclose.
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All authors declare that they have no conflicts of interest.
Credit Author Statement
Peer Asad Aziz: Conceptualization, Supervision, Study design, Methods. Salma Farrukh
Memon: Conceptualization, Supervision, Study design, Methodology. Mubarak Hussain:
Critical appraisal. A. Rauf Memon: Critical appraisal. Kiran Abbas Resources, Data Curation,
Project administration. Shurjeel Uddin Qazi: Writing – Original draft Preparation, Data
of
curation. Riaz A. R. Memon: Writing – Original draft Preparation, Data curation. Kanwal Ali
ro
Qambrani: Writing – Original draft Preparation, Data curation. Osama Taj: Writing – Original
-p
draft Preparation, Data curation. Shamas Ghazanfar: Writing- Reviewing and Editing, Formal
re
analysis, Resources, Investigation. Ayat Ellahi: Formal analysis, Resources, Investigation. Moiz
Jo
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lP
Ahmed: Writing- Reviewing and Editing, Visualization.