Journal of the Egyptian National Cancer Institute (2016) xxx, xxx–xxx
Cairo University
Journal of the Egyptian National Cancer Institute
www.elsevier.com/locate/jnci
www.sciencedirect.com
Review
Management of glioblastoma after recurrence:
A changing paradigm
Supriya Mallick *, Rony Benson, Abdul Hakim, Goura K. Rath
Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi, India
Received 15 May 2016; revised 30 June 2016; accepted 3 July 2016
KEYWORDS
Recurrent;
Glioblastoma;
Re-irradiation;
Bevacizumab;
Chemotherapy;
NovoTTF
Abstract Glioblastoma remains the most common primary brain tumor after the age of 40 years.
Maximal safe surgery followed by adjuvant chemoradiotherapy has remained the standard treatment for glioblastoma (GBM). But recurrence is an inevitable event in the natural history of
GBM with most patients experiencing it after 6–9 months of primary treatment. Recurrent GBM
poses great challenge to manage with no well-defined management protocols. The challenge starts
from differentiating radiation necrosis from true local progression. A fine balance needs to be maintained on improving survival and assuring a better quality of life. Treatment options are limited and
ranges from re-excision, re-irradiation, systemic chemotherapy or a combination of these.
Re-excision and re-irradiation must be attempted in selected patients and has been shown to
improve survival outcomes. To facilitate the management of GBM recurrences, a treatment algorithm is proposed.
Ó 2016 National Cancer Institute, Cairo University. Production and hosting by Elsevier B.V. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Search methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Diagnosis of a recurrence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Selection of patients for retreatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Surgical salvage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Re-irradiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Bevacizumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Nitrosureas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Temozolomide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Novel treatment techniques. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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* Corresponding author. Fax: +91 11 26589243.
E-mail address: drsupriyamallick@gmail.com (S. Mallick).
Peer review under responsibility of The National Cancer Institute, Cairo University.
http://dx.doi.org/10.1016/j.jnci.2016.07.001
1110-0362 Ó 2016 National Cancer Institute, Cairo University. Production and hosting by Elsevier B.V.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: Mallick S et al. Management of glioblastoma after recurrence: A changing paradigm, J Egyptian Nat Cancer Inst (2016), http://dx.
doi.org/10.1016/j.jnci.2016.07.001
2
S. Mallick et al.
Impact of anti-epileptic drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Management of recurrent GBM in elderly and pediatric patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Quality of life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Disclosures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Meeting presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Financial support. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Levels of evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction
Glioblastoma (GBM) is the most common primary brain cancer in the age group after 40 years and the prognosis gets worse
as the age increases. The land mark trial by Stupp et al. led to
acceptance that maximal safe surgery followed by adjuvant
chemoradiotherapy and adjuvant chemotherapy to be the
standard of care [1]. But local infield recurrence is an inevitable
event, with most patients experiencing it after 6–9 months of
primary treatment because of resistant GBM stem cell and
neuronal stem cells, suboptimal mean dose to the ipsilateral
subventricular zone (SVZ) or involvement of corpus callosum
[2,3]. Different molecular factors like P53 mutation, MIB-1
labeling index, and O-6-methylguanine-DNA methyltransferase (MGMT) methylation have been correlated with recurrence in GBM [4,5]. The various radiation treatment protocols
with dose escalation beyond 60 Gy have been unsuccessful and
have led to increased toxicity. There has been much controversy in the diagnosis of recurrence with the definitive diagnosis only via histopathological examination. But most of the
patients with imaging finding suggestive of progression may
not be fit for a surgical procedure, making the diagnosis of
recurrent GBM difficult. The main differential diagnosis
includes radiation necrosis which also occurs at the same time
period and may be symptomatic thus mimicking progression.
But the recent advances in imaging have helped us in a great
way in differentiation between the two. The treatment of recurrent glial tumors has always been challenging and is associated
with significant toxicities and always a balance has to be
achieved between local control and treatment related morbidities and mortalities [6,7].
Surgery remains an important therapeutic strategy. However, only a small proportion of patients are found eligible
for a total surgical resection. Re-irradiation (ReRT) has
evolved as a salvage option in the last decade [8]. Evolution
of new radiotherapy techniques and better image guidance
may help in giving highly conformal doses and thus limiting
toxicity. Chemotherapy has also been used by various groups
with an aim to improve survival outcomes. But despite these
various treatment options, outcome of these patients has
remained dismal [9–11]. There has been some recent interest
with some new modalities showing promising results available
for some of these. But the presence of the blood–brain barrier
(BBB) limits the delivery of most chemotherapeutic agents
[12,13]. However, most of the treatment regimens have surfaced with single institute retrospective analysis or few phase
II clinical studies. So, there hardly exists any standard treat-
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ment. In this review we intend to review available investigations for the diagnosis and treatment modalities with
meaningful impact on survival and derive a possible therapeutic algorithm for patients with recurrent GBM.
Search methodology
We searched the PubMed for literature of recurrent glioblastoma. We used the following MeSH terminology: recurrent
glioblastoma retrieved 2023 entries; recurrent glioblastoma
AND treatment retrieved 1775 entries (4 phase III, 230 Phase
II, 104 phase I study, 2-metaanalysis). We retrieved a total of
57 articles pertaining to recurrent glioblastoma AND reirradiation but none of these were a phase I/II study. Only 16 found
to describe retrospective result of treating recurrent GBM with
reirradiation. We also searched for recurrent glioblastoma
AND surgery we retrieved 31 entries with one phase II study.
There were 56 entries for the MeSH term of recurrent glioblastoma AND vaccine out of which only fourteen described a
phase I/II study. 187 phase I/II and 2 phase III trials described
chemotherapy/targeted therapy for rGBM.
Diagnosis of a recurrence
Diagnosing a recurrence in GBM patients remains a challenge
with radio necrosis closely resembling changes of recurrence
on imaging. Examination of the surgically resected specimen
remains the gold standard for the diagnosis of radiation necrosis. The picture is in fact further complicated by coexistence of
both in many cases. The new advances in radiology and
nuclear medicine may help in some cases to differentiate these
entities. A good clinical judgment along information from
these various imaging modalities may help us in majority of
the cases.
Combination of contrast enhanced (CE) T1-weighted imaging, diffusion-weighted (DW) imaging, and perfusion MR
imaging resulted in significantly better diagnostic accuracy
without much impact from selection of perfusion MR method
(dynamic CE [DCE]) vs dynamic susceptibility CE) [14]. In
magnetic resonance spectroscopy (MRS) tumor recurrence is
characterized by a higher Choline (Ch)/N-acetylaspartate
(NAA) and Ch/(creatine) Cr ratio but a low NAA/Cr ratio.
Lower lipid signals in MRS are also characteristic of tumor
recurrence. Hence, the presence of elevated lipid signals along
with low choline/NAA ratios may help to differentiate radiation changes from tumor recurrence [15]. Relative cerebral
Please cite this article in press as: Mallick S et al. Management of glioblastoma after recurrence: A changing paradigm, J Egyptian Nat Cancer Inst (2016), http://dx.
doi.org/10.1016/j.jnci.2016.07.001
Management of Glioblastoma after recurrence
Table 1
3
Comparison of imaging characteristics of Recurrent Glioblastoma vs. Radio necrosis.
Radiation necrosis
Glioma recurrence
Magnetic Resonance ImagingSuggestive features
Usually in the areas of high dose (>60 Gray)
Can occur anywhere, But infield recurrence
is the most common
Contrast enhancement, edema, and mass effect may be seen in both
Classical Swiss cheese appearance
Unlikely
Less likely
Involvement of corpus-callosum or peri-ventricular
white matter
Magnetic Resonance Spectroscopy
[17]
Low Cho/NAA <1.11
Low Ch/Cr ratio <1.17
Elevated lipid signals
High Cho/NAA >1.11
High Ch/Cr ratio >1.17
Low lipid signals
Diffusion weighted magnetic
resonance imaging [18]
Higher apparent diffusion coefficient (ADC)-maxima ADC in range of 2.3
Lower ADC values in range of 1.7
Perfusion magnetic resonance
imaging [19]
Cerebral blood volume (CBV) <0.6
Higher fractional anisotropy(FA) values- 0.89
± 0.15
CBV usually more than 2.6
Lower fractional anisotropy(FA) values0.74 ± 0.14
Positron Emission Tomography
Low metabolic activity
High metabolic activity
Single Photon Emission Computed
Tomography
Low metabolic activity
High metabolic activity
blood volume (CBV) in perfusion images is also helpful to differentiate radiation necrosis and recurrence with a high relative
CBV (more than 2.6) for tumor and low CBV (usually <0.6)
for radiation necrosis. Positron emission tomography (PET)
image tumor shows more metabolic activity compared to radiation necrosis. However a low image resolution remains the
limiting factor but this may be overcome with integration of
MRI or computed tomography with PET scans. Tc-GH
SPECT/CT is not inferior to F-FDOPA PET/CT for detection
of recurrence and can be used as a low-cost alternative [16].
The radiological features of radiation necrosis vs. recurrence
of tumor are summarized in Table 1.
Selection of patients for retreatment
A number of factors have been evaluated to correlate with the
prognosis of patients [17–20]. In a recent review Weller et al.
found Karnofsky performance score (KPS) >60, tumor size
<4 cm and progression after >6 months to confer better survival [20]. These factors may also be helpful in selecting suitable patients for treatment also. Those patients who have a
young age, recurrence occurring after 6 months and with good
performance status may be selected for an aggressive
approach. Size of the lesion at the time of recurrence and presence of symptoms, may be also the factors taken into account
when planning for an aggressive approach. Surgical approach
helps in getting the final diagnosis and early relief of symptoms
in the patient.
Surgical salvage
Surgery in recurrent GBM is aimed to reduce the tumor bulk
and achieve symptom relief. It also helps us in the definitive
diagnosis of a recurrence and repeat morphological and evaluation helps us in evaluating for tumor heterogeneity which is
common in brain tumors. Salvage surgery alone has yielded
short term disease control only and literature authors have
found surgery to increase morbidity in a recurrent setting
[20]. However, Bartsch et al. reported improved survival for
patients treated with surgery as a component of the salvage
therapy [21]. In a study by Sughrue et al. it was found that
the median PFS was 7.8 months, 6.0 months, and 4.8 months
following the second, third, and fourth-sixth craniotomies,
respectively [22]. Bloch et al. reported median PFS after resurgery: GTR 11.3 month’s vs. STR 6.7 months [23]. They
found that age, performance status and extent of resection at
repeat surgery to be significant factors influencing survival.
Franceschi et al. in a recent series also failed to show a survival
advantage with re-surgery [24].
In the earlier reported studies there was little agreement to
the importance of surgery as salvage treatment and survival
benefit associated with it. The tumor extension to eloquent
areas and lack of intraoperative imaging were drawbacks in
these series. However intraoperative neuro navigation and
use of 5 Aminolevulinic acid (ALA) as guide to resect tumor
helps in reducing the toxicity and improving the tumor control.
In the recently reported series authors have a reported survival
benefit of complete tumor resection which appears appealing
but the better results may be attributable to selection bias.
The principles of surgery in recurrent setting must follow those
of the upfront setting. A maximal safe surgery must be
attempted and intra operative use of ultrasound and cavitron
ultrasonic surgical aspirator must be encouraged. As the
patients get symptom relief and are associated with improved
survival surgical resection must be done in all patients found
suitable based on available evidence. The added advantage is
that a confirmatory diagnosis of tumor recurrence is got.
Re-irradiation
Re-irradiation may be done in patients with small volume
recurrence, if far from the primary area of irradiation, if surgery is not possible due to eloquent location of the tumor.
Another factor that should be assessed before re-irradiation
is the time period of recurrence and first irradiation the longer
the interval the better may be the outcome [25]. Re-irradiation
Please cite this article in press as: Mallick S et al. Management of glioblastoma after recurrence: A changing paradigm, J Egyptian Nat Cancer Inst (2016), http://dx.
doi.org/10.1016/j.jnci.2016.07.001
4
has also been tried in surgery to improve outcomes and must
be given to patients who are found suitable. The major issue
with the use of radiation is the anticipation of debilitating toxicity in the form of radiation necrosis [25]. The radiation tolerance is the most important limiting factor [26]. However, in the
last decade there was a paradigm shift in the understanding
and practice of radiation for recurrent gliomas [26,27].
Re-irradiation may be done by external beam radiotherapy
or by brachytherapy. Most of the published literature on reirradiation has used external beam radiotherapy. Newer treatment techniques enable delivery of radiation more precisely to
the target without crossing the tolerance of normal surrounding structure [10,28–30]. MRI, SPECT and PET images found
are of real help for target delineation. Sminia et al. recently
reviewed all published data of re-irradiation to compare the
impact of conventional, stereotactic radiotherapy (SRT)/
surgery (SRS) in the management of recurrent glioma [31].
The review compiled the published literature to show that
across different re-irradiation series the dose prescribed ranged
from 20 to 45.5 Gy with recurrence equivalent total dose
(rEQD2) 30–51.3 Gy. The total equivalent radiation dose
(EQD2) was 81.6–102.8 Gy. The PFS ranged from 6.2 to
27.5 months with maximum 6% radiation necrosis [31].
Radio-necrosis in retreated glial tumor is the most fearful complication. However, in the published literature only a handful
of evidence exists reporting radio necrosis. The paucity of true
incidence and its reporting can also be attributed to truncated
follow up. Ramona Mayer et al. in a review correlated radiation necrosis to be commoner with normalized total dose of
more than 100 Gy [25]. Survival after re-irradiation varies
widely with a median DFS 7–9 months reported across the different studies. However, it should be noted that patient characteristic is variable in different cohorts.
The target volume is generally the contrast enhancing tumor
volume that is contoured as the gross tumor volume (GTV). A
5 mm margin around the GTV is generally given to form the
clinical target volume. Whenever possible the MRI of the
patient must be fused to the planning CT for better target delineation. The dose to be prescribed must depend on various factors like time since the previous irradiation, volume of
recurrence, location of recurrence and dose and fractionation
used in the first plan. The other factor that should be taken into
consideration when planning for re-irradiation is the proximity
to the brain stem and optic structures. Generally the cumulative
EQD2 is kept at around 100 Gy. The dose prescribed for reirradiation in most of the studies has ranged from 30 Gy to
45 Gy. The dose prescribed should be individualized for each
patient depending on the above mentioned factors.
Although re-irradiation can be tried after a time period of
6 months the ideal case would be a patient recurring after
2 years. The tolerance of various critical structures during reirradiation is also an area of great concern and there is a lack
of convincing data on the same. The tolerance of the critical
structures like brain stem and optic structures is usually
reached in the first irradiation. The recovery of these neural
structures is not as other organs in the body and is limited.
But there are animal models which have shown good recovery
of these structures. Keeping a cumulative EQD2 of less than
80 Gy for the optic structures and EQD2 of 90 Gy for the
brain stem would be logical for these patients, although convincing data are not available. The EQD2 for the rest of the
brain may be kept below 90–100 Gy. But these should be indi-
S. Mallick et al.
vidualized for each patient depending on various factors like
dose and fractionation schedule of the first irradiation, time
that has elapsed and presence of any radiation changes in
imaging of these patients. This should also take into account
the expected survival of these patients, as these patients with
recurrent GBM are having very poor survival a more liberal
risk of toxicity may be accepted in some patients.
The technique to be used for re-irradiation varies from 3dconformal radiotherapy to intensity modulated radiotherapy.
Most of the current published literature uses stereotactic techniques for re-irradiation of these patients. When using 3-D
conformal techniques one should be careful to use a different
field arrangement than the one used for initial irradiation.
Generally intensity modulated radiotherapy with good immobilization is preferred for such patients. A summary of the
major trials which have used external beam radiotherapy for
re-irradiation is summarized below in Table 2. Brachytherapy
is also being evaluated as a treatment option for recurrent
GBM. In a large series Kickingereder et al. reported experience
of treating inoperable primary and recurrent glioblastoma with
low-dose rate stereotactic iodine-125 brachytherapy [30]. Median cumulative surface dose was 60 Gy; and median dose-rate
6 cGy/h. In addition to brachytherapy, 90.3% of patients in
the primary treatment group received external boost radiotherapy (median dose, 25.2 Gy) and 30.8% received adjuvant
chemotherapy with Temozolomide being the most commonly
used drug. The authors reported impressive 10.5 and
6.2 months median OS and PFS rates respectively and Karnofsky performance score, age, and adjuvant chemotherapy were
reported as independent prognostic factors [30]. Archavlis
et al. in another retrospective study compared high dose rate
(HDR) brachytherapy to re-surgery and dose dense temozolomide for recurrent GBM patients. The HDR-brachytherapy
consisted of an after loading 192Ir implant which delivered a
median dose of 40 Gy [32–52] at twice-daily fractions of
5.0 Gy to a CT-MRI fusion-defined planning treatment volume. The authors reported a median survival 37, 30 and
26 weeks after salvage therapy of the recurrence was, respectively with no added complication in the HDR brachytherapy
group [33].
There is no consensus on what technique is used in reirradiation. The poor survival in these patients along with
the invasive nature of brachytherapy leads to external beam
radiotherapy being preferred by most. But brachytherapy is
a very promising form of radiotherapy with good conformal
dose distribution and may be tried in superficial tumors. But
the lack of expertise is a major limiting factor.
The role of adjuvant radiotherapy after re-excision also
remains as an area of conflict of interest. There may be benefit
of adjuvant radiotherapy in patients who have undergone a
resection other than a gross total resection. The benefit of
adjuvant radiation after gross total excision remains a debatable issue. When planning a patient for re-irradiation the additional toxicity associated must be kept in mind. There is no
consensus adjuvant radiation and may have role of radiation
and chemo on a case to case basis.
Chemotherapy
In the recent years different chemotherapeutic drugs have been
used in patients with recurrent GBM improve disease control
Please cite this article in press as: Mallick S et al. Management of glioblastoma after recurrence: A changing paradigm, J Egyptian Nat Cancer Inst (2016), http://dx.
doi.org/10.1016/j.jnci.2016.07.001
Management of Glioblastoma after recurrence
Table 2
5
Summary of the major trials which have used external beam radiotherapy for re-irradiation.
Study
Radiation
technique
Radiation dose
Concurrent
Survival outcome
Toxicity
Henke et al. [26]
n = 31
Niyazi et al. [34]
n = 30
Cho et al. [28]
n = 71
3d-CRT
20 Gray over 1 week
Nil
No severe toxicity
Conventional
36 Gray in 18
fractions
Median dose
37.5 Gy in 15
fractions -FSRT
17 Gy -SRS
24–35 Gray at 3.0–
3.5 Gy per fraction
Bevacizumab
Temozolomide
Nil
Median overall survival10.2 months
Median survival was
311 days
Median OS
11 months - SRS
12 months FSRT
Nil
Median OS 10.5 months
Wound dehiscence 5%
Grade III DVT 5%
Late complication rate
23%
Worsening of
neurological deficit 41%
No grade 3 toxicities
Paclitaxel
Overall median survival
was 7.0 months
8% incidence of radiation
necrosis
Adjuvant
Temozolomide
in 60%
Nil
Overall median survival
was 8.0 months
No acute Grade 3/4
neurologic and
hematologic toxicity
No higher than grade II
toxicity
Hudes et al. [35]
n = 20
Lederman et al. [36]
n = 88
Grosu et al. [10]
n = 44
Combs et al. [30]
n = 172
Fokas et al. [9]
n = 53
Fogh et al. [37]
n = 147
Minniti et al. [38]
n = 36
Van Kampen et al.
[39]
n = 27
Biswas et al. [38]
n = 18
Patel et al. [41]
n = 18
SRS vs. FSRT
Hypo fractionated
stereotactic
radiotherapy
Fractionated
stereotactic radio
surgery
Fractionated
stereotactic
radiotherapy
Fractionated
stereotactic
radiotherapy
Hypo fractionated
stereotactic
radiotherapy
Hypo fractionated
stereotactic
radiotherapy
Fractionated
stereotactic
radiotherapy
Stereotactic radio
surgery
Stereotactic radio
surgery
SRS or FSRT
Four weekly
treatments (median
dose: 6.0 Gy)
Six fractions of 5 Gy
Median dose of
36 Gy
Median overall survival
8 months for patients with
GBM
Median overall survival
9 months
Median total dose of
30 Gy (20–60 Gy)
Nil
Median dose, 35 Gy
in 3.5-Gy fractions
Nil
Median overall survival
9 months
No severe toxicity
7.5 Gy delivered in
15 fractions
Temozolomide
Median overall survival
9.7 months
8% incidence of radiation
necrosis
17 Gy in one fraction
Nil
Median survival 9 months
No severe toxicity
10–20 Gy in one
fraction
FSRT-36 Gy in six
fraction
SRS-18 Gy (range:
12–20 Gy) in one
fraction
Nil
Median survival
6.7 months
Median OS
8.5 months - SRS
7.4 months FSRT
No higher than grade II
acute side effects
No severe toxicity
[10,34]. A wide range of chemotherapy and targeted drugs
failed to show any benefit in phase I/II studies and limited
phase III studies as well (Table 3). Temozolomide, Bevacizumab, Nitrosureas are the agents that have shown moderate
activity in the treatment of recurrent GBM and further discussion will be on these efficacious regimens only. The patient
must be also assessed thoroughly before starting chemotherapy
in these patients with special attention to KPS, presence of
co-morbidities. The patients who have undergone a surgical
excision must undergo an immunohistochemical study for
the various predictive factors like MGMT methylation which
also help us in tailoring treatment. The chemotherapy may
be given alone or after surgery or along with and after radiotherapy in suitable patients.
Bevacizumab
Glioblastomas are highly vascularized tumors in which the
vascular endothelial growth factor (VEGF) signaling pathway
is upregulated. Bevacizumab is a humanized monoclonal
Nil
No higher than grade II
toxicity
antibody against circulating VEGF. Several phase I/II studies
reported high responses and improved 6-month progressionfree survival with Bevacizumab. Based on these results Bevacizumab, a vascular endothelial growth factor inhibitor
received FDA approval for use in recurrent gliomas. Subsequently, a better planned randomized phase 2 BRAIN trial
investigated bevacizumab alone and in combination with
irinotecan did not show a convincing benefit of Bevacizumab
compared with historical series [42]. The trial randomly allocated 167 patients with first or second relapse to receive
Bevacizumab monotherapy or in combination with Irinotecan. The primary end points were 6-months PFS and overall
response rate. The trial reported 6 months PFS 42.6% and
50.3% in the monotherapy and combination arm, and
ORR 28.2% and 37.8% respectively. Median Overall survival
was 9.2 months and 8.7 months respectively. Subsequently
two metaanalysis established 6-month progression-free survival rates 38–45% and median time to tumor progression
6.1 months. Addition of Irinotecan failed to improve survival
Please cite this article in press as: Mallick S et al. Management of glioblastoma after recurrence: A changing paradigm, J Egyptian Nat Cancer Inst (2016), http://dx.
doi.org/10.1016/j.jnci.2016.07.001
6
S. Mallick et al.
Table 3 Summarizes different agents used for the treatment of rGBM alone or in combination failed to achieve significant response in
phase I/II/III trials.
Drug/Phase
Type of drug
Verubulin/Phase II
Erlotinib + temsirolimus/PhaseII
Microtubule destabilizer and Vascular disrupting agent
Epidermal growth factor receptor (EGFR) and the
mechanistic target of rapamycin (mTOR)
Inhibitor of several receptor tyrosine kinases
VEGF inhibitor with Nitrosurea
Selective oral inhibitor of protein kinase Cb
Vascular endothelial growth factor receptor (VEGFR)
tyrosine kinase inhibitor
Multitargeted tyrosine kinase inhibitor
Kinase inhibitor of Src and Abl
av integrin antagonist
Inhibitor of VEGFR-2
PARP inhibitor
Antiangiogenic pazopanib; ErbB inhibitor lapatinib
Lipophilic oral camptothecin analog
Triple angiokinase inhibitor
Multi targeted tyrosine kinase inhibitor
Natural microtubule-stabilizing cytotoxic agent
Histone deacetylase (HDAC) inhibitor
Ras-MAPK signaling pathway inhibitor
VEGF Trap
Lipophylic and synthetic analog of epothilone B
A fully human monoclonal antibody against hepatocyte
growth factor/scatter factor (HGF/SF)
Protein-tyrosine kinase inhibitor that inhibits the BCR-ABL
tyrosine kinase
Natural product derived from the Caribbean Tunic inhibit all
phases of the cell cycle
Induces rapid and wholesale apoptosis through dual inhibition
of PPT1 and EEF1A1
A novel morpholino anthracycline with capacity to cross BBB
Putative inhibitor of angiogenesis
Enhances the polymerization of tubulin to stable microtubules
Nitrosourea
Matrix metalloproteinase inhibitor
Tricyclic carboxamide that intercalates DNA and inhibits
both topoisomerase I and II
Epidermal growth factor receptor tyrosine kinase inhibitor
Novel alkylating agent belonging to 1,2-bis(sulfonyl)
hydrazines class
Anti EGFR monoclonal Antibody
TGF-b2 inhibitor
Proteasome inhibitor
Nitrosurea in Wafer
Sunitinib/Phase II
Fotemustine/Phase I; Phase II
Enzastaurin/Phase II, Phase III
Cediranib/Phase III [monotherapy or in combination
with Lomustine]
Dasatinib/Phase II
Bosutinib/Phase II
Cilengitide/Phase II
CT-322/Phase II
Veliparib/Phase I
Pazopanib + Lapatinib/Phase II
Gimatecan/Phase II
Nintedanib/Phase II
Vandetanib/Phase II
Patupilone/Phase II
Vorinostat/Phase II; Romidepsin/Phase II
TLN-4601/Phase II
Aflibercept/Phase II
Sagopilone/Phase II
Rilotumumab/Phase II
Imatinib + hydroxyurea/Phase II
Didemnin B/Phase II
KRN8602(MX2)/Phase II
Thalidomide/Phase II
Paclitaxel/Phase II
Cystemustine/Phase II
Marimastat/Phase II
XR5000/Phase II
Gefitinib/Phase II; Erlotinib/Phase II
Cloretazine/Phase II
Cetuximab/Phase II
Trabedersen/Phase II
Bortezomib/Phase II
Convection-enhanced delivery (CED) of cintredekin besudotox
(CB) was compared with Gliadel wafers (GW)/Phase III
but increased the rate of treatment discontinuation [43,44].
The metaanalysis found no difference in bevacizumab dose–
response benefit between 5 mg/kg and 10 to 15 mg/kg. In
an interesting revelation Piccioni et al. reported non-inferior
outcome with deferred use of bevacizumab in recurrent
GBM [45]. In addition discontinuation of Bevacizumab for
reason other than tumor progression appears not to adversely
affect patient’s outcome [46]. This finding may have an
impact in curtailing the cost of care as well. Several phase
I/II studies have attempted to combine Bevacizumab with
Irinotecan, carboplatin, panobinostat, sorafenib, temsirolimus, Bortezomib, Gefitinib, Erlotinib, Cetuximab,
Lenalidomide, Nintedanib, and Veliparib but failed to show
improved outcome [47–51].
Nitrosureas
There is also few published literature reporting the efficacy of
Nitrosureas in recurrent GBM. These were generally retrospective series or phase II studies. Hence the phase II BELOB
trial randomly allocated 153 patients with recurrent GBM to
treatment with oral lomustine 110 mg/m2 once every 6 weeks,
intravenous bevacizumab 10 mg/kg once every 2 weeks, or
combination treatment with lomustine 110 mg/m2 every
6 weeks and bevacizumab 10 mg/kg every 2 weeks [52]. However, lomustine dose was reduced to 90 mg/m2 following high
rate of grade III/IV thrombocytopenia. The primary endpoint
was overall survival at 9 months, analyzed by intention to
treat. The trial reported a median survival of 4 months in the
combination arm compared to 3 and 1 month in the
Please cite this article in press as: Mallick S et al. Management of glioblastoma after recurrence: A changing paradigm, J Egyptian Nat Cancer Inst (2016), http://dx.
doi.org/10.1016/j.jnci.2016.07.001
Management of Glioblastoma after recurrence
Bevacizumab or Lomustine monotherapy arm. 6-month PFS
41%, 16%, 13% and median OS was 11, 8, 8 months respectively in the combination arm and the Bevacizumab or Lomustine monotherapy arm. This trial established an important
combination regimen of the Bevacizumab with Lomustine
which merits evaluation in phase III study. In addition the survival curves of the two monotherapy arm appear superimposed over each other and there by establish equal
effectiveness as monotherapy and may be used in a tailored
therapy. Another phase II AVAREG trial randomized patients
to receive bevacizumab (BEV) or fotemustine (FTM). The primary end point OS at 6 months was 62% and 73% for bevacizumab and fotemustine, respectively. OS9 (47% and 38%),
and median OS (8.7 and 7.2 months) was similar between fotemustine and bevacizumab arms [53]. These findings are also
not different to that of the BELOB trial.
Temozolomide
Metronomic Temozolomide has long been considered as an
important therapeutic option for recurrent GBM. Different
dose schedules 50 mg/m2 daily, 120 mg/m2 one week on and
one week off or 80 mg/m2 three weeks on and one week off
have been used. In a well-designed phase II RESCUE trial
metronomic dose of Temozolomide was used for recurrent
glioma. The study revealed significant survival benefit for
patients recurring during the course of adjuvant Temozolomide or after longer interval [54]. Grosu et al. in a series of
44 patients administered Temozolomide to 29 patients. Temozolomide was administered one-two cycles before and four to
five cycles after re-irradiation [10]. Unlike other studies evaluating chemotherapy, Grosu et al. reported significantly
improved survival both in univariate and multivariate analysis.
Re-challenge with Temozolomide was further evaluated in a
phase II randomized DIRECTOR Trial [55]. Patients with
glioblastoma at first progression after Temozolomide/Radiotherapy ? Temozolomide and at least two maintenance temozolomide cycles were randomized to one week on (120 mg/m2
per day)/one week off or 3 weeks on (80 mg/m2 per day)/one
week off. Primary endpoint was median time to-treatment failure (TTF). The trial was closed prematurely after 105 patents.
Median TTF (1.8 vs. 2 months) and OS (9.8 vs. 10.6 months)
were not different between the two arms. The findings support
both the regimens of metronomic temozolomide. In addition
median TTF was 3.2 months for MGMT methylated tumors
compared to 1.8 months in unmethylated tumors. Han et al.
evaluated the dose dense temozolomide for recurrent GBM
reported modest 10% PFS-6 with median OS of 21.6 weeks
[56]. However exploratory analysis revealed median PFS
7.57 weeks in patients with unmethylated MGMT and median
OS 19.4 weeks compared to 11.57 weeks and 65.3 weeks for
patients with methylated MGMT. This points to an important
fact that patients with MGMT methylation are candidates for
salvage metronomic temozolomide but MGMT unmethylated
patients should be considered for an alternative treatment
approach. Attempts to incorporate Irinotecan or other
chemotherapeutic agents failed to improve survival [57].
Thus based on current available literature Bevacizumab or
Nitrosureas may be used as single agents in patients with
recurrent GBM. Based on the current literature the choice
must be based on expected toxicity and cost issues. A combination of Bevacizumab and Nitrosureas may be used in
7
patients with good performance status and good expected tolerance. Re-challenge with Temozolomide is also a valid option
and is of maximum benefit in patients with MGMT methylation. The decision to use chemotherapy thus needs to be personalized regarding the agent, the dose and duration. The
chemotherapy may be continued till progression of disease
or till when severe toxicity appears.
The patients who undergo surgery may also be considered
for adjuvant chemotherapy, with special attention to the various molecular predicative markers in the specimen. The
patients with MGMT methylation in the resected specimen
may benefit from adjuvant Temozolomide. Bevacizumab must
be also used with caution in patients in the immediate postoperative time due to complications of delayed wound healing
and lack of evidence of it in the adjuvant setting in re-excised
patients. The duration for which the agent must be given is
also debatable and there is a lack of any consensus on the
same. But if the patient has undergone a biopsy or decompression only chemotherapy may continue till progression.
The addition of Temozolomide with radiotherapy in the reirradiation setting also merits evaluation. The benefit of concurrent Temozolomide in the primary setting may be extrapolated
in the recurrent setting and it is logical to use it in re-irradiation
setting also. There are studies reporting the feasibility of concurrent Temozolomide in the concurrent setting, although studies evaluating the specific question are lacking. The adjuvant
chemotherapy after re-irradiation may follow the principles of
adjuvant chemotherapy after re-excision.
A possible treatment algorithm for recurrent GBM is
depicted in Fig. 1.
Novel treatment techniques
NovoTTF is a portable device delivering low-intensity, intermediate frequency electric fields via non-invasive, transducer
arrays. The electric fields interfere with cell division by causing
misalignment of microtubule subunits in the mitotic spindle
during the metaphase to anaphase transition and by dielectrophoretic movement of intracellular macromolecules and
organelles during telophase. Kirson et al. reported encouraging
26.1 weeks median time to disease progression and 62.2 weeks
median overall survival and paved for a phase III trial [58].
The trial randomized recurrent GBM patients to NovoTTF
(20–24 h/day) or chemotherapy of physician’s choice with Primary endpoint of improvement of overall survival. The trial
randomly allocated 237 patients to the study and experimental
arm. Patient characteristics were well balanced between the two
groups. Median survival was 6.6 months in the experimental
arm and 6.0 in the chemotherapy arm, progression-free survival
rate at 6 months was 21.4% and 15.1% (p = 0.13). Responses
were more common in the TTF arm (14% versus 9.6%,
p = 0.19). The TTF-related adverse events were mild (14%)
to moderate (2%). Severe adverse events occurred in 6% and
16% (p = 0.022) of patients treated with TTF and chemotherapy, respectively. Quality of life analyses was also favorable in
the TTF arm [59]. Though the trial did not find a superiority of
the TTF over chemotherapy it must be considered an equivalent and less toxic treatment options for these patients. The
radiological response which is becoming more a synonym with
treatment response for recurrent GBM also favors TTF.
Recently a post hoc analysis reported significantly higher OS
Please cite this article in press as: Mallick S et al. Management of glioblastoma after recurrence: A changing paradigm, J Egyptian Nat Cancer Inst (2016), http://dx.
doi.org/10.1016/j.jnci.2016.07.001
8
S. Mallick et al.
Figure 1
Possible treatment algorithm for recurrent GBM.
in patient’s receiving P1 course of NovoTTF Therapy versus
BPC (7.7 v 5.9 months). Additional post hoc analysis showed
significantly higher median OS with NovoTTF Therapy than
with BPC for patients with prior low-grade glioma, tumor size
P18 cm, Karnofsky performance status P80, and those who
had previously failed Bevacizumab therapy [60]. These findings
are quite encouraging but should be considered hypothesis generating and may be validated in a prospective trial.
of many studies which were not intended to answer the question [66].
Similar to AED steroid plays an important role in the management of recurrent GBM also. Dexamethasone is one of the
commonly used drugs for these patients to help in reducing
symptoms. However, in an exploratory analysis of the
NovoTTF trial researchers found a negative impact of using
more than 4.1 mg of dexamethasone daily.
Impact of anti-epileptic drugs
Management of recurrent GBM in elderly and pediatric patients
In the last decade preclinical studies have suggested that valproic acid (VPA) and its analogs could affect tumor cells in
many respects, such as inhibition of a subset of histone
deacetylases (HDAC) and cellular kinases, which could affect
gene transcription through histone hyper acetylation, DNA
hypo-methylation, and modulation of the MAP Kinase signaling pathway [61]. As a result VPA could inhibit tumor angiogenesis and induce differentiation and apoptosis in different
types of tumor cells. In addition, clinical studies also have
reported prolonged survival in patients with GBM when treated with valproic acid for seizure prophylaxis or treatment [62].
A recently published meta-analysis confirmed the benefit of
treatment with VPA (HR, 0.56; 95% CI, 0.44–0.71) [63].
Another recent study evaluated the beneficial role of Levetiracetam in the seizure management or patients with GBM
reported encouraging 2.5 months improved PFS for patients
receiving LVE for at least a period of three months. This leads
researchers to initiate phase II study to evaluate the impact of
the anti-epileptic drug (AED) in GBM. In recurrent GBM also
the use of AED plays a crucial role and may derive survival
benefit [64]. In a recent update Happold et al. conducted a
pooled analysis of survival association of AED use at the start
of chemoradiotherapy with temozolomide but found no association of PFS and OS advantage for patients taking either
VPA or levetiracetam [65]. However, there is much criticism
to the pooled analysis as it is also a retrospective study only
Management of elderly patients with GBM itself is a challenge
and is evolving from conventional radiation with concurrent
temozolomide to hypofractionated radiation alone or temozolomide alone. However, outcome remains dismal even after
any of the treatment approach. However, the management of
recurrent GBM poses further challenge as the patients have
limited life expectancy and propensity for high rate of complication. Interestingly retrospective data show no increased rate
of complication in these patients and median survival for the
reoperation group, single-surgery group, and biopsy only
group were 18.4, 8.9, and 3.4 months, respectively [67]. Socha
et al. analyzed data of 98 elderly frail recurrent GBM patients
[68]. Median overall survival from randomization for all
patients was 35 weeks and 55 versus 30 weeks for any treatment
versus best supportive care (BSC). Median post-progression
survival was 15 weeks in the entire cohort and 23 weeks with
any treatment versus 9 weeks with BSC. In addition, local treatment (surgery and/or RT) leads to better median PPS of 51 versus 21 weeks for chemotherapy. In patients with poor KPS at
relapse median PPS was 9 weeks with BSC versus 21 weeks with
any treatment.
Management of newly diagnosed pediatric GBM is another
area of concern because of anticipated long term toxicity and
concurrent radiation with temozolomide is considered standard [69,70]. However, data are extremely sparse regarding
the management of recurrent GBM. However, given the poor
Please cite this article in press as: Mallick S et al. Management of glioblastoma after recurrence: A changing paradigm, J Egyptian Nat Cancer Inst (2016), http://dx.
doi.org/10.1016/j.jnci.2016.07.001
Management of Glioblastoma after recurrence
outcome treatment option may follow the approach of adult
patients.
9
GBM when treated with autologous cyto-megalo virus-specific
T cells and chemotherapy [76]. These may prove to be beneficial in future trials in recurrent GBM.
Quality of life
Conclusions
Assessment of Quality (QOL) of life and reporting of QOL are
areas of unmet need. Presently available therapies are associated with limited survival of less than 12 months. Hence, cost
of care and quality of life assessment becomes important for
advocating any modality. However, there is limited information on the humanistic burden among patients with recurrent
GBM. Only a few studies reported QOL and showed improvement in QOL. Recently Signorovitch et al. conducted a systematic review of Overall Survival, QOL, and Neurocognitive
function in rGBM [71]. The authors found very limited data
about QOL in rGBM and concluded worse baseline QoL
among patients with rGBM than among the general population and patients with other cancers. Most importantly the
authors reported no improvement in QOL with the presently
evaluated treatment options. Bevacizumab alone or in combination also failed to improve QOL [51]. NovoTTF is the only
intervention with favorable QOL over chemotherapy in most
domains, possibly due to the absence of treatment related toxicities [59].
Future directions
In a pioneering work Verhaak et al. established four different
classes of GBM viz., proneural, neural, classical and mesenchymal subtypes with distinct molecular aberration and clinical behavior. The Classical subtype is characterized by
Chromosome 7 amplification paired with chromosome 10 loss,
and fourfold increase in EGFR expression and lack of p53
mutation. The proneural class shows alterations of PDGFRA
and IDH1 mutations. Mesenchymal subtype is characterized
by lower NF1 expression, whereas neural subtype shows
expression of neuron markers such as NEFL, GABRA1,
SYT1 and SLC12A5 [72]. In an interesting revelation Li
et al. show a wide difference in the pattern of molecular aberration in primary and recurrent GBM. The authors reported
Gene set enrichment analysis revealed that chromatin fracture,
repair, and remodeling genes were enriched in recurrent
glioblastoma [73]. Majority solid tumors are characterized by
increased glucose uptake which may be reflected by elevated
glycolysis even in the presence of oxygen (aerobic glycolysis,
the Warburg effect). Preclinical models have shown glioma
growth inhibition with reduction in dietary carbohydrates.
Feasibility trials are evaluating low-carbohydrate, ketogenic
diet containing plant oils for patients with recurrent GBM
with encouraging early results [74,75].
In the recent years the efficacy of immunotherapy for cancer has been validated. A wide range of drugs viz. dendritic cell
cancer vaccine, Heat-shock protein peptide complex-96 vaccination, humanized monoclonal antibody against the cytotoxic
T-lymphocyte antigen-4 (CTLA-4) immune checkpoint, blockade of programed death 1 (PD-1) and its ligand PD-L1 as well
as bioengineered chimeric antigen-receptor T cells has shown
appealing response in the treatment of different cancers. Early
clinical trials are ongoing with these agents and the results of
these trials are eagerly awaited. In one the recent studies
Schuessler et al. reported possible survival benefit in recurrent
Recurrent GBM is a challenge to manage with dismal prognosis. Treatment of rGBM requires a delicate balance between
aggressiveness of treatment, outcome, cost of care and quality
of life. Surgery, re-irradiation and systemic chemotherapy provide short term disease control and modest survival. Younger
patients with preserved performance status should be offered
Surgery followed by reirradiation or additional salvage
chemotherapy, whereas patients with smaller primary in eloquent location and recurrence after long time after primary
radiation should be considered for salvage reirradiation along
with chemotherapy. MGMT methylation guides to decide
between Temozolomide and bevacizumab. Newer targeted
therapy, novel treatment technique like NovoTTF,
immunotherapy holds promise to impart better survival without compromising on the quality of life.
Disclosures
The authors have nothing to disclose.
Meeting presentation
Not presented.
Financial support
No financial support received.
Conflict of interest
The authors have no conflict of interest.
Levels of evidence
(I) Evidence from at least one large randomised, controlled
trial of good methodological quality (low potential for
bias) or meta-analyses of well conducted randomised trials without heterogeneity.
(II) Small randomised trials or large randomised trials with a
suspicion of bias (lower methodological quality) or
meta-analyses of such trials or of trials with demonstrated heterogeneity.
(III) Prospective cohort studies.
(IV) Retrospective cohort studies or case–control studies.
(V) Studies without control group, case reports, experts
opinions.
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