cancers

Article
Treatment Strategies for Glioblastoma in the Elderly: What
Should We Focus on Compared to Younger Patients
Hanah Hadice Gull 1,2,3,4, * , Antonia Carlotta Von Riegen 1 , Greta Theresa Beckmann 1 , Pikria Ketelauri 1,2 ,
Sebastian Walbrodt 1,2 , Alejandro N. Santos 1,2 , Christoph Oster 3,4,5 , Teresa Schmidt 3,4,5 , Martin Glas 2,3,4,5 ,
Ramazan Jabbarli 1,2 , Neriman Özkan 1,2 , Philipp Dammann 1,2 , Björn Scheffler 3,4,6,7,8 , Ulrich Sure 1,2
and Yahya Ahmadipour 1,2,3,4

1 Department of Neurosurgery and Spine Surgery, University Hospital Essen, University of Duisburg-Essen,
45147 Essen, Germany; [email protected] (A.C.V.R.); [email protected] (G.T.B.);
[email protected] (S.W.); [email protected] (A.N.S.);
[email protected] (P.D.)
2 Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University of Duisburg-Essen,
45147 Essen, Germany; [email protected]
3 DKFZ-Division Translational Neurooncology at the WTZ, DKTK Partner Site, University Hospital Essen,
45147 Essen, Germany; [email protected] (C.O.); [email protected] (T.S.)
4 West German Cancer Center (WTZ), University Hospital Essen, 45147 Essen, Germany
5 Department of Neurology, Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Division of
Clinical Neurooncology, University Medicine Essen, University of Duisburg-Essen, 45147 Essen, Germany
6 German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
7 German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
8 Center of Medical Biotechnology (ZMB), University of Duisburg-Essen, 45147 Essen, Germany
* Correspondence: [email protected]

Simple Summary: Although the incidence of glioblastoma (GB) in people over 65 years is more
than twice as high as in younger people, no standard of care for the treatment of the elderly with
GB has been established so far. With this study, we aimed to investigate the predictors affecting
Citation: Gull, H.H.; Von Riegen, outcomes in elderly GB patients with regard to their overall survival (OS) and progression-free
A.C.; Beckmann, G.T.; Ketelauri, P.; survival (PFS). MGMT promoter methylation, gross total resection (GTR), and hypofractionated
Walbrodt, S.; Santos, A.N.; Oster, C.; radiation were associated with a longer OS in elderly glioblastoma patients. These findings may
Schmidt, T.; Glas, M.; Jabbarli, R.; et al. induce the optimization of the treatment regimen for elderly patients that has not yet been established.
Treatment Strategies for Glioblastoma
in the Elderly: What Should We Focus Abstract: (1) Background: Although the incidence of glioblastoma (GB) has a peak in patients
on Compared to Younger Patients.
aged 75–84 years, no standard treatment regimen for elderly patients has been established so far.
Cancers 2024, 16, 1231. https://
The goal of this study was to analyze the outcome of GB patients ≥ 65 years to detect predictors
doi.org/10.3390/cancers16061231
with relevant impacts on overall survival (OS) and progression-free survival (PFS). (2) Methods:
Academic Editors: Ondrej Kalita and Medical records referred to our institution from 2006 to 2020 were analyzed. Adult GB patients with
Tomas Kazda clinical data, postoperative MRI data, and ≥1 follow-up investigation after surgical resection were
Received: 17 February 2024
included. The complete cohort was divided into a younger (<65) and an elderly group (≥65 years).
Revised: 8 March 2024 Multiple factors regarding OS and PFS were scanned using univariate and multivariable regression
Accepted: 18 March 2024 with p < 0.05. (3) Results: 1004 patients were included with 322 (61.0%) male individuals in the
Published: 21 March 2024 younger and 267 (56.1%) males in the older cohort. The most common tumor localization was frontal
in both groups. Gross total resection (GTR) was the most common surgical procedure in both
groups, followed by subtotal resection (STR) (145; 27.5%) in the younger group, and biopsy (156;
32.8%) in the elderly group. Multivariate analyses detected that in the younger cohort, MGMT
Copyright: © 2024 by the authors.
promoter methylation and GTR were predictors for a longer OS, while MGMT methylation, GTR,
Licensee MDPI, Basel, Switzerland.
and hypofractionated radiation were significantly associated with a longer OS in the elderly group.
This article is an open access article
distributed under the terms and
(4) Conclusions: Elderly patients benefit from surgical resection of GB when they show MGMT
conditions of the Creative Commons promoter methylation, undergo GTR, and receive hypofractionated radiation. Furthermore, MGMT
Attribution (CC BY) license (https:// methylation seems to be associated with a longer PFS in elderly patients. Further investigations
creativecommons.org/licenses/by/ are required to confirm these findings, especially within prospective radiation therapy studies and
4.0/). molecular examinations.

Cancers 2024, 16, 1231. https://doi.org/10.3390/cancers16061231 https://www.mdpi.com/journal/cancers

Cancers 2024, 16, 1231 2 of 12

Keywords: glioblastoma; elderly patients; progression-free survival; overall survival; elderly

glioblastoma patients

1. Introduction
Despite multimodal treatment including microsurgical tumor resection followed by
combined radio (RT)- and temozolomide (TMZ)-based chemotherapy, glioblastoma patients
develop disease progression. As a result, the median survival after standard-of-care treat-
ment is about ~18 months with survival after progression at 6–8 months [1]. Several predic-
tors regarding the prognosis of glioma, such as initial clinical condition, age of the patient,
extent of resection, molecular characteristics like mutation of the isocitrate-dehydrogenase
1 (IDH1) gene, and methylation of the O6-methylguanin-DNA-methyltransferase (MGMT)
promotor are already described [2–6], but their significance regarding different age groups
is not sufficiently investigated [2,7,8]. In particular, no clear indication exists for elderly
glioblastoma patients ≥ 65 years, as no standard of care for the treatment of the elderly with
glioblastoma (GB) has been established so far [9–11], although the incidence of GB in people
over 65 years is more than twice as high as in younger people [12], it has a peak in patients
aged from 75–84 years, and the population will be constantly increasing [13]. The key
treatment recommendations at diagnosis for adult patients with common diffuse gliomas
according to the EANO guidelines consist of temozolomide chemoradiotherapy (54–60 Gy
in 1.8–2 Gy fractions); for patients aged > 65–70 years and with MGMT unmethylated
tumors, radiotherapy (40 Gy in 2.67 Gy fractions); for patients aged > 65–70 years and with
MGMT methylated tumors, temozolomide chemoradiotherapy or temozolomide only [14].
Treatment recommendations for progression or recurrence for these patients are nitrosourea,
temozolomide rechallenge, bevacizumab, and radiotherapy (for patients not previously
treated with radiotherapy) [15–19]. However, elderly glioblastoma patients are less likely
to receive combined radiation and chemotherapy after surgical resection [20,21] resulting
in a worse prognosis [22]. In addition, Pretanvil et al. determined that the therapeutic
effect of elderly GB patients gradually deteriorates with age; however, surgical debulking
followed by radiation and chemotherapy leads to an improved OS [20]. Using a large
institutional cohort in the present study, we aimed to investigate the course of the disease
glioblastoma in elderly patients. Furthermore, using this large cohort, we aimed to detect
the predictors affecting outcomes in elderly GB patients. This may provide doctors with
comprehensive information achieving a better understanding and treatment of this disease
in the elderly population.

2. Materials and Methods

2.1. Data Collection and Clinical Management
This study was based on an institutional observational database and retrospectively
included newly diagnosed glioblastoma treated between January 2006 and December 2020
in our neurosurgical department. It was conducted according to the STROBE guidelines.
Histological evaluation according to the 2021 Classification of the Central Nervous
System Tumors of the World Health Organization (WHO) approved the diagnosis after
stereotactic biopsy or tumor resection [23]. IDH1/2 mutated GB were completely excluded
to conform to the recent WHO classification ensuring consistency in diagnosis and reduction
in patient selection bias [23]. After tumor resection, an early postoperative MRI within 72 h
was performed to evaluate the extent of resection, categorized as gross total resection by the
absence of an enhancing lesion on T1-weighted contrast-enhanced images and as debulking
in remaining instances. If the patient’s neurological and clinical status were appropriate
as measured by the Karnofsky performance status scale (KPS), standard chemoradiation
with simultaneous and adjuvant temozolomide was performed after surgery. Repeated
follow-ups with MRI, and if required with positron emission tomography (PET) imaging
at various time intervals, such as 2–3 months or earlier in the case of clinical deterioration
Cancers 2024, 16, 1231 3 of 12

were used to distinguish true progression from pseudoprogression. Demographic data (age
and sex), anthropometric parameters (body height, weight, and body mass index), clinical
characteristics (KPS at admission and discharge, medical history), tumor characteristics
(location, immunohistochemical and molecular genetic parameters [24], such as expression
of Ki-67 proliferation index, isocitrate dehydrogenase 1 gene (IDH) mutation [7], O6-
methylguanine DNA methyltransferase [10] promoter methylation status), and extent of
resection (EOR; gross total resection (GTR, >95% by volume) vs. subtotal resection (STR,
≤95%) vs. biopsy at initial consultation (stereotactic and open)), and outcome (progression-
free survival, overall survival or date of the last outpatient follow-up) were analyzed.
Pediatric patients (<18 years old), patients with an extracranial location, and incomplete
data sets were excluded. OS was defined as the period from first diagnosis to the date
of glioblastoma-related death. The appearance of tumor progression (PFS) was defined
according to the recent RANO (Response Assessment in Neuro-Oncology) criteria [25].

2.2. Cohort Division

We categorized the entire cohort into two groups as follows: patients with diagnosed
glioblastoma < 65 and ≥ 65 years old. Based on leading international studies like the Stupp
trial selecting cutoff values of 70 years [15] and 60 years [22], or the Nordic trial including
patients > 60 years [19], we have decided to choose the golden mean and take 65 years as
the cutoff [8,26,27]. According to the 2021 Classification of the Central Nervous System
Tumors of the WHO, we retrospectively excluded all patients with diffuse glioma and IDH
mutation [23].

2.3. Study Endpoints and Statistical Analysis

The effect of different parameters on OS and PFS were the study endpoints in both
groups, measured from the date of diagnosis to death from glioblastoma. The different
parameters could be divided into different sections, such as tumor data (localization, molec-
ular status), patient data (sex, age, Karnofsky Performance Index, Charlson Comorbidity
Index), surgical data (extent of resection), and postoperative data (radiation, relapse, overall
survival). For all statistical analyses, we used SPSS 26 (IBM Corporation, Armonk, New
York, NY, USA). Univariate analyses were performed to determine predictors of poor or
good outcomes at the first and last follow-ups. For dichotomized variables, the χ2 test was
used. Continuous variables were analyzed using the Student’s t-test (normally distributed
data) or the Mann–Whitney U test (non-normally distributed data). Kendall’s tau-b was
assessed for continuous and ordinal variables; Spearman’s rho was used for continuous
and dichotomous variables. Predictive factors regarding outcomes were assessed by the
calculation of odds ratios (ORs) and 95% confidence intervals (95% Cis) using logistic,
linear, or ordinal regression models. Significant parameters detected through univari-
ate analysis as well as parameters with p values < 0.1 were ultimately assessed using
multivariate analysis.

2.4. Ethics
This study was conducted in accordance with the Strengthening the Reporting of
Observational Studies in Epidemiology (STROBE) guidelines after approval by the In-
stitutional Review Board (Medical Faculty, University of Duisburg-Essen, Registration
Number: 15-6504-BO) and followed The Code of Ethics of the World Medical Association
(Declaration of Helsinki).

3. Results
3.1. Patient Demographics
A total of 1004 patients were included in this study. The mean age in the complete
cohort was 61.91 ± 13.38 years with a range from 19.3 to 88.1 years and with 415 (41.6%)
female and 589 (58.3%) male individuals. Furthermore, 476 of 1004 patients diagnosed
with glioblastoma from 2006 to 2020 were ≥65 years. The most frequent tumor localization
Cancers 2024, 16, 1231 4 of 12

was in the frontal lobe in both age groups. Concerning clinical presentation, a seizure
as the first symptom was observed in 185 (35.0%) cases in the younger group and in
121 (25.4%) cases in the elderly group. The extent of resection in patients older than 65
years was mainly gross total resection (GTR) in 229 (48.1%) patients, followed by biopsy
in 156 (32.8%) patients, and then debulking in 91 (19.1%) patients. In contrast, in the
younger group, debulking was the second most common extent of resection (145, 27.5%),
directly after GTR in 267 (50.6%) patients. Biopsy was conducted in 116 (22.0%) cases.
The mean KPS at admission in patients < 65 years was 83.34 ± 13.52, and 78.84 ± 14.9 in
patients ≥ 65 years. At discharge, the mean KPS was 78.7 ± 16.32 in the younger group,
and 70.54 ± 20.49 in the elderly group. Regarding postoperative therapy with radiation,
we determined that the mean total/cumulative dose was 58.3 ± 6.3 Gy in the younger
group, while the elderly group received a mean total dose of 51.6 ± 14.5 Gy. Moreover, we
investigated the Ki-67 proliferation index. Here, the mean Ki-67 proliferation index was
18.96 ± 14.16% in glioblastoma patients < 65 years old and 16.04 ± 10.70% in glioblastoma
patients ≥ 65 years old. Detailed baseline population information is shown in Table 1.

Table 1. Patient and surgical characteristics summarized.

Characteristics Complete Cohort <65 Years ≥65 Years

Period of time 2006–2020
Number of patients 1004 528 476
Age (years), mean ± SD 61.91 ± 13.38 53.42 ± 8.77 72.70 ± 5.34
Sex (n, %)
Male 589 (58.3%) 322 (61.0%) 267 (56.1%)
Female 415 (41.6%) 206 (39.0%) 209 (43.9%)
Tumor localization (n, %)
Frontal 192 (36.5%) 156 (32.8%)
Temporal 145 (27.6%) 128 (26.9%)
Parietal 81 (15.3%) 88 (18.5%)
Occipital 55 (10.5%) 56 (11.8%)
Midline/Infratentorial/Bi-hemispheric. 55 (10.5%) 48 (10.1%)
Clinical presentation (n, %)
Seizure 306 (30.5%) 185 (35.0%) 121 (25.4%)
Molecular status (n, %)
MGMT methylation 203 (38.4%) 215 (45.1%)
Missing 77 (14.6%) 81 (17.0%)
Ki-67 proliferation index 18.96 ± 14.16 16.04 ± 10.70
KPS at admission (%) 83.34 ± 13.52 78.84 ± 14.9
KPS at discharge (%) 78.7 ± 16.32 70.54 ± 20.49
EOR
Gross Total resection (GTR) 267 (50.6%) 229 (48.1%)
Subtotal Resection (STR) 145 (27.5%) 91 (19.12%)
Biopsy 116 (22.0%) 156 (32.8%)
Radiation Total Dose (mean, Gy) 58.3 ± 6.3 51.6 ± 14.5
Progression free survival (PFS, months) 8.0 7.0
Overall survival (OS, months) 15.73 ± 14.93 13.86 ± 15.73

Furthermore, we performed subgroup analyses concerning OS and PFS; In the younger

group, female patients had a longer OS than the male patients (16.77 ± 15.88 months vs.
14.73 ± 17.97) while female and male patients had approximately the same PFS length
(11.94 ± 11.38 and 12.90 ± 15.76 months). At the same time, in elderly GB patients, male
patients had a longer OS and PFS (10.87 ± 14.23 vs. 8.95 ± 13.13 and 10.51 ± 18.63 and
9.88 ± 13.24 months). In both groups, GTR led to the longest OS and PFS compared to SR
or biopsy. MGMT methylation was associated with a longer OS and PFS in both groups,
especially with a longer PFS in elderly GB patients. Extensive data are listed in Table 2.
Cancers 2024, 16, 1231 5 of 12

Table 2. Mean Overall Survival and Progression-Free Survival in subgroup analyses.

Overall Survival (Mean ± SD) Progression Free Survival (Mean ± SD)

Characteristics
<65 Years ≥65 Years <65 Years ≥65 Years
Sex
Male 14.73 ± 17.97 10.87 ± 14.23 12.90 ± 15.76 10.51 ± 18.63
Female 16.77 ± 15.88 8.95 ± 13.13 11.94 ± 11.38 9.88 ± 13.24
EOR
Gross Total resection 15.48 ± 17.12 13.44 ± 14.34 12.77 ± 14.89 12.24 ± 15.69
Subtotal Resection 11.31 ± 7.45 9.79 ± 14.08 11.5 ± 11.81 9.73 ± 12.91
Biopsy 7.51 ± 5.98 4.12 ± 4.57 12.01 ± 10.22 6.21 ± 7.83
Molecular status
MGMT methylation 19.10 ± 23.13 10.81 ± 14.68 14.07 ± 14.44 15.38 ± 21.71
unmethylated 12.63 ± 9.69 9.10 ± 12.68 11.14 ± 13.50 6.70 ± 3.60

3.2. Basic Differences between Glioblastoma Patients < 65 Years and ≥65 Years
Both groups presented no differences regarding sex (p = 0.125), tumor localization
(p = 0.445), GTR as the extent of resection (p = 0.445), and differences in comorbidities
(p = 0.116) (Table 3). The median CCI in the younger group was 2.77, while the median CCI
was 3.23 in the elderly group. Mann–Whitney U and Chi-square tests identified significant
differences in KPS at admission and at discharge between the groups (p < 0.001) (Table 3).
The younger group showed a better KPS at admission as well as at discharge (83.34 ± 13.52
vs. 78.84 ± 14.9 and 78.7 ± 16.32 vs. 70.54 ± 20.49). Furthermore, Mann–Whitney U
and Chi-square determined significant differences in radiation dose (p < 0.001), MGMT
methylation status (p = 0.001), in subtotal resection as the extent of resection (p = 0.002),
and in biopsy (p < 0.001), as well as in Ki-67 values (p = 0.005) (Table 3). The elderly group
was exposed to a lower total radiation dose, presented fewer cases of methylated MGMT
status, and underwent biopsy more often (n = 156 vs. n = 116) after gross total resection
(GTR), while the younger group experienced more frequent subtotal resection (n = 145 vs.
n = 91) after GTR and had higher Ki-67 values (18.96 ± 14.16 vs. 16.04 ± 10.70). Detailed
characteristics are summarized in Tables 1–3.

Table 3. Analyses between the two groups pointing out the main differences.

Differences in Different Age Groups

p
Mann-Whitney U Test
KPS at admission <0.001 *
KPS at discharge <0.001 *
Charlson Comorbidity Index 0.116
Radiation Dose <0.001 *
Ki-67 proliferation index 0.005 *
Progression Free Survival 0.252
Overall Survival 0.068
Chi-Square Test
Sex 0.125
Localization (Frontal vs. Temporal vs. Parietal vs. Occipital
vs. Midline/Infratentorial/Bi-hemispheric) 0.445
MGMT methylation 0.001 *
Extent of Resection
GTR 0.4
STR 0.002 *
Biopsy <0.001*
* and digits in bold illustrate significant p-value (≤0.05).

3.3. Basic Predictors Regarding Overall Survival and Progression-Free Survival

Univariate ordinal regression analysis revealed in both groups that MGMT methyla-
tion and GTR were statistically significant predictors for a longer OS, while biopsy was
Cancers 2024, 16, 1231 6 of 12

significantly associated with a shorter OS in both groups. Furthermore, in the elderly group,
a total radiation dose of 51.6 ± 14.5 Gy was correlated significantly with a longer OS. In
multivariate analysis, including significant parameters detected through univariate analy-
sis, MGMT methylation and GTR as the extent of resection were confirmed as significant
predictors for a longer OS in the younger group, while MGMT methylation, a specific,
abovementioned total radiation dose, and GTR were confirmed as significant predictors for
a longer OS in the elderly group. At the same time, multivariate analysis detected biopsy
as a predictor for a lower OS in the elderly group. Considering the total cohort, a higher
age was associated with a lower OS [OR: 0.68, 95% CI: 0.57–0.82, p = 0.01]. Regarding
progression-free survival, ordinal regression analysis could only detect MGMT methylation
as a significant predictor for a longer PFS in the elderly group. Detailed characteristics are
listed in Tables 4 and 5.

Table 4. Univariate analysis and multivariate ordinal regression regarding overall survival in glioblas-
toma patients < 65 years and ≥65 years.

<65 Years ≥65 Years

Parameter p-value OR 95% CI p-value OR 95% CI
Sex 0.625 0.89 0.55–1.44 0.243 0.14 0.01–3.73
Localization
Frontal lobe 0.674 0.9 0.55–1.47 0.732 1.84 0.06–9.95
Temporal lobe 0.146 1.45 0.88–2.38 0.678 2.24 0.05–10.83
Parietal lobe 0.574 0.82 0.42–1.62 0.873 0.72 0.01–37.47
Occipital lobe 0.225 0.65 0.32–1.31 0.899 0.72 0.00–12.44
M/I/Bi-hemispheric 0.707 1.16 0.53–2.54 0.439 0.12 0.00–17.34
Molecular status
MGMT methylation 0.002 10.29 0.76–22.17 0.03 15.68 1.41–42.38
Extent of resection
GTR 0.034 1.55 1.04–2.33 0.003 1.72 2.00–2.48
Biopsy 0.014 0.55 0.34–0.89 0.001 0.43 0.29–0.64
STR 0.951 0.99 0.63–1.55 0.186 1.37 0.86–2.20
Radiation Dose 0.176 1.21 0.91–1.56 0.008 1.02 1.01–1.04
Multivariate Analysis—Ordinal Regression
Parameter p-value aOR 5% CI p-value aOR 95% CI
MGMT methylation 0.001 7.17 6.52–45.93 0.001 1.87 1.28–2.71
Extent of resection
GTR 0.046 3.3 0.83–5.39 0.001 2.30 1.52–3.48
Biopsy 0.049 0.07 0.01–0.92 0.001 0.43 0.28–0.65
STR 0.344 0.79 0.49–1.28 0.114 1.98 1.15–3.42
Radiation Dose – – – 0.006 1.25 1.06–1.46
Complete cohort—Ordinal Regression
p-value OR 95% CI
Ki-67 index 0.155 0.21 0.12–1.31
Age 0.001 0.68 0.57–0.82
bold illustrates significant p-value (≤0.05).

Table 5. Univariate analysis regarding progression-free survival in glioblastoma patients < 65 years
and ≥65 years.

<65 Years ≥65 Years

Parameter p-value OR 95% CI p-value OR 95% CI
Sex 0.625 0.89 0.54–1.44 0.628 0.18 0.00–185.67
Cancers 2024, 16, 1231 7 of 12

Table 5. Cont.

<65 Years ≥65 Years

Localization
Frontal lobe 0.674 0.90 0.55–1.47 0.204 9.36 0.08–29.61
Temporal lobe 0.496 5.04 0.05–28.80 0.224 13.27 0.05–35.24
Parietal lobe 0.490 0.13 0.00–15.75 0.109 0.002 0.00–4.05
Occipital lobe 0.276 0.03 0.00–17.77 0.464 0.04 0.00–9.55
M/I/Bi-hemispheric 0.786 2.71 0.00–16.67 0.501 0.01 0.00–2.48
Molecular status
MGMT methylation 0.346 1.29 0.76–2.17 0.001 7.86 1.39–35.81
Extent of resection
GTR 0.534 4.21 0.05–28.60 0.456 2.58 0.01–6.76
Biopsy 0.546 0.08 0.002–2.62 0.536 0.02 0.00–4.54
STR 0.752 0.45 0.003–6.58 0.685 0.13 0.00–23.11
Radiation Dose 0.820 0.94 0.54–1.63 0.211 1.43 0.82–2.50
Complete cohort—Ordinal Regression
p-value OR 95% CI
Ki-67 index 0.136 0.77 0.75–5.33
Age 0.731 0.73 0.12–4.40
bold illustrates significant p-value (≤0.05).

4. Discussion
To date, the treatment and management options of elderly patients with glioblastoma
have not been thoroughly highlighted [9,21]. In particular, for older patients with glioblas-
toma, there is currently no consensus on the most appropriate surgery and subsequent
adjuvant therapy [21]. Furthermore, the available studies are restricted by small cohort
sizes [20]. As the aging population expands, the median age of glioblastoma, which is
64 years, is expected to further increase [28,29]. Therefore, we see the necessity of the exam-
ination of elderly GB patients intending to optimize treatment regimens for elderly patients
that have not yet been established [20]. Our study focused on the course of glioblastoma
in two different cohort groups, younger (<65 years) and elderly (≥65 years) patients, by
investigating a set of parameters for OS and PFS.

4.1. OS, PFS, MGMT Methylation, and Ki-67 Proliferation Index

Interestingly, significant differences were neither observed in OS nor in PFS in these
two different patient groups in our cohort. This could be explained by the high percentage
of elderly patients with MGMT promoter methylation in our cohort that is in accordance
with the findings of Connon et al. [28]. In our cohort, methylated MGMT status was
observed more frequently in the elderly group than in the younger patients with GB
(215 (45.1%) vs. 203 (38.4%), p = 0.001). Indeed, MGMT promoter methylation is associated
with a longer OS [19] and is a strong predictor of benefit with temozolomide chemotherapy
in elderly patients [4,5,17,19,30]. This may explain why OS and PFS are equally “good”.
Regarding PFS, our study could not determine significant predictors in the younger cohort.
Even MGMT promoter methylation was no significant parameter for a longer PFS. These
findings confirm the results of Wang et al. [31]. Considering the elderly group, a trend
toward better OS was seen when the lesion was located in the frontal and temporal lobe.
We could observe a slight trend toward a better PFS when GTR was conducted as the extent
of resection. However, these results did not show statistical significance (Tables 4 and 5).
Contrastingly, our study could also detect a significant predictor for a longer PFS in
the elderly group, namely MGMT promoter methylation. This could provide important
information about the necessity of further investigation into novel molecular biomarkers
in elderly glioblastoma patients [31]. With our study, we could confirm Pretanvil et al.’s
Cancers 2024, 16, 1231 8 of 12

findings, namely that in the elderly, the incidence of MGMT methylation is comparable to
that of the younger glioblastoma patients. However, Pretanvil et al. reported, that IDH-1
mutations are always absent in the elderly population, which may be one of the reasons
for the poorer outcome of elderly patients [20]. According to the 2021 Classification of the
Central Nervous System Tumors of the World Health Organization, all of the included
patients in our study presented with IDH-1 wild type. Therefore, in this cohort, we cannot
distinguish between the impact of IDH-1 mutation or wild type on different glioblastoma
age groups. Furthermore, in our study, the most frequent extent of resection in the younger
as well as in the elderly group was gross total resection, while in the cohort of Pretanvil
et al., elderly glioblastoma patients were more likely to undergo biopsy and less likely to
receive combined radiation and chemotherapy [20].
Wang et al. confirmed that elderly patients differ from younger patients in genome,
molecular subtypes, epigenetics, and prognostic-related molecular markers [31,32]. Inter-
estingly, in our study, MGMT promoter methylation was associated with a longer PFS not
in the younger group, but in the elderly group of glioblastoma patients.
Furthermore, Wang et al. found out that protein phosphatase 1D (PPM1D), which
is a potential prognostic biomarker and correlates with immune cell infiltration in hep-
atocellular carcinoma [33], was an effective prognostic marker for elderly patients [31]
and its silencing was associated with tumor sensitivity to treatment in gliomas [34], while
Khadka et al. examined that PPM1D is a good prognostic marker for diffuse midline
gliomas [35]. Moreover, Akamandisa et al. found out that PPM1D inhibitors can enhance
the anti-proliferative and pro-apoptotic effects of ionizing radiation in diffuse intrinsic
pontine glioma [36].
Apart from this, Wang et al. observed a correlation between Ki-67 and the age of
glioblastoma patients; elderly patients had higher Ki-67 indices compared to younger pa-
tients [31]. Furthermore, Liu et al. observed in univariate analysis that higher Ki-67 values
(median Ki-67 index > 25%) were associated with worse OS [37]. Interestingly, in our cohort,
the elderly glioblastoma patients revealed lower mean Ki-67 values [16.04 ± 10.70% vs.
18.96 ± 14.16%]. This may explain the average OS in the elderly group, which did not sig-
nificantly differ from the OS in the younger group [13.86 ± 15.73 vs. 15.73 ± 14.93 months,
p = 0.068]. Additionally, Dahlrot et al. investigated that median Ki-67 values increased with
increasing WHO grade; however, median Ki-67 values were not associated with survival in
glioblastoma [38]. We could confirm these findings in our study; concerning the complete
cohort, higher Ki-67 values were not significantly associated with worse OS [OR: 0.21; 95%
CI: 0.12–1.31; p = 0155]. Overall, Ki-67 proliferation indices seem to be valuable in some
settings, e.g., differential diagnostic settings; however, they should not be over-interpreted
in the clinical context [39].
Unfortunately, in this study, we did not investigate PPM1D values in particular with
correlation to age. However, we explored a correlation between MGMT promoter methy-
lation and a longer PFS in glioblastoma patients ≥ 65 years emphasizing the importance
of molecular and genetic characteristics. So, our study calls for further exploration of the
molecular characteristics of elderly patients with glioblastoma intending to determine clear
treatment regimes for this subgroup. PPM1D seems to be a valuable prognostic signature
molecule, especially in elderly GB patients. Focusing future research directions on the
PPM1D status of the tumor and its effect on response to radiation is recommended as part
of prospective studies [36].

4.2. Radiation in Elderly Glioblastoma Patients

With increasing age, the benefit of chemotherapy decreases, and the risk of cognitive
side effects of cranial irradiation increases [11]. So, the effect of radiotherapy on elderly
glioblastoma patients should be thoroughly reflected. In our cohort, the radiation total
dose in the elderly group differed significantly from the total radiation dose in the younger
cohort as it was lower in total (51.6 ± 14.5 Gy vs. 58.3 ± 6.3 Gy in the younger group,
p < 0.001 in Mann–Whitney U Test) and was a predictor for a longer OS. This confirms the
Cancers 2024, 16, 1231 9 of 12

EANO guidelines on the diagnosis and treatment of diffuse gliomas in adulthood [14]. Here,
Weller et al. verified that hypofractionated radiotherapy with a higher dose per fraction
and a lower total dose is suitable for elderly (>65 to 70 years) glioblastoma patients [14,40].
Furthermore, Perry et al. advised that additional temozolomide to hypofractionated ra-
diotherapy improved OS in patients older than ≥60 years [16]. In our cohort, we did
not implement subgroup analysis regarding additional temozolomide during the obser-
vation period of our study, as the therapeutical scheme for chemotherapy especially in
elderly patients with glioblastoma was constantly changing according to the recent WHO
classification [23]. So, we excluded this subgroup analysis to avoid inconsistency and
bias in the evaluation. However, hypofractionated radiation seemed to be a predictor of
longer OS [41].
In addition, Weller et al. investigated that radiation fractionation depends on tumor
size and that larger lesions require smaller single fraction sizes to improve safety and
tolerability [14]. Indeed, examinations of tumor size and outcome would be interesting,
and more particularly the tumor size and the applied radiation in different age groups
of patients with glioblastoma. Measurements of the size of the lesions in our cohorts are
missing, but would certainly be relevant for the detection of differences between younger
and older glioblastoma patients and the potential implications associated with them [42,43].

4.3. Extent of Resection

In both groups, GTR seems to be the matter of choice for a longer OS. Following the
literature, our large study approved this method as a standard for the extent of resection as
far as surgically and clinically possible [8]. Here, we emphasize the preoperative mean value
of the KPI that was >70% even in both groups. Indeed, this KPI is associated with a good
prognosis in general [3] and especially in combination with GTR [3,14,44]. Interestingly,
despite the older age, the elderly group in our cohort proved to be fit overall as their
median CCI was 3.23 and their preoperative KPI was 78.84 ± 14.9%. Moreover, regression
analysis revealed no significant differences in KPI and CCI between the elderly and the
younger group in our cohort. This may explain why GTR was the most common extent
of resection in both groups as GTR is favored when the KPI is ≥70 [15,22]. These results
underline the fact that the safest surgical approach was investigated interdisciplinarily to
avoid postoperative physical damage. So, when KPI is ≥70, it seems that GTR should be
favored regardless of increased age [22].

4.4. Limitations
The retrospective study design could be associated with inherent bias and bears the
risk of incomplete data and selection biases. Moreover, further parameters could have
been investigated. For instance, the interesting aspects not considered in this study were
radiological features of the tumor lesion, such as detailed information about tumor size,
the necrosis area, concomitant edema, or subventricular zone involvement in the different
cohorts [45].
In addition, broad data about molecular and genetic characteristics or extensive data
on postoperative systemic therapy in different age groups were potential parameters that
could have been investigated further.
Furthermore, based on international leading studies, we set 65 years as the cutoff
value to divide the cohort into a younger and older age group. However, it is questionable
whether this threshold will remain representative in an aging society [28]. The study spans
from 2006 to 2020, and treatment practices for glioblastoma may have progressed during
this period. Changes in diagnostic techniques, surgical approaches, or adjuvant therapies
could impact the relevance of historical data to current clinical practice, which has to
be considered.
Although our study determined a large cohort, it only represented the results of a
single center. Prospective multicenter studies are recommended to confirm our findings
and to assess further predictors of the outcome of elderly glioblastoma patients.
Cancers 2024, 16, 1231 10 of 12

5. Conclusions
Elderly patients with glioblastoma (≥65 years) benefit from GTR, methylated MGMT
promoter status, and hypofractionated radiation. Molecular pathways should be targeted
for affecting PFS in the future. This study encourages investigations on elderly glioblastoma
patients with a special emphasis on molecular characteristics such as PPM1D values of the
tumor and lesion size, as well as postoperative treatment. As the incidence of glioblastoma
has a peak in patients aged 75–84 years while the population is getting older, we must
urgently focus on elderly patients with glioblastoma to identify clear treatment modalities
for this subgroup.

Author Contributions: Conceptualization: Y.A., H.H.G. and R.J.; methodology: Y.A., H.H.G.,
A.C.V.R., G.T.B. and P.K.; software: S.W. and H.H.G.; validation: A.N.S. and Y.A.; formal analy-
sis: Y.A., U.S., B.S., M.G. and P.D.; investigation: H.H.G., A.C.V.R. and G.T.B.; resources: Y.A. and
N.Ö.; data curation: H.H.G., A.C.V.R., G.T.B., C.O. and T.S.; writing—original draft preparation:
H.H.G.; writing—review and editing: Y.A., N.Ö., P.D., R.J., S.W., U.S. and A.N.S.; visualization:
H.H.G., Y.A. and C.O.; supervision: Y.A. and U.S.; project administration: Y.A. and U.S. All authors
have read and agreed to the published version of the manuscript.
Funding: We acknowledge support by the Open Access Publication Fund of the University of
Duisburg-Essen.
Institutional Review Board Statement: The study was conducted in accordance with the Declaration
of Helsinki, and approved by the Institutional Review Board Medical Faculty, University of Duisburg-
Essen (Registration Number: 15-6504-BO, approved on 10 February 2020).
Informed Consent Statement: Patient consent was waived due to anonymized data evaluation and
the identity of each patient was fully protected.
Data Availability Statement: Data are contained within the article.
Conflicts of Interest: The authors declare no conflicts of interest.

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