Cilengitide treatment of newly diagnosed glioblastoma patients does not alter patterns of progression

TLDR: Analysis of patterns of progression on MRI in 21 patients enrolled onto a phase 2 trial of cilengitide added to TMZ/RT → TMZ in newly diagnosed glioblastoma provides no evidence for an anti-invasive activity of cILENGitide in patients with newly diagnosed GliOBlastoma.

Abstract: The integrin antagonist cilengitide has been explored as an adjunct with anti-angiogenic properties to standard of care temozolomide chemoradiotherapy (TMZ/RT → TMZ) in newly diagnosed glioblastoma. Preclinical data as well as anecdotal clinical observations indicate that anti-angiogenic treatment may result in altered patterns of tumor progression. Using a standardized approach, we analyzed patterns of progression on MRI in 21 patients enrolled onto a phase 2 trial of cilengitide added to TMZ/RT → TMZ in newly diagnosed glioblastoma. Thirty patients from the experimental treatment arm of the EORTC/NCIC pivotal TMZ trial served as a reference. MRIcro software was used to map location and extent of initial preoperative and recurrent tumors on MRI of both groups into the same stereotaxic space which were then analyzed using an automated tool of image analysis. Clinical and outcome data of the cilengitide-treated patients were similar to those of the EORTC/NCIC trial except for a higher proportion of patients with a methylated O(6)-methylguanyl-DNA-methyltransferase gene promoter. Analysis of recurrence pattern revealed neither a difference in the size of the recurrent tumor nor in the distance of the recurrences from the preoperative tumor location between groups. Overall frequencies of distant recurrences were 20 % in the reference group and 19 % (4/21 patients) in the cilengitide group. Compared with TMZ/RT → TMZ alone, the addition of cilengitide does not alter patterns of progression. This analysis does not support concerns that integrin antagonism by cilengitide may induce a more aggressive phenotype at progression, but also provides no evidence for an anti-invasive activity of cilengitide in patients with newly diagnosed glioblastoma.

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Year:2014
Cilengitidetreatmentofnewlydiagnosedglioblastomapatientsdoesnot
alterpatternsofprogression
Eisele,G;Wick,A;Eisele,AC;Clément,PM;Tonn,J;Tabatabai,G;Ochsenbein,A;Schlegel,U
;Neyns,B;Krex,D;Simon,M;Nikkhah,G;Picard,M;Stupp,R;Wick,W;Weller,M
Abstract:Theintegrinantagonistcilengitidehasbeenexploredasanadjunctwithanti-angiogenicprop-
erties tostandard of caretemozolomide chemoradiotherapy (TMZ/RT→ TMZ)in newlydiagnosed
glioblastoma.Preclinicaldataaswellasanecdotalclinicalobservationsindicatethatanti-angiogenic
treatmentmayresultinalteredpatternsoftumorprogression.Usingastandardizedapproach,wean-
alyzedpatternsofprogressiononMRIin21patientsenrolledontoaphase2trialofcilengitideadded
toTMZ/RT→TMZinnewlydiagnosedglioblastoma.Thirtypatientsfromtheexperimentaltreatment
armoftheEORTC/NCICpivotalTMZtrialservedasareference.MRIcrosoftwarewasusedtomap
locationandextentofinitialpreoperativeandrecurrenttumorsonMRIofbothgroupsintothesame
stereotaxicspacewhichwerethenanalyzedusinganautomatedtoolofimageanalysis.Clinicaland
outcomedataofthecilengitide-treatedpatientsweresimilartothoseoftheEORTC/NCICtrialexcept
forahigherproportionofpatientswithamethylatedO(6)-methylguanyl-DNA-methyltransferasegene
promoter.Analysisofrecurrencepatternrevealedneitheradierenceinthesizeoftherecurrenttumor
norinthedistanceoftherecurrencesfromthepreoperativetumorlocationbetweengroups.Overall
frequenciesofdistantrecurrenceswere20%inthereference groupand19 %(4/21patients)inthe
cilengitidegroup.ComparedwithTMZ/RT→TMZalone,theadditionofcilengitidedoesnotalter
patternsofprogression.Thisanalysisdoesnotsupportconcernsthatintegrinantagonismbycilengitide
mayinduceamoreaggressivephenotypeatprogression,butalsoprovidesnoevidenceforananti-invasive
activityofcilengitideinpatientswithnewlydiagnosedglioblastoma.
DOI:https://doi.org/10.1007/s11060-014-1365-x
PostedattheZurichOpenRepositoryandArchive,UniversityofZurich
ZORAURL:https://doi.org/10.5167/uzh-95404
JournalArticle
AcceptedVersion
Originallypublishedat:
Eisele,G;Wick,A;Eisele,AC;Clément,PM;Tonn, J;Tabatabai,G;Ochsenbein, A;Schlegel,U;
Neyns,B;Krex,D;Simon,M;Nikkhah,G;Picard,M;Stupp,R;Wick,W;Weller,M(2014).Cilengitide
treatmentofnewlydiagnosedglioblastomapatientsdoesnotalterpatternsofprogression.Journalof
Neuro-Oncology,117(1):141-145.
DOI:https://doi.org/10.1007/s11060-014-1365-x

1
Cilengitide treatment of newly diagnosed glioblastoma patients
does not alter patterns of progression
Günter Eisele
1*
, Antje Wick
2*
, Anna-Carina Eisele
1
, Paul M. Clement
3
, Jörg Tonn
4
,
Ghazaleh Tabatabai
5
, Adrian Ochsenbein
6
, Uwe Schlegel
7
, Bart Neyns
8
, Dietmar
Krex
9
, Matthias Simon
10
, Guido Nikkhah
11,+
, Martin Picard
12
, Roger Stupp
13
,
Wolfgang Wick
2,14
, and Michael Weller
1
1
Department of Neurology, University Hospital Zurich, Frauenklinikstrasse 26, 8091 Zurich,
Switzerland;
2
Department of Neurooncology, University Hospital Heidelberg, Im Neuenheimer Feld
400, 68120 Heidelberg, Germany;
3
Department of Oncology, KU Leuven, Herestraat 49, 3000 Leuven,
Belgium;
4
Department of Neurosurgery, University Hospital of Munich LMU, Marchioninistrasse 15,
81377 Munich, Germany;
5
Department of General Neurology, University Hospital Tübingen, Hoppe-
Seyler Strasse 3, 72076 Tübingen, Germany;
6
Department of Medical Oncology, University Hospital
Bern, Freiburgstrasse 4, 3010 Bern, Switzerland;
7
Department of Neurology, University Hospital
Bochum, Knappschaftskrankenhaus Bochum-Langendreer, In der Schonau 23-25, 44892 Bochum,
Germany;
8
Department of Medical Oncology, UZ Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium;
9
Department of Neurosurgery, University Hospital Carl-Gustav Carus Dresden, Fetscherstrasse 74,
01307 Dresden, Germany;
10
Department of Neurosurgery, University Hospital Bonn, Sigmund-Freud
Strasse 25, 53105 Bonn, Germany;
11
Department of Neurosurgery, University Hospital Freiburg,
Breisacher Strasse 64, 79106 Freiburg, Germany;
12
Merck Serono, Alsfelder Strasse 17, 64289
Darmstadt, Germany;
13
Multidisciplinary Oncology Center, University of Lausanne Hospitals, 46 Rue
du Bugnon, 1011 Lausanne, Switzerland,
14
German Cancer Consortium (DKTK), Clinical Cooperation
Unit Neurooncology, German Cancer Research Center (DKFZ), INF 280, 69120 Heidelberg
*GE and AW contributed equally to this work;
+
current address: Department of Neurosurgery,
University Hospital Erlangen, Schwabachanlage 6, 91054 Erlangen, Germany
Address for correspondence: Günter Eisele, MD, Department of Neurology, University Hospital
Zurich, Frauenklinikstrasse 26, 8091 Zurich, Switzerland, E-Mail: guenter.eisele@usz.ch

2
Abstract
The integrin antagonist cilengitide has been explored as an adjunct with anti-
angiogenic properties to standard of care temozolomide chemoradiotherapy
(TMZ/RT→TMZ) in newly diagnosed glioblastoma. Preclinical data as well as
anecdotal clinical observations indicate that anti-angiogenic treatment may result in
altered patterns of tumor progression. Using a standardized approach, we analyzed
patterns of progression on MRI in 21 patients enrolled onto a phase 2 trial of
cilengitide added to TMZ/RT→TMZ in newly diagnosed glioblastoma. Thirty patients
from the experimental treatment arm of the EORTC/NCIC pivotal TMZ trial served as
a reference. MRIcro software was used to map location and extent of initial
preoperative and recurrent tumors on MRI of both groups into the same stereotaxic
space which were then analyzed using an automated tool of image analysis. Clinical
and outcome data of the cilengitide-treated patients were similar to those of the
EORTC NCIC trial except for a higher proportion of patients with a methylated O
6
-
methylguanyl-DNA-methyltransferase (MGMT) gene promoter. Analysis of
recurrence pattern revealed neither a difference in the size of the recurrent tumor nor
in the distance of the recurrences from the preoperative tumor location between
groups. Overall frequencies of distant recurrences were 20% in the reference group
and 19% (4/21 patients) in the cilengitide group. Compared with TMZ/RT→TMZ
alone, the addition of cilengitide does not alter patterns of progression. This analysis
does not support concerns that integrin antagonism by cilengitide may induce a more
aggressive phenotype at progression, but also provides no evidence for an anti-
invasive activity of cilengitide in patients with newly diagnosed glioblastoma.
Key words: glioblastoma; integrins; cilengitide; relapse pattern; MRIcro

3
Introduction
Most current efforts to improve the outcome for patients with newly diagnosed
glioblastoma focus on the addition of anti-angiogenic agents to the standard of care
of concomitant chemoradiotherapy with temozolomide (TMZ/RT→TMZ) [1]. The
majority of pharmacological approaches focus on inhibition of the vascular
endothelial growth factor (VEGF) pathway, but additional targets are being explored,
notably integrins. Preclinical data obtained in rodent glioma models suggest that
VEGF antagonism may induce a more infiltrative, disseminated phenotype of gliomas
[2,3]. No such animal data are available for integrin antagonism.
We have previously developed an analysis tool to explore whether comparable
groups of patients differ in their patterns of progression. This tool was first used for
analysis of the pivotal EORTC/NCIC TMZ trial; and allowed to falsify the hypothesis
that the addition of TMZ to RT alters the pattern of progression of glioblastomas [4].
Similarly, using this tool we did not confirm the notion that bevacizumab therapy
alters tumor biology to a more invasive phenotype [5]. In the present study, we asked
whether patients treated with the integrin antagonist cilengitide would exhibit an
altered pattern of progression.

4
Patients and methods
We retrieved the matched pre- and post-operative MRI scans as well as the MRI
scan documenting progression of patients enrolled into a single-arm phase 2 clinical
trial of cilengitide plus TMZ/RT→TMZ in newly diagnosed glioblastoma [6]. Thirty
patients from the experimental treatment arm of the EORTC/NCIC 26981/22981
National Cancer Institute of Canada (NCIC) CE.3 trial served as a reference [1,4].
From these patients MRI scans at baseline and progression were available for a
retrospective recurrence pattern analysis [4]. Patterns of progression were analyzed
as described hereib; in brief, brain lesions were demonstrated by contrast-enhanced
T
1
-weighted MRI sequences. The MR scans were oriented along the bicommissural
plane. Mapping of lesions was performed blinded to the clinical features of the
patients. The boundaries of the tumor location at baseline and at follow-up were
delineated using MRIcro software [7] and mapped on the T
1
-template MRI from the
Montreal Neurological Institute (www.bic.mni.mcgill.ca/cgi/icbm_view) that is
distributed with MRIcro. Tumors were mapped for each individual patient, with
separate tumor maps generated for both the baseline and recurrence scan. By
transforming each individual brain and lesion into the same stereotaxic space, the
procedure allowed us to superimpose lesions of different individuals to find regions of
mutual involvement and conduct subtraction analysis. These techniques are well
established in stroke research
and have been applied to brain tumor patients before
[4,5].
Further, by using MRIcro, tumor volume and the location of the center-of-mass of the
tumor for each individual were computed. The center-of-mass is the mean position
for all tumor-affected voxels in each of the three spatial dimensions, resulting in a
single cartesian coordinate (X,Y,Z position). In the case of a single spherical tumor,
the center-of-mass thus will be located right in its center, while with, e.g. a U-shaped

Frequently asked questions

Q1. What contributions have the authors mentioned in the paper "Cilengitide treatment of newly diagnosed glioblastoma patients does not alter patterns of progression" ?

Using a standardized approach, the authors analyzed patterns of progression on MRI in 21 patients enrolled onto a phase 2 trial of cilengitide added to TMZ/RT → TMZ in newly diagnosed glioblastoma. This analysis does not support concerns that integrin antagonism by cilengitide may induce a more aggressive phenotype at progression, but also provides no evidence for an anti-invasive activity of cilengitide in patients with newly diagnosed glioblastoma. 

Q2. What are the future works in "Cilengitide treatment of newly diagnosed glioblastoma patients does not alter patterns of progression" ?

The major limitation of the present study is the small sample size and the uncertainty of its relevance in the future: preliminary results from the subsequently performed phase 3 trial, CENTRIC, indicate that the primary endpoint of prolonging overall survival was not reached [ 13 ]. Yet, their analysis serves as a baseline and reference for the future study of the role of modulation of integrins in the treatment of newly diagnosed glioblastoma. 

Q3. What was used to map the location and extent of initial preoperative and recurrent tumors?

MRIcro software was used to map location and extent of initial preoperative and recurrent tumors on MRI of both groups into the same stereotaxic space which were then analyzed using an automated tool of image analysis. 

Q4. What is the role of cilengitide in glioma?

Preclinical data obtained in rodent glioma models suggest that VEGF antagonism may induce a more infiltrative, disseminated phenotype of gliomas [2,3]. 

Q5. What is the main limitation of the present study?

The major limitation of the present study is the small sample size and the uncertainty of its relevance in the future: preliminary results from the subsequently performed phase 3 trial, CENTRIC, indicate that the primary endpoint of prolonging overall survival was not reached [13]. 

Q6. What was the purpose of the study?

By transforming each individual brain and lesion into the same stereotaxic space, the procedure allowed us to superimpose lesions of different individuals to find regions of mutual involvement and conduct subtraction analysis. 

Q7. How many patients were treated with cilengitide?

For 21 representative patients (21/53, 40%) treated prospectively within the cilengitide added to standard TMZ/RTTMZ 010 pilot phase II protocol complete digitized imaging was available for review and analysis [6]. 

Q8. How many patients were enrolled in the NCIC CE.3 trial?

Thirty patients from the experimental treatment arm of the EORTC/NCIC 26981/22981 National Cancer Institute of Canada (NCIC) CE.3 trial served as a reference [1,4]. 

Q9. What is the definition of a distant recurrence?

For an additional case-by-case analysis a distant recurrence on T1 contrastenhanced (T1+c) sequences was defined as one of the following: a) qualitative assessment of well-defined recurrence centered outside a 2 cm margin around the outer border of the primary site or margin of the resection cavity or a shift of the center-of-mass by more than half of the diameter of the pretreatment tumor, b) new tumor satellites, c) new involvement of the contralateral hemisphere [4]. 

Q10. What is the role of cilengitide in glioblastoma?

The integrin antagonist cilengitide has been explored as an adjunct with antiangiogenic properties to standard of care temozolomide chemoradiotherapy (TMZ/RT→TMZ) in newly diagnosed glioblastoma. 

Q11. How long did the median time between MRI and first diagnosis be?

The median time between imaging used for the baseline MRI scanning and first histological diagnosis was 0.2 months in both groups. 

Q12. How was the survival for the cilengitide group calculated?

Median progression-free and overall survival for the cilengitide group were calculated by Kaplan-Meier survival analysis using SPSS software version 21 for Windows (IBM, Armonk, NY, USA). 

Q13. How long did the MRI show recurrence?

The median time between baseline MRI and the MRI demonstrating recurrence was 7.3 months in the reference group and 9.0 months in the cilengitide group, comparable to the whole study cohort.