Journal of Neuro-Oncology (2022) 159:95–101

https://doi.org/10.1007/s11060-022-04046-z

CLINICAL STUDY

Prognostic impact of obesity in newly‑diagnosed glioblastoma:

a secondary analysis of CeTeG/NOA‑09 and GLARIUS
Johannes Weller1   · Niklas Schäfer1 · Christina Schaub1 · Anna‑Laura Potthoff2 · Joachim P. Steinbach3 ·
Uwe Schlegel4 · Michael Sabel5 · Peter Hau6 · Clemens Seidel7 · Dietmar Krex8 · Roland Goldbrunner9 ·
Torsten Pietsch10 · Theophilos Tzaridis1 · Thomas Zeyen1 · Valeri Borger2 · Erdem Güresir2 · Hartmut Vatter2 ·
Ulrich Herrlinger1 · Matthias Schneider2

Received: 1 February 2022 / Accepted: 23 May 2022 / Published online: 15 June 2022
© The Author(s) 2022

Abstract
Purpose  The role of obesity in glioblastoma remains unclear, as previous analyses have reported contradicting results. Here,
we evaluate the prognostic impact of obesity in two trial populations; CeTeG/NOA-09 (n = 129) for MGMT methylated glio-
blastoma patients comparing temozolomide (TMZ) to lomustine/TMZ, and GLARIUS (n = 170) for MGMT unmethylated
glioblastoma patients comparing TMZ to bevacizumab/irinotecan, both in addition to surgery and radiotherapy.
Methods  The impact of obesity (BMI ≥ 30 kg/m2) on overall survival (OS) and progression-free survival (PFS) was inves-
tigated with Kaplan–Meier analysis and log-rank tests. A multivariable Cox regression analysis was performed including
known prognostic factors as covariables.
Results  Overall, 22.6% of patients (67 of 297) were obese. Obesity was associated with shorter survival in patients with
MGMT methylated glioblastoma (median OS 22.9 (95% CI 17.7–30.8) vs. 43.2 (32.5–54.4) months for obese and non-
obese patients respectively, p = 0.001), but not in MGMT unmethylated glioblastoma (median OS 17.1 (15.8–18.9) vs 17.6
(14.7–20.8) months, p = 0.26). The prognostic impact of obesity in MGMT methylated glioblastoma was confirmed in a
multivariable Cox regression (adjusted odds ratio: 2.57 (95% CI 1.53–4.31), p < 0.001) adjusted for age, sex, extent of resec-
tion, baseline steroids, Karnofsky performance score, and treatment arm.
Conclusion  Obesity was associated with shorter survival in MGMT methylated, but not in MGMT unmethylated glioblas-
toma patients.

Keywords  Glioblastoma · Temozolomide · Obesity · MGMT

6
* Johannes Weller Department of Neurology and Wilhelm Sander
Johannes.weller@ukbonn.de NeuroOncology Unit, University Hospital Regensburg,
Regensburg, Germany
1
Division of Clinical Neurooncology, Department 7
Department of Radiation Oncology, University of Leipzig,
of Neurology, University Hospital Bonn, Venusberg‑Campus
Leipzig, Germany
1, 53127 Bonn, Germany
8
2 Department of Neurosurgery, University of Dresden,
Department of Neurosurgery, University Hospital Bonn,
Dresden, Germany
Bonn, Germany
9
3 Department of Neurosurgery, University of Cologne,
Dr. Senckenberg Institute of Neurooncology, University
Cologne, Germany
of Frankfurt, Frankfurt, Germany
10
4 Institute of Neuropathology, University Hospital Bonn, Bonn,
Department of Neurology, University Hospital
Germany
Knappschaftskrankenhaus, Ruhr–Universität Bochum,
Bochum, Germany
5
Department of Neurosurgery, University of Düsseldorf,
Düsseldorf, Germany

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96 Journal of Neuro-Oncology (2022) 159:95–101

Introduction and with a KPS of 70% or higher. Patients were recruited

between June 2010 and August 2012 and randomized to
Despite recent therapeutic progress, glioblastoma remains standard TMZ concomitant to radiotherapy followed by six
a devastating disease with short survival [1]. Prognostic courses of TMZ, or standard radiotherapy with concomitant
factors including age, Karnofsky performance scale (KPS), bevacizumab every 2 weeks followed by bevacizumab and
extent of resection, and MGMT promoter methylation sta- irinotecan every 2 weeks.
tus, aid to estimate the course of disease and enable shared
decision-making regarding therapeutic options [2]. The
Statistical analysis
impact of obesity on survival in high grade glioma has been
retrospectively analyzed with contradicting results, as it
Descriptive statistics are provided as mean and standard
was associated with better [3–6], indifferent [7], or worse
deviation or median and interquartile range (IQR) where
survival [8, 9]. Notably, these studies exhibit limitations,
appropriate. Obesity was defined as a BMI of 30 kg/m2 or
including recruitment before current standard therapies
higher according to the WHO definition. Groupwise com-
[7], inclusion of different tumor grades [8, 9], the single-
parisons were performed using unpaired Student’s t-test,
or bicentric retrospective nature of analyses [3–8], and not
Wilcoxon rank-sum test or Fisher’s exact test, depending
accounting for MGMT promoter methylation status.
on scale and distribution. OS and PFS were analyzed with
Here, we aim to analyze the prognostic impact of obesity
Kaplan–Meier analysis and log-rank test. Multivariable Cox
in glioblastoma with or without MGMT methylation using
regression analysis including age, sex, extent of resection,
two well-characterized study cohorts.
KPS, baseline steroid medication and treatment arm was
performed to validate the findings. Significance level was
set to alpha ≤ 0.05 and all analyses were two-sided. Statisti-
Methods cal analyses were carried out with R (version 4.0.3, The R
Foundation for Statistical Computing, https://​www.r-​proje​
This study is a retrospective analysis of the prognostic ct.​org, package survminer).
impact of obesity in two prospective clinical trials of glio-
blastoma, which recruited at overlapping time periods at
largely the same German university medical centers.
Results
CeTeG/NOA‑09 BMI was unknown in two cases, resulting in 297 patients
included in this analysis. 22.5% (67/297) of patients were
This randomized phase III trial (ClinicalTrials.gov obese (BMI ≥ 30 kg/m2). The median age of the cohort was
NCT01149109, [10]) included 129 patients aged 56 years (IQR 49–63); 58 years (IQR 50–63) for MGMT
18–70 years with newly diagnosed glioblastoma, harboring methylated and 56 years (IQR 48–63) for MGMT unmeth-
a methylated MGMT promoter as determined by real-time ylated patients. Further characteristics and outcome of the
methylation-specific PCR (msPCR [11]) and with a KPS of included studies have been published previously [10, 12].
70% or higher. Patients were recruited between June 2011 Baseline characteristics were similar between obese and
and April 2014 and randomized to standard temozolomide non-obese patients (Table 1).
(TMZ) concomitant to radiotherapy followed by six courses
of temozolomide or six courses of lomustine (CCNU) and
TMZ starting during standard radiotherapy. As the study Entire study cohort
recruited before the 2016 WHO classification of tumours of
the central nervous system, 23 patients with unknown IDH For the entire study cohort, both median OS (obese vs. non-
mutation status or confirmed IDH mutation were included obese: 19.2 (95% CI 16.2–21.9) vs. 23.0 (20.1–26.7) months,
[1]. p = 0.0014) and PFS (obese vs. non-obese: 8.8 (6.0–11.4) vs.
10.0 (9.2–11.7) months, p = 0.008) were shorter in obese
patients. The known prognostic and predictive impact of
GLARIUS
MGMT methylation is emphasized by a greatly differing
median OS (GLARIUS: 17.1 (95% CI 15.8–18.1) months,
This randomized phase II trial (ClinicalTrials.gov
CeTeG/NOA-09: 33.6 (29.3–47.2) months, p < 0.001) and
NCT00967330 [12]) included 170 patients aged 18 or older
median PFS (8.6 (95% CI 7.9–9.7) vs. 15.7 (11.5–20.4)
with newly diagnosed glioblastoma harboring an unmeth-
months, p < 0.001), thus patients with MGMT methylated
ylated MGMT promoter (same msPCR test as in CeTeG)

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Journal of Neuro-Oncology (2022) 159:95–101 97

Table 1  Baseline characteristics
All patients MGMT unmethylated MGMT methylated
Non-obese Obese p Non-obese Obese p Non-obese Obese p
n = 230 n = 67 n = 130 n = 38 n = 100 n = 29

BMI, median 24.6 (22.7– 32.3 (31.0–  < 0.001 24.5 (22.6– 32.1 (31.0–  < 0.001 25.0 (22.8, 33.3 (31.2–  < 0.001
(IQR) 26.8) 34.2) 27.0) 33.9) 26.8) 35.2)
Standard treat- 88 (38.3) 29 (43.3) 0.48 44 (33.8) 10 (26.3) 0.43 44 (44.0) 19 (65.5) 0.06
ment arm*(%)
Age, mean (SD) 55.6 (10.3) 56.9 (8.7) 0.37 55.6 (10.8) 55.9 (8.4) 0.86 55.7 (9.5) 58.1 (9.1) 0.22
Male sex (%) 148 (64.3) 42 (62.7) 0.89 87 (66.9) 26 (68.4) 1.0 61 (61.0) 16 (55.2) 0.67
KPS, median 90 (90–100) 90 (90–100) 0.15 90 (90–100) 90 (82.5–100) 0.22 95 (90–100) 90 (90–100) 0.42
(IQR)
Baseline steroid 37 (16.1) 14 (20.9) 0.36 24 (18.5) 8 (21.1) 0.82 13 (13.0) 6 (20.7) 0.37
(%)
Extent of resec- 0.55 0.75 0.73
tion (%)
 Biopsy 6 (2.6) 0 (0) 2 (1.6) 0 (0) 4 (4.0) 0 (0)
 PR 99 (43.2) 31 (46.3) 63 (48.8) 21 (55.3) 36 (36.0) 10 (34.5)
 CR 124 (54.1) 36 (53.7) 64 (49.6) 17 (44.7) 60 (60.0) 19 (65.5)
Study = GLAR- 130 (56.5) 38 (56.7) 1.00 130 (100) 38 (100) NA 0 (0) 0 (0) NA
IUS (%)

Values represent number of patients unless indicated otherwise

BMI body mass index; CR complete resection; IQR interquartile range; n number of patients; KPS Karnofsky performance score; PR partial
resection; SD standard deviation
*Focal radiotherapy, concomitant daily temozolomide, up to six courses of adjuvant temozolomide

(CeTeG/NOA-09) and unmethylated tumors (GLARIUS) Multivariate analysis

were subsequently analyzed separately.
Multivariable Cox regression analysis including age, sex,
Patients with MGMT unmethylated glioblastoma extent of resection, KPS, baseline steroid medication,
and treatment arm as covariates confirmed obesity as an
In patients with MGMT unmethylated glioblastoma, PFS independent negative predictor of PFS and OS in MGMT
(obese vs. non-obese: 8.1 (95% CI 6.0–11.3) vs. 9.0 (7.9–9.8) methylated glioblastoma (adjusted odds ratio (aOR) for
months, p = 0.23; Fig. 1a) and OS (obese vs. non-obese: 17.6 PFS: 1.95 (95% CI  1.21–3.14), p = 0.007; aOR for OS:
(14.7–20.8) vs. 17.1 (15.8–18.9) months, p = 0.26; Fig. 1b) 2.57 (1.53–4.31), p < 0.001; Table 2), but not in MGMT
did not differ between obese and non-obese patients (Fig. 1). unmethylated glioblastoma (aOR for PFS: 1.28 (0.78–1.87),
p = 0.20; aOR for OS: 1.17 (0.78–1.75), p = 0.44). Sensitiv-
Patients with MGMT methylated glioblastoma ity analyses restricted to IDH wildtype tumors confirmed
these findings for both MGMT methylated glioblastoma
Among MGMT methylated patients, obesity was associated (aOR for PFS: 1.78 (1.06–3.00), p = 0.029; aOR for OS: 2.43
with shorter PFS (obese vs. non-obese: 11.3 (5.5–20.9) vs. (1.39–4.24), p = 0.002) and MGMT unmethylated glioblas-
16.6 (12.1–22.1) months, p = 0.007; Fig. 1a) and OS (obese toma (aOR for PFS: 0.91 (0.58–1.41), p = 0.66; aOR for OS:
vs. non-obese: 22.9 (17.7–30.8) vs. 43.2 (32.5–54.4) months, 1.46 (0.91–2.35), p = 0.11) [13].
p = 0.001, Fig. 1b). Restricting the analysis to patients with
known IDH wildtype status (n = 103) confirmed the findings
(p = 0.0208 for PFS and p = 0.0011 for OS). Furthermore, Discussion
hematotoxicity CTCAE grade 3 or higher occurred with
similar frequency in obese and non-obese patients (44.8 vs. This analysis of two study cohorts provides evidence for a
57.0%, p = 0.29). negative prognostic impact of obesity in MGMT-methylated
glioblastoma, but not in MGMT-unmethylated glioblastoma.
We have previously reported that in elderly and frail
patients with glioblastoma (median age 72, range 65–86);

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Fig. 1  Overall survival and progression-free survival of obese and all survival of MGMT methylated (left) and unmethylated (right)
non-obese patients with MGMT methylated and unmethylated glio- glioblastoma patients. The number of patients at risk is given below
blastoma. a Progression-free survival of MGMT methylated (left each diagram. MGMT O6-methylguanine-DNA methyltranferase; OS
panel) and unmethylated (right panel) glioblastoma patients. b Over- overall survival; PFS progression-free survival

median KPS 80%, range 50–100), obesity was associated rate of complete resections (53.8%) and high KPS (median
with improved survival [4]. Although these results may 90%), suggesting sufficient fitness to endure the burden of
seem contradicting, they are in line with the known sur- surgery and radiochemotherapy [10, 12]. These beneficial
vival benefit of obesity in elderly [14] and frail patients features might also contribute to the observed median OS
[15] suffering from different diseases such as diabetes [16], of 43 months for the subgroup of non-obese patients with
heart failure [17], and metastatic cancer diseases [18] among MGMT methylated glioblastoma, comparing favorably to a
others. In comparison to this cohort, the study populations recent study on the use of immune checkpoint inhibitors in
of CeTeG/NOA-09 and GLARIUS had favorable baseline MGMT methylated glioblastoma [19].
characteristics with younger age (median 56 years), a high

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Table 2  Multivariate analysis identifies obesity as a negative predictor for overall and progression-free survival in MGMT methylated newly-
diagnosed glioblastoma
OS Adjusted odds ratio 95% CI p

Obese (vs. non-obese) 2.57 1.53–4.31  < 0.001

Partial resection (vs. biopsy) 0.96 0.25–3.62 0.10
Complete resection (vs. biopsy) 0.76 0.22–2.70 0.67
KPS (per 10% increment) 0.76 0.56–1.01 0.06
Age (per year increment) 1.03 1.00–1.06 0.03
Baseline steroid medication 1.15 0.62–2.14 0.64
Male sex (vs. female) 1.17 0.71–1.92 0.53
TMZ arm (vs. CCNU/TMZ) 0.84 0.51–1.38 0.49
PFS Adjusted odds ratio 95% CI p

Obese (vs. non-obese) 1.95 1.21–3.14 0.007

Partial resection (vs. biopsy) 0.54 0.16–1.85 0.33
Complete resection (vs. biopsy) 0.41 0.13–1.33 0.14
KPS (per 10% increment) 9.83 0.65–1.04 0.11
Age (per year increment) 1.02 0.99–1.04 0.10
Baseline steroid medication 0.87 0.47–1.57 0.64
Male sex (vs. female) 0.98 0.64–1.49 0.91
TMZ arm (vs. CCNU/TMZ) 0.83 0.54–1.28 0.40

CI confidence interval; CCNU lomustine; IDH isocitrate dehydrogenase; KPS Karnofsky performance score, OS overall survival; PFS progres-
sion-free survival; TMZ temozolomide

The finding of a negative effect of obesity on OS, at least termed obesity paradox, might be explained by the inad-
in MGMT-methylated patients, is in line with a previous equacy of BMI to measure body fat in cancer patients under-
publication showing an association of obesity with reduced going weight changes, as it does not distinguish adipose
OS in a large retrospective case–control study [9], but incon- and muscle tissue [22]. Indeed, skeletal muscle status is an
sistent with results from a recent meta-analysis [20]. How- independent prognostic parameter in glioblastoma [20, 23],
ever, studies that reported no or even a favorable associa- and obese patients have on average higher levels of muscle.
tion of obesity with OS had aspects that make it difficult Therefore, the obesity paradox might be most significant in
to compare their results to the findings of the GLARIUS elderly, frail or dependent patients, where sarcopenia is fre-
and CeTeG/NOA-09 trial cohort reported here: Jones et al. quent. On the other hand, it is absent in our trial cohort (with
included patients from 1991 to 2008 who mostly did not comparably favorable prognostic factors), resulting from the
receive first-line chemotherapy [7], and three other studies assumed relative absence of sarcopenia, and potentially det-
mostly included patients with inferior prognostic factors rimental effects of adipose tissue on glioblastoma treatment
such as low KPS and/or low complete resection rates [3, might be demasked. Future studies considering body compo-
5, 8]. One study that found a positive correlation of obesity sition might contribute to solving this interesting dichotomy.
and OS is difficult to interpret since obese and non-obese The mechanistic link between survival and obesity
patients were imbalanced regarding percentage of complete remains elusive, as no death was related to obesity itself
resections (68.8% vs. 55.2%) and female patients (66% vs. in the CeTeG/NOA-09 trial (unknown: 2 cases). Obesity is
35%) [6]. Female sex may be a favorable prognostic factor linked to reduced glucose sensitivity and increased blood
that was not included in univariate and multivariate analy- glucose levels, a known risk factor in glioblastoma [24, 25].
ses [21]. Considering all available data, the best hypothesis HbA1c and glucose levels were not available in our cohorts,
regarding the association of obesity and OS would be that but previous data suggests an independent prognostic effect
in patients with inferior prognostic factors such as compa- of diabetes mellitus and obesity [8, 9]. Recently, an obesity-
rably low performance status and even more in elderly and inducing high-fat diet was described to promote aggressive
frail patients, obesity may have a positive impact, while in disease with shortened survival via intracerebral fat accumu-
patients with favorable prognostic factors (e.g. populations lation and impaired hydrogen sulfide production leading to
in clinical trials) obesity may be a negative prognostic factor, increased proliferation and chemotherapy resistance in glio-
especially in the context of effective, survival-prolonging blastoma [26]. Furthermore, obesity is inversely correlated
chemotherapy. The survival benefit of obesity in oncology,

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100 Journal of Neuro-Oncology (2022) 159:95–101

with socioeconomic status, a known prognostic factor for Data availability  Restrictions apply to the availability of these data due
survival in glioblastoma [27, 28]. to privacy restrictions.
Of note, obesity was associated with shorter survival
Code availability  Not applicable.
in MGMT methylated, but not in MGMT unmethylated
tumors. While it is possible that the shorter overall survival
Declarations 
in MGMT unmethylated tumors impeded detection of a
survival difference between obese and non-obese patients, Conflict of interest UH has received lecture and/or advisory board
an alternative mechanistic hypothesis seems promising: honoraria from Medac, Noxxon, AbbVie, Bayer, Janssen, and Karyop-
MGMT promoter methylation reduces MGMT expression, harm. JS has received honoraria for lectures, travel or advisory board
an enzyme removing alkyl groups from the O6 position of participation from Abbvie, Medac, Med-Update, Roche, Novocure
and Seagen. CS has received lecture, consultation or advisory board
guanine [29]. These lesions trigger cytotoxicity and apop- honoraria from AbbVie, Bristol-Myers Squibb, HRA Pharma, Medac,
tosis in a process requiring a functioning mismatch repair Roche and Seagen. The other authors declare that they have no finan-
pathway and DNA damage signaling by ATR and ATM cial interests.
[29]. Elevated fatty acid levels were reported to compro-
Ethical approval  Both trials were performed in line with the princi-
mise the induction of p21 downstream of ATM [30], which ples of the Declaration of Helsinki the Guidelines for Good Clinical
is required for temozolomide sensitivity [31]. Similarly, Practice. The trials were approved by the ethics committee of all par-
increased levels of free fatty acids lead to mitochondrial ticipating centers.
DNA damage culminating in cellular apoptosis induction
Consent to participate  Written informed consent was obtained from
[32, 33]. A recent study revealed that the combinatory treat- all individual participants included in the studies.
ment with the glycolytic inhibitor dichloracetate and the par-
tial fatty acid oxidation inhibitor ranolazine yielded reduced Consent to publish  All authors agreed to the publication of the manu-
colony forming activity and apoptosis of glioblastoma cells script.
in vitro [31]. Murine in vivo experiments under this combi-
nation treatment resulted in increased median survival [34], Open Access  This article is licensed under a Creative Commons Attri-
supporting the proposed mechanistic link to reflect an intra- bution 4.0 International License, which permits use, sharing, adapta-
tion, distribution and reproduction in any medium or format, as long
tumoral cellular effect. Thus, elevated fatty acid levels in as you give appropriate credit to the original author(s) and the source,
obese patients might compromise the therapeutic response provide a link to the Creative Commons licence, and indicate if changes
to alkylating chemotherapy in MGMT methylated glioblas- were made. The images or other third party material in this article are
toma. In MGMT unmethylated glioblastoma, on the other included in the article's Creative Commons licence, unless indicated
otherwise in a credit line to the material. If material is not included in
hand, the benefit of temozolomide is at best limited, render- the article's Creative Commons licence and your intended use is not
ing this effect negligible [35]. permitted by statutory regulation or exceeds the permitted use, you will
need to obtain permission directly from the copyright holder. To view a
copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/.

Conclusions
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