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Bevacizumab does not increase the risk of remote relapse in malignant glioma.

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ANNALS
of Neurology
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Bevacizumab Does Not
Increase the Risk of Remote
Relapse in Malignant Glioma
Antje Wick, MD,1 Nils Dörner, MD,2
Navina Schäfer, CandMed,1 Silvia Hofer, MD,3
Sabine Heiland, PhD,2,4
Daniela Schemmer, RN,1 Michael Platten, MD,1
Michael Weller, MD,3 Martin Bendszus, MD,2
and Wolfgang Wick, MD1
Preclinical evidence and uncontrolled clinical studies
suggest an increased risk for distant spread and development of a gliomatosislike phenotype at recurrence or
progression of malignant glioma patients treated with
bevacizumab (BEV), an antibody to vascular endothelial
growth factor (VEGF). Here we asked whether BEV
treatment of recurrent malignant glioma increases the
risk of distant or diffuse tumor spread at further recurrence. BEV-treated patients were compared with
matched pairs of patients treated without anti-VEGF regimens. T1 contrast-enhanced (T1þc) and fluid-attenuated
inversion recovery (FLAIR) images were analyzed using a
novel automated tool of image analysis. At the start of
the study, 20.5% of BEV-treated and 22.7% of non–BEVtreated patients had displayed distant or diffuse recurrence. Distant or diffuse recurrences were observed in
22% (BEV) and 18% (non-BEV) on T1þc and in 25% and
18% on FLAIR (p > 0.05). The correlation between
changes on T1þc and FLAIR at progression was high.
The risk of distant or diffuse recurrence at the time of failure of BEV-containing treatments was not higher than
with anti-VEGF–free regimens, arguing against a specific
property of BEV that promotes distant tumor growth or
a gliomatosislike phenotype at recurrence.
ANN NEUROL 2011;69:586–592
wo uncontrolled phase II studies1,2 were the basis for
the approval of the vascular endothelial growth factor
(VEGF) antibody bevacizumab (BEV) for patients with
T
From the 1 Department of Neuro-oncology and 2 Department of
Neuroradiology, University Clinic Heidelberg, Heidelberg, Germany;
3
Department of Neurology, University Hospital Zurich, Zurich,
Switzerland; and 4Division Experimental Radiology, University Clinic
Heidelberg, Heidelberg, Germany.
Address correspondence to Dr W. Wick, Department of Neuro-oncology,
Neurology Clinic and National Center for Tumor Diseases, University of
Heidelberg, Im Neuenheimer Feld 400, D-69120 Heidelberg, Germany.
E-mail: wolfgang.wick@med.uni-heidelberg.de
Additional Supporting Information can be found in the online version of
this article.
Received Sep 8, 2010, and in revised form Oct 26, 2010. Accepted for
publication Nov 5, 2010.
View this article online at wileyonlinelibrary.com. DOI: 10.1002/
ana.22336
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Wick et al: Bevacizumab and Remote Relapse
recurrent glioblastoma in the United States in May 2009.
In contrast, the European Medical Agency rejected approval
in the European Union.3 In the United States, the rate of
objective responses4 was accepted as a surrogate marker of
clinical efficacy. The mode of action of anti-VEGF/VEGF
receptor compounds includes the normalization of the vasculature via inhibition of pathological proliferation of endothelial cells and immature vessel formation.5,6 Antiangiogenic agents may decrease contrast enhancement and edema
as early as 1 to 2 days after initiation of therapy and induce
high radiological response rates of 25 to 60%.1,2,5,7,8 These
responses are not necessarily due to a true antitumor effect.
There is a disappointing disparity between the unprecedented high response rates with these agents in recurrent
glioblastoma and the modest, if any, progression-free survival (PFS) or overall survival (OS) benefit.9
Preclinical studies have indicated that anti-VEGF
therapy increases the tendency of tumor cells to invade
by co-opting existing blood vessels.10,11 For BEV, various
patient series have also suggested an increase in invasive
tumor at recurrence.9,12 This is commonly coined ‘‘gliomatosis-like phenotype’’ and best depicted on fluid-attenuated inversion recovery (FLAIR) magnetic resonance
imaging (MRI) sequences.9 Determination of the extent of
this nonenhancing component of the tumor on the T2weighted and FLAIR image sequences can be difficult, especially when peritumoral edema, which also appears as a T2
and FLAIR abnormality, is present. It has been hypothesized that even with ongoing reduction in contrast enhancement, an increase in nonenhancing FLAIR hyperintensity
suggestive of infiltrative tumor may subsequently develop.9,12,13 Among others, this potential discordance
between T1 contrast-enhanced (T1þc) and FLAIR images
has led to a reconsideration of traditional imaging response
criteria. The new response assessment criteria developed by
the Response Criteria in Neuro-oncology Working Group
(RANO) will at least qualitatively consider enlarging areas
of nonenhancing tumor as evidence of tumor progression.14
Using a novel tool to analyze recurrence patterns in
a group-wise manner,15 we sought to answer the following questions: first, do antiangiogenic treatments enhance
distant tumor spread compared with classical salvage regimens; second, how do FLAIR and T1þc magnetic resonance response patterns correlate in BEV-treated versus
non–BEV-treated patients?
treated without anti-VEGF regimens (n ¼ 44) from Heidelberg
(for ethical considerations see Supporting Information text 1) were
generated according to histology, tumor location, size, and contrast
enhancement pattern, and number and type of prior therapies (Table 1 and Supporting Information text 2).
Analysis of Tumor Location, Size,
and FLAIR/T1 Correlations
The group-wise analysis was carried out as detailed.15 For the
case-by-case analysis, a distant recurrence on T1þc or FLAIR
sequences was defined as 1 of the following: (a) qualitative
assessment of well-defined recurrence centered outside a 2cm
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, or (c) new involvement of the contralateral hemisphere.15 (d) A diffuse recurrence was defined as a recurrence
with at least 50% of the tumor mass with indistinct edges
located outside the borders of the original contrast-enhancing
tumor on T1-weighted images plus a 2cm margin plus a shift of
the center of mass by more than half of the diameter of the pretreatment tumor15 (Fig and Supporting Information text 3).
Statistics
A McNemar test was conducted to determine if the 2 treatments influenced the size or location of the recurrent tumors
relative to baseline. Forty pairs were determined to be sufficient
to detect a 30% difference, which was regarded as clinically
meaningful, with a power of 80%. For the FLAIR/T1þc correlations, Pearson product moment correlations were used before
and after treatment at the prespecified 3-month intervals for
T1þc and FLAIR areas for the group as a whole using JMP
7.0 software. Probability values of p < 0.05 were considered
significant.
Results
Patient Characteristics and Outcome
Forty-four matched pairs were analyzed. They had a median of 3 (range, 1–5) prior relapses and treatments (see
Table 1). The median area of the tumors depicted on
T1þc or FLAIR was larger in the BEV treatment group:
1,245mm2 (BEV) versus 975mm2 (non-BEV) for T1þc
(p ¼ 0.041) and 3,984mm2 (BEV) versus 3,681mm2
(non-BEV) for FLAIR (p ¼ 0.045). Complete response
(CR) or partial response (PR) according to RANO criteria14 were seen in 32% (BEV) and 7% (non-BEV) (p ¼
0.7). Median PFS with treatments compared here was
6.2 (BEV) and 4.9 (non-BEV) months (Supporting Information text 4).
Patients and Methods
Patients and Eligibility
To assess the impact of BEV on the recurrence pattern, matched
pairs of BEV-treated patients with progressive or recurrent malignant glioma (n ¼ 44) from Heidelberg and Zurich and patients
March 2011
Group-Wise Analysis
To investigate whether there were preferred directions of
tumor growth in the BEV versus the non-BEV group, the
tumor locations at baseline were subtracted from the
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TABLE 1: Patient Characteristics
Characteristic
Bevacizumab, n 5 44
Control, n 5 44
Median age, yr (range)
47 (28–75)
52 (31–72)
Sex, No., female/male
13/31
19/25
Histopathology, No.
44
44
Anaplastic oligodendroglial tumors
5
5
Anaplastic astrocytoma
8
8
Glioblastoma
31
31
Median Karnofsky performance status, % (range)
80 (50–100)
80 (50–100)
Steroid use at start of treatment, yes/no
18/26
20/24
8
8
3 (1–5)
3 (1–5)
1
7
7
2
16
16
3
14
14
4
5
5
5
2
Median dose, mg
a
No. of prior regimens, median (range)
2
b
Concurrent chemotherapy, No. (%)
Irinotecan
24/44 (54)
Lomustine
6/44 (14)
Concurrent radiotherapy, No. (%)
2/44 (5)
Bevacizumab monotherapy, No. (%)
12/44 (27)
There were a median of 2 relapses (range, 1–5).
a
Prior regimens in both groups included for glioblastoma (n ¼ 31) treated with bevacizumab: 4/31 RT, 18/31 RT/TMZ, 6/31
RT/TMZ/cetuximab, 3/31 RT/enzastaurin as first treatments; 7/29 TMZ, 18/29 TMZ 1 week on/1 week off, 4/29 PCV as second
treatments; 12/21 ACNU/VM26, 5/21 TMZ 1 week on/1 week off, 4/21 re-RT as third treatments; 3/7 re-RT, 3/7 temsirolimus,
1/7 ACNU as a fourth treatment; 2/2 TMZ at a daily continous schedule as a fifth treatment. Control: 5/31 RT, 21/31 RT/
TMZ, 4/31 RT/TMZ/cetuximab, 1/31 RT/enzastaurin at first treatments; 10/29 TMZ, 16/29 TMZ 1 week on/1 week off, 3/29
PCV at second treatments; 11/21 ACNU/VM26, 6/21 TMZ 1 week on/1 week off, 4/21 re-RT as third treatments; 2/7 re-RT, 3/
7 temsirolimus, 2/7 ACNU as a fourth treatment; 2/2 TMZ at a daily continous schedule as a fifth treatment. Prior regimens in
both groups included for anaplastic gliomas (n ¼ 13): 6/13 RT, 5/13 TMZ, 2 RT/TMZ at first treatments; 6/8 TMZ, 2/8 RT at
second treatments; 1/1 re-RT/TMZ as third treatment.
b
Comparator regimens for glioblastoma in the control group (matched pairs): 10/31 TMZ, 8/31 ACNU (Nimustine) þ VM26
(Teniposide) or Ara-C, 5/31 temsirolimus, 4/31 PCV, 4/31 re-RT. Comparator regimens for anaplastic gliomas in the control
group (matched pairs): 6/13 ACNU/VM26, 4/13 TMZ 1 week on/1 week off, 1/13 PCV, 2/13 re-RT (þTMZ in 1 patient).
RT ¼ radiotherapy; TMZ ¼ temozolomide; re-RT ¼ second radiotherapy at recurrence; PCV ¼ procarbazine, vincristine, and
lomustine.
superimposed tumor locations at failure in each treatment
group.15 For both treatment groups, we found no anatomical shift of tumor locations after treatment. In summary,
the group-wise approach did not reveal differences in the
recurrence pattern (local vs distant) in the BEV-treated
versus the non–BEV-treated group (p ¼ 0.78).
Case-by-Case Analysis of Recurrence Pattern
At the recurrence qualifying for inclusion in this analysis,
20.5% (9 of 44) of BEV-treated and 22.7% (10 of 44)
588
of non–BEV-treated patients had displayed distant or diffuse recurrence on T1þc. Distant or diffuse recurrences
at failure with the treatments of this analysis were
observed in 22% (10 of 44, BEV) and 18% (8 of 44,
non-BEV) of the patients on T1þc and in 25% (11 of
44, BEV) and 18% (8 of 44, non-BEV) of the patients
on FLAIR sequences (p > 0.05, t test) (Table 2 and Supporting Information text 5). Of note, there was no difference when grade III and grade IV tumors with versus
without BEV treatments were compared in these analyses
(T1þc: p ¼ 0.11; FLAIR: p ¼ 0.09).
Volume 69, No. 3
Wick et al: Bevacizumab and Remote Relapse
FIGURE: Representative images show a local recurrence; a distant, well-defined recurrence; new involvement of the contralateral hemisphere; and a diffuse, not well-delineated gliomatosislike recurrence in T1 contrast-enhanced (T11c) and fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging.
T1þc/FLAIR Concordance?
There is ongoing discussion about discordant information provided by T1þc and FLAIR images in patients
treated with BEV compared with non–BEV-containing
regimens.13,14
Pearson product moment correlation (r) was significant between the imaging modalities for both groups
before, during, and after therapy, both in BEV-treated
and in control patients. The correlation between T1þc
and FLAIR areas in the BEV group was similar on the
MRI on which the progression was diagnosed (post-BEV
MRI), as on the pre-BEV MRI (r ¼ 0.61 vs r ¼ 0.57).
The same was seen for the control group (post: r ¼
0.73; pre: r ¼ 0.7). The correlation of the 12 of 44
patients treated with BEV monotherapy revealed no difference from the other groups either (pre-BEV MRI: r ¼
0.63; post-BEV MRI: r ¼ 0.71). A representative subMarch 2011
group of the BEV patients (n ¼ 22) was studied in more
detail. At weeks 1 and 6, there was a discrepancy between
the responses in the T1þc-weighted MRI and FLAIR
images. Edema-equivalent FLAIR signal was reduced by
>50% in only 43% of patients with CR/PR in the T1þc
images, resulting in discordant T1þc and FLAIR information at these time points (Table 3). However, even in the
responding patients of the full cohort (n ¼ 44), the best
results of the MRI performed every 3 months did not show
a discrepancy between T1þc and FLAIR when the patients
were at least stable (CR þ PR þ stable disease) according
to RANO criteria (r ¼ 0.66, p < 0.05) (Table 4).
Discussion
A major concern with antiangiogenic treatments for glioblastoma is transformation of a proangiogenic into a
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TABLE 2: Matched Pairs Recurrence Patterns
Patterna
MRI Sequence
Totalb
a, No.c
b, No.c
c, No.c
d, No.c
BEV (n ¼ 44)
T1þc
10
10
3
5
4
8
8
2
4
3
11
6
3
5
5
8
5
2
2
4
Non-BEV (n ¼ 44)
BEV (n ¼ 44)
FLAIR
Non-BEV (n ¼ 44)
a
According to Patients and Methods.
Total of distant or diffuse recurrences.
c
a–d refer to patterns of progression defined in the Patients and Methods section.
MRI ¼ magnetic resonance imaging; BEV ¼ bevacizumab; T1þc ¼ T1 contrast-enhanced; FLAIR ¼ fluid-attenuated inversion
recovery.
b
promigratory phenotype, resulting in more diffusely infiltrating tumors and finally more neurological morbidity
after an initial phase of symptom relief.16 Further, there
is concern from earlier clinical observations that antiangiogenic treatment may prevent the formation of a tumor
bulk, but may not be effective against progression in the
infiltrative zone, which is held responsible for morbidity
and survival.9,17 Diffusely infiltrative recurrence18 may
escape classical T1þc MRI response assessments. Preclinical data suggest vascular co-option as an escape mechanism for antiangiogenic treatments. This is challenged by
the fact that the area infiltrated by these tumor satellites10,16,19 may not exceed the area of the untreated control tumors, and antiangiogenic agents nevertheless results
in impressive effects on OS in animal models.8,11,20 Clinical data are not supportive of the notion of specifically
enhanced invasiveness with BEV treatment, although
there are slight differences in the methodology.21,22 Our
approach is consistent with the analysis of the BRAIN
trial1 except for a lesser variance (<2cm instead of
<3cm) in the definition of local recurrence and the addition of the group-wise analysis. The distant recurrences
were between 20 and 30% and not predictive for a poor
outcome compared to patients with local recurrences.22
Although Norden et al13 did not demonstrate a difference in recurrence patterns, they concluded that there
might occur a relevant discordance between the T1þc
and the FLAIR appearance of the recurrent BEV-treated
tumors. They observed an increase in the FLAIR lesions
especially in patients who had at least a minor response
in T1þc. Hence, in the era of antiangiogenic treatments,
contrast enhancement may not reliably signify tumor
response. There is thus a need to account for the nonenhancing component of the tumor to accurately assess the
efficacy of novel therapeutic modalities.14
The obvious discrepancy of our recurrence analysis
from published observations13,23 might be explained by
analyses of individual patients over time at smaller intervals and their focus on responding patients only (see also
Supporting Information text 6).
The 2 groups selected for matched pair analysis
were well balanced. Moreover, potential influencing factors like different PFS with the BEV versus control treatments or tumor size prior to this analysis were, if at all,
TABLE 3: Responses Over Time in a Subgroup of Bevacizumab Patients
MRI Sequence
Time, wk
CR
PR
SD
PD
T1þc
1 (n ¼ 22)
0
21 (95%)
1 (5%)
0
6 (n ¼ 22)
1 (5%)
14 (64%)
7 (31%)
0
12 (n ¼ 21)
1 (5%)
6 (29%)
11 (52%)
3 (14%)
1 (n ¼ 22)
0
9 (41%)
9 (41%)
4 (18%)
6 (n ¼ 22)
0
8 (36%)
11 (50%)
3 (14%)
0
7 (33%)
11 (52%)
3 (14%)
FLAIR
12 (n ¼ 21)
14
Responses are according to RANO criteria.
MRI ¼ magnetic resonance imaging; CR ¼ complete response; PR ¼ partial response; SD ¼ stable disease; PD ¼ progressive
disease; T1þc ¼ T1 contrast-enhanced; FLAIR ¼ fluid-attenuated inversion recovery.
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TABLE 4: T11c/FLAIR Correlations
FLAIR, Start
T1þc
T1þc
BEV, n 5 44
Control, n 5 44
0.61
0.57
FLAIR, 3 mo,
BEV-Responding,14 n 5 36
0.66
FLAIR, Recurrence14
BEV, n 5 44
Control, n 5 44
0.73
0.7
BEV monotherapy, n ¼ 12
BEV monotherapy, n ¼ 12
0.63
0.71
Correlations between the maximal extension on T1þc and FLAIR images at 3-month intervals to identify the occurrence of a gliomatosislike growth pattern were analyzed. The analysis resulted in T1þc and FLAIR planes for each individual patient at the time
of treatment initiation and at recurrence.
T1þc ¼ T1 contrast-enhanced; FLAIR ¼ fluid-attenuated inversion recovery; BEV ¼ bevacizumab.
against the hypothesis. This is because a longer time to
progression would allow more distant recurrences to develop if a specific proinvasive mechanism was happening.
Therefore, and because anaplastic gliomas with a generally
longer time to progression have been treated in an uncontrolled trial24 and will be included into the European Organization for Research and Treatment of Cancer 26091
trial comparing BEV plus temozolomide with temozolomie
alone in recurrent grade II and III gliomas (www.eortc.be,
accessed September 22, 2010), it was regarded as important that the current retrospective study also included anaplastic gliomas. Larger tumors are also more likely to meet
the criteria for progression in this analysis.
We also addressed the issues of discordance of
T1þc and FLAIR information and the occurrence of a
T1þc-negative and a gliomatosislike phenotype on
FLAIR images upon treatment with BEV (see Table 4).
Our data challenge the view that BEV treatment systematically leads to a situation where the T1þc measurements demonstrate stability or even regression and the
FLAIR measurements demonstrate more hyperintensity,
either to edema or to infiltrative tumor. We demonstrate
that T1þc measurements are significantly associated with
FLAIR image measurements, and that this association is
durable during the phase of stability or response and at
progression (see Tables 1 and 2). A subgroup analysis
confirmed that the absence of discordance in BEV-treated
patients was not an effect of the parallel chemotherapy,
because a small group of patients treated with BEV alone
(n ¼ 12) also showed concordant T1þc/FLAIR information. In a similar analysis from the BRAIN trial,1 there
was even a larger shift in the recurrence pattern from
local to distant or diffuse in the BEV þ irinotecan arm
as compared to BEV alone.22 More discordance is only
seen in the early response phase, in which a steroidlike
effect of BEV is potentially more relevant than at later
stages. However, a definitive differentiation between the
March 2011
FLAIR hyperintensity-comprising components is only possible with biopsies or at autopsy and would probably reveal
a mixture of edema, treatment-related leukoencephalopathy,
gliosis, and infiltrative tumor.20 A separate recognition of
T2/FLAIR changes in the context of antiangiogenic treatments as proposed by the RANO criteria14 remains an
open and important issue for prospective evaluation.
After the first approaches to study recurrence patterns with BEV treatment,13,21,22 which also suggest no
specific proinvasive property of BEV, the current study is
the first controlled analysis of patterns of BEV failure in
recurrent malignant glioma patients. Our findings argue
against a clinically relevant propensity of BEV to induce
clinically meaningful and T1þc MRI-negative invasiveness as demonstrated by FLAIR images.
Acknowledgments
This study was supported by the Hertie Foundation and
the Olympia Morata Program of the Medical Faculty in
Heidelberg (A.W.).
Authorship
W.W. was the principal investigator and together with M.W.
designed the project. A.W. was the coinvestigator, and
collected and assessed data together with N.S., D.S., S.
Hofer, and M.P. A.W. performed data analyses, and with
W.W. and M.W. prepared the statistics and wrote the draft of
the article. N.D., S. Heiland, and M.B. were neuroradiology
coinvestigators and took part in the data collection and
analyses. All authors were involved in writing the final report.
Potential Conflicts of Interest
M.P.: advisory board for Miltenyi Biotech and speakers
honoraria from Merck Serono, Sigma Tau, and Miltenyi
Biotech (each below $2,000); unrestricted research
funding from Merck Serono and Nuon Therapeutics for
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projects unrelated to the current article. M.W.: advisory
boards for Astra Zeneca, Bayer Schering, BMS (Bristol
Myers Squibb), MSD (Merck Sharp & Dohme), Merck
Serono, Miltenyi Biotech, Roche/Genentech, and Schering-Plough (each below $3,000); speakers honoraria from
Merck Serono and Schering-Plough (each below $2,000);
unrestricted research funding from Merck Serono and
MSD for projects unrelated to the current article. M.B.:
advisory boards for Roche/Genentech (below $3,000).
W.W.: advisory boards for Astra Zeneca, BMS, MSD,
Merck Serono, Pfizer, Roche/Genentech, and ScheringPlough (each below $3,000); speakers honoraria from
Merck Serono, MSD, Roche, Schering-Plough, and
Wyeth/Pfizer (each below $2,000); unrestricted research
funding from Eli Lilly and MSD/Schering-Plough for
projects unrelated to the current article.
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