the role of targeted therapies in the management of progressive glioblastoma
TRANSCRIPT
TOPIC REVIEW & CLINICAL GUIDELINES
The role of targeted therapies in the management of progressiveglioblastoma
A systematic review and evidence-based clinical practice guideline
Jeffrey J. Olson • Lakshmi Nayak • D. Ryan Ormond •
Patrick Y. Wen • Steven N. Kalkanis •
Timothy Charles Ryken
Received: 23 November 2013 / Accepted: 28 December 2013 / Published online: 17 April 2014
� Springer Science+Business Media New York 2014
Abstract
Question What is the influence of targeted medical
therapies on disease control and survival in the adult
patient with progressive glioblastoma?
Targeted population This recommendation applies to
adult patients with progressive glioblastoma
Recommendations Level III Treatment with bev-
acizumab is recommended as it provides improved disease
control compared to historical controls as measured by best
imaging response and progression free survival at
6 months.
Given that there are a large number of therapies are
available for progressive glioblastoma that may be applied
under selected circumstances dependent on patient
characteristics and treating physician judgment, it is
strongly recommended that patients with progressive
glioblastoma be enrolled in properly designed clinical
investigations to provide convincing evidence of thera-
peutic value.
Keywords Adult � Glioblastoma � Malignant glioma �Progressive � Recurrent � Relapse � Targeted therapy �Molecular agents � Quality of life � Survival � Mortality
Targeted therapies rationale
Glioblastoma carry a nearly uniformly dismal outcome.
Even the most optimistic predictions of long term survival
of greater than 5 years after diagnosis only approach 1 or
2 % although higher 5-year survival rates have been
recently published in one Phase 3 study. The median
survival of patients with newly diagnosed glioblastoma
has improved slightly in the last decade and may approach
15–18 months [1, 2]. Because of the dismal prognosis,
patients with these tumors are treated early in the course
of the disease with aggressive multimodality regimens
including surgical resection, radiotherapy and chemo-
therapy [3–5]. Targeted cancer therapies are drugs or
other substances that block the growth and spread of
cancer by interfering with specific molecules involved in
tumor growth and progression [6]. The proliferation and
application of these therapies, though more commonly
applied to tumors in other portions of the body, has also
come to the forefront in the treatment of progressive
glioblastoma [7]. This guideline is a cataloging, review,
and systematic evaluation of these treatments to allow the
practicing physician to determine their role in patient
management.
J. J. Olson (&) � D. R. Ormond
Department of Neurosurgery, Emory University School of
Medicine, Atlanta, GA, USA
e-mail: [email protected]
L. Nayak � P. Y. Wen
Dana-Farber Cancer Institute, Boston, MA, USA
L. Nayak � P. Y. Wen
Department of Neurology, Brigham and Women’s Cancer
Center, Boston, MA, USA
S. N. Kalkanis
Department of Neurosurgery, Henry Ford Health System,
Detroit, MI, USA
T. C. Ryken
Department of Neurosurgery, Iowa Spine and Brain Institute,
Waterloo, IA, USA
123
J Neurooncol (2014) 118:557–599
DOI 10.1007/s11060-013-1339-4
Targeted therapies methodology
Search strategy
The following electronic databases were searched from
January 1990 through June 2012: MEDLINE�, and Em-
base�. A broad search strategy using a combination of
subheadings and text words was employed. In brief, a
search was executed for progressive glioblastoma treat-
ment with targeted therapies. Specifically that included
progressive, recurrent, or relapsing glioma or glioblastoma
and combined with targeted therapy and molecular agents
and then quality of life, survival and mortality. The search
strategy is documented in the methodology section of this
guideline. Reference lists of included studies were also
reviewed.
Targeted therapies search summary
The search resulted in 232 publications being identified
as having potential relevance. Importantly the search for
cytotoxic chemotherapy related publications identified a
number of manuscripts also dealing with targeted ther-
apies and resulted in additions to this group. A total of
1,673 publications were identified by the search method
and underwent title and abstract screening. Of those,
299 were deemed better information regarding this
guideline.
Targeted therapies scientific foundation
Antiangiogenic therapies
The greatest experience with targeted therapies for the
purpose of this guideline lies with antiangiogenic agents.
The rationale for using antiangiogenic therapies in glio-
blastoma is based on various facts. These are among the
most vascular of all tumors [8–16]. Glioblastoma cells
produce VEGF [9, 12]. The tumors are characterized by
endothelial proliferation, i.e., tumor angiogenesis [9, 12,
13]. Also, patients with glioblastoma have been identified
as having circulating neoplastic endothelial cells [17, 18].
The hypothesis that follows is that disruption of the vas-
cular component of malignant brain tumors in humans
will allow tumor control by directly inducing tumor death
by loss of blood supply or by sensitizing the tumor
endothelial cells to the effects of radiation and
chemotherapy.
Single anti-angiogenic agents
Bevacizumab Significant experience with bevacizumab (a
humanized monoclonal antibody that inhibits vascular endo-
thelial growth factor A and in turn inhibits tumor angiogenesis)
alone is reported by Friedman et al. in a report comparing the
use of that agent alone to bevacizumab plus irinotecan (a
cytotoxic agent that prevents DNA from unwinding for tran-
scription by inhibition of topoisomerase) in a prospective ran-
domized phase II study. In that investigation the progression
free survival at 6 months, and median overall survival for
bevacizumab alone (n = 85) were 42.6 % and 9.2 months,
respectively. When compared to historical reports of salvage
therapy with cytotoxic agent, these outcomes were significantly
better (P \ 0.0001) [19, 20]. These outcomes are not signifi-
cantly different than the same parameters when irinotecan was
added in a group of 82 patients. In both groups, it was
hypothesized that some clinical benefit was derived from the
ability of the bevacizumab to reduce cerebral edema and mass
effect by diminishes blood–brain-barrier leakage. The response
rate was 28.2 % including one complete response and 23 par-
tial responses, again not significantly different than what was
observed with the addition of irinotecan. Tumor response and
progression as determined by imaging is more challenging with
the vascularity altering effects of bevacizumab and the topic
and definitions are addressed by Wen et al. [21]. The use of
bevacizumab alone is not without toxicities as the authors
report the most common grade 3 or greater toxicities for the use
of this agent alone include hypertension (8.3 %) and convul-
sions (6.0 %). As the outcome data is only compared to his-
torical data, this yields class II data (see Table 1) [22].
In another report published the same year, Kreisl
described their experience with 48 glioblastomas treated
with bevacizumab alone. They noted a 29 % six-month
progression free survival and median progression free
survival at 16 weeks. There was one complete response
and 16 partial responses yielding an overall response rate
of 35 %. As did Friedman et al., they concluded single
agent bevacizumab has meaningful activity. The study
included a second stage of addition of irinotecan at pro-
gression with no comparisons to historical or internal
controls yielding class III data [22, 23].
In a retrospective study of bevacizumab alone in 50
recurrent glioblastomas after one form of cytotoxic che-
motherapy, Chamberlain et al. reported progression free
survival at 6 months of 42 % and the partial response rate
was 42 % but the median time to progression was only
1 month. This is clearly class III data and the authors state
there is a role for this therapy in ‘‘alkylator-refractory’’
tumors [24].
558 J Neurooncol (2014) 118:557–599
123
Ta
ble
1T
arg
eted
ther
apy
agen
tsal
on
e
Auth
or
(yea
r)D
escr
ipti
on
of
study
Dat
a
clas
s
Concl
usi
ons
Burk
har
dt
(2012)
Pro
spec
tive,
single
inst
ituti
on,
phas
eI
tria
lof
intr
a-ar
teri
albev
aciz
um
abaf
ter
blo
od
bra
inbar
rier
dis
rupti
on
inre
curr
ent
gli
obla
stom
a
Pat
ient
popula
tion:
Adult
pat
ients
wit
hre
curr
ent
gli
obla
stom
atr
eate
dw
ith
radia
tion
and
tem
ozo
lom
ide,
but
wer
ebev
aciz
um
abnaı̈
ve.
(n=
14)
Tre
atm
ent
regim
en:
Pat
ients
rece
ived
asi
ngle
‘‘su
per
sele
ctiv
ein
tra-
arte
rial
cere
bra
lin
fusi
on’’
dose
of
man
nit
ol
(1.4
Mm
annit
ol
at10
mL
per
120
s).
Bev
aciz
um
abw
asth
engiv
enw
ith
dose
esca
lati
on
from
2to
15
mg/k
g.
12/1
4pat
ients
wer
eth
enst
arte
don
intr
aven
ous
bev
aciz
um
ab
(10
mg/k
g)
on
abiw
eekly
bas
is.
2/1
4re
ceiv
edre
pea
ted
month
lydose
sof
intr
a-ar
teri
al
bev
aciz
um
abonly
III
Med
ian
PF
S:
10
month
s
Med
ian
OS
:8.8
month
s(s
hort
erth
anP
FS
bec
ause
4pat
ients
die
dpri
or
topro
gre
ssin
g)
Res
ponse
totr
eatm
ent:
PR
:8
Toxic
ity:
Sin
gle
epis
odes
of
wound
deh
isce
nce
,se
izure
s,an
dtr
unca
lra
sh
Auth
ors
’co
ncl
usi
ons:
Intr
a-ar
teri
albev
aciz
um
abaf
ter
blo
od
bra
inbar
rier
dis
rupti
on
foll
ow
edby
IV
bev
aciz
um
abgiv
es‘‘
enco
ura
gin
g’’
outc
om
esin
com
par
ison
totr
ials
of
IVbev
aciz
um
aban
d
irin
ote
can
Gil
ber
t(2
012)
Phas
eII
,double
arm
ed,
mult
i-ce
nte
rtr
ial
of
cile
ngit
ide
inre
curr
ent
gli
obla
stom
a
Pat
ient
popula
tion:
Adult
pat
ients
wit
hpro
gre
ssiv
egli
obla
stom
aor
gli
osa
rcom
aat
leas
t4
wee
ks
from
radio
ther
apy
com
ple
tion
and
am
axim
um
of
2pri
or
tum
or
rela
pse
s.P
atie
nts
had
tobe
a
candid
ate
for
gro
ss-
or
nea
r-to
tal
rese
ctio
naf
ter
pre
oper
ativ
ead
min
istr
atio
nof
cile
ngit
ide
(n=
30)
Tre
atm
ent
regim
en:
Pat
ients
wer
era
ndom
ized
tohig
hdose
(2,0
00
mg)
or
low
dose
(500
mg)
cile
ngit
ide
on
day
s-8,
-4,
and
-1pri
or
totu
mor
rese
ctio
n
III
Stu
dy
ended
bec
ause
of
slow
accr
ual
PF
S-6
:12
%
Med
ian
PF
S:
8w
eeks
Toxic
ity:
Cil
engit
ide
cause
d9
gra
de
3–4
toxic
itie
s,m
ainly
lym
phopen
iath
atm
ayhav
ebee
nre
late
d
topri
or
cyto
toxic
chem
oth
erap
y.
Ther
ew
ere
no
dose
reduct
ions
for
toxic
ity
and
no
trea
tmen
t
rela
ted
dea
ths
Auth
ors
’co
ncl
usi
ons:
The
auth
ors
stat
eth
atth
ere
iscl
earl
ydru
gdel
iver
yto
tum
or
and
gen
erousl
y
note
the
trea
tmen
tef
fect
tohav
ebee
nm
odes
t
Fri
day
(2012)
Apro
spec
tive,
mult
i-in
stit
uti
onal
,phas
eII
,si
ngle
arm
study
of
vori
nost
atan
dbort
ezom
ibin
recu
rren
tm
alig
nan
tgli
om
a
Pat
ient
popula
tion:
Adult
sw
ith
his
tolo
gic
ally
confi
rmed
gli
obla
stom
aor
gli
osa
rcom
aat
leas
t
8w
eeks
foll
ow
ing
radia
tion
trea
tmen
tat
tim
eof
recu
rren
cean
dw
ho
had
rece
ived
only
one
syst
emic
chem
oth
erap
euti
cag
ent
(n=
37)
Tre
atm
ent
regim
en:
Vori
nost
atw
asgiv
enat
adose
of
400
mg
ora
lly
once
dai
lyon
day
s1–14
of
a
21-d
aycy
cle.
Bort
ezom
ibw
asgiv
enat
adose
of
1.3
mg/m
2on
day
s1,
4,
8,
and
11
of
a21-d
ay
cycl
e
III
PF
S-6
:0
%
Mea
nti
me
topro
gre
ssio
n:
1.5
month
s
Med
ian
OS
:3.2
month
s
Res
ponse
:
CR
and
PR
:N
one
Toxic
ity:
Gra
de
3–4
hem
atolo
gic
toxic
ity
was
obse
rved
in37
%of
the
pat
ients
:th
rom
bocy
topen
ia
(30
%),
neu
tropen
ia(4
%),
and
lym
phopen
ia(4
%).
The
over
all
inci
den
ceof
gra
de
3–4
nonhem
atolo
gic
toxic
ity
was
30
%(m
ost
com
mon)
Auth
ors
’co
ncl
usi
ons:
Ther
eis
no
evid
ence
of
effi
cacy
of
this
med
icat
ion/d
ose
com
bin
atio
nin
recu
rren
tgli
obla
stom
a
Mas
on
(2012)
Phas
eII
,m
ult
icen
ter,
single
arm
open
label
study
of
TL
N-4
601(R
as-M
AP
Ksi
gnal
ing
pat
hw
ay
inhib
itor)
monoth
erap
yin
recu
rren
tgli
obla
stom
a
Pat
ient
popula
tion:
Adult
sw
ith
ahis
tolo
gic
ally
confi
rmed
dia
gnosi
sof
gli
obla
stom
aat
firs
t
pro
gre
ssio
nw
ho
had
com
ple
ted
pri
or
trea
tmen
tw
ith
radio
ther
apy
and
one
syst
emic
chem
oth
erap
euti
cag
ent
(n=
20)
Tre
atm
ent
regim
en:
TL
N-4
601
was
pro
vid
edat
adose
of
480
mg/m
2/d
ayby
conti
nuous
intr
aven
ous
adm
inis
trat
ion
usi
ng
aport
able
pum
pli
nked
toa
centr
alven
ous
line.
Eac
h21-d
aytr
eatm
ent
cycl
e
consi
sted
of
a14-d
ayad
min
istr
atio
nof
study
dru
gfo
llow
edby
a7-d
ayre
cover
yper
iod
III
Stu
dy
term
inat
edat
20
case
sdue
tola
ckof
effi
cacy
PF
S-6
:0
%
Mea
nO
S:
132
day
s
Med
ian
OS
:150
day
s
Res
ponse
CR
and
PR
:N
one
Toxic
ity:
The
most
freq
uen
tly
report
edad
ver
seev
ents
,re
port
edin
four
or
more
pat
ients
incl
uded
fati
gue
(50
%,
n=
10),
hea
dac
he
(30
%,
n=
6),
cath
eter
site
eryth
ema
(25
%,
n=
5),
musc
ula
r
wea
knes
s(2
5%
,n
=5),
anxie
ty(2
0%
,n
=4)
and
seiz
ure
s(2
0%
,n
=4)
Auth
ors
Concl
usi
ons:
This
agen
tis
inef
fect
ive
inpro
gre
ssiv
eG
BM
when
adm
inis
tere
das
monoth
erap
yin
this
sched
ule
.F
urt
her
eval
uat
ion
of
TL
N-4
601
inG
BM
should
be
susp
ended
unti
l
its
mec
han
ism
of
acti
on
isfu
lly
eluci
dat
ed
J Neurooncol (2014) 118:557–599 559
123
Ta
ble
1co
nti
nu
ed
Auth
or
(yea
r)D
escr
ipti
on
of
study
Dat
a
clas
s
Concl
usi
ons
Bogdah
n(2
011)
Phas
eII
b,
pro
spec
tive,
mult
inat
ional
,open
-lab
el,
random
ized
contr
ol
tria
lof
the
TG
F-b
eta
inhib
itor
trab
eder
sen
inre
curr
ent
hig
hgra
de
gli
om
a
Pat
ient
popula
tion:
Adult
pat
ients
wit
hre
curr
ent
hig
hgra
de
gli
om
a(n
=103
gli
obla
stom
asof
whic
h
95
wer
eev
aluab
lefo
rtr
eatm
ent
effe
ct)
Tre
atm
ent
regim
en:
Pat
ients
wer
era
ndom
ized
bet
wee
nst
andar
dch
emoth
erap
y,
and
trab
eder
sen
at
10
or
80
lM
conce
ntr
atio
ns.
Chem
oth
erap
yco
ntr
ol
was
eith
erT
MZ
(150–200
mg/m
2on
day
s1–5
of
a28-d
aycy
cle)
or
pro
carb
azin
e/C
CN
U/v
incr
isti
ne
(60
mg/m
2on
day
s8–21,
lom
ust
ine
110
mg/
m2
on
day
1,
and
vin
cris
tine
1.4
mg/m
2on
day
s8
and
29
in56-d
aycy
cles
)dep
endin
gon
pre
vio
us
ther
apy
(TM
Zif
naı̈
ve,
PC
Vif
TM
Zpre
vio
usl
yfa
iled
(n=
33
inal
l)
Inth
etr
abed
erse
ngro
ups,
pat
ients
rece
ived
agen
tfo
r7
day
sw
ith
afl
ow
rate
of
4m
L/m
in,
foll
ow
ed
by
isoto
nic
sali
ne
for
7day
sw
ith
afl
ow
rate
of
1m
L/m
in(1
4day
sper
cycl
e,up
to11
cycl
es).
The
trab
eder
sen
dose
per
cycl
ew
as2.4
8m
g(1
0l
Mgro
up,
n=
28)
or
19.8
1m
g(8
0l
Mgro
up,
n=
34).
Tra
bed
erse
nw
asin
fuse
din
trat
um
ora
lly
usi
ng
convec
tion-e
nhan
ced
del
iver
yvia
a
subcu
taneo
us
port
acce
sssy
stem
connec
ted
toan
exte
rnal
pum
pal
low
ing
outp
atie
nt
trea
tmen
t
III
PF
S-6
ingli
obla
stom
a:14,
12,
and
15
%fo
r10,
80
lM
and
contr
ol,
resp
ecti
vel
y
Med
ian
OS
:7.3
,10.9
,an
d10.0
month
sfo
r10,
80
lM
,an
dco
ntr
ol,
resp
ecti
vel
y.
Of
note
,at
2an
d
3yea
rs,
the
OS
rate
was
3-f
old
hig
her
for
10
mM
trab
eder
sen
(40
%,
95
%C
I:6–74)
com
par
ed
wit
hst
andar
dch
emoth
erap
y(1
3%
,95
%C
I:0–31)
Res
ponse
:T
her
ew
asone
PR
or
CR
(not
dif
fere
nti
ated
)in
the
80
lM
gro
up
at6
month
san
done
PR
or
CR
inth
e10
lM
gro
up
and
two
PR
or
CR
sin
the
contr
ol
gro
up
at14
month
s
Toxic
ity:
The
most
com
mon
toxic
itie
sin
the
contr
ol
gro
up
incl
uded
blo
od
and
lym
phat
icdis
ord
ers
(5,
8an
d11
%in
the
10
lM
trab
eder
sen,
80
lM
trab
eder
sen
and
stan
dar
dch
emoth
erap
ygro
ups,
resp
ecti
vel
y).
The
most
com
mon
toxic
itie
sin
the
trab
eder
sen
gro
ups
wer
ener
vous
syst
em
dis
ord
ers.
This
incl
uded
ahem
ipar
esis
rate
of
27,
22
and
2%
inth
e10
lM
trab
eder
sen,
80
lM
trab
eder
sen
and
stan
dar
dch
emoth
erap
ygro
ups,
resp
ecti
vel
y;
abra
ined
ema
rate
of
27,
20
and
4%
inth
e10
lM
trab
eder
sen,80
lM
trab
eder
sen
and
stan
dar
dch
emoth
erap
ygro
ups,
resp
ecti
vel
y;
and
anin
crea
sed
intr
acra
nia
lpre
ssure
rate
of
20,
14
and
4%
inth
e10
lM
trab
eder
sen,
80
lM
trab
eder
sen
and
stan
dar
dch
emoth
erap
ygro
ups,
resp
ecti
vel
y.
Ther
ew
ere
4se
rious
adver
seev
ents
(men
ingit
is,
hyponat
rem
iaan
dbra
ined
ema,
and
thro
mbocy
topen
iafo
rtr
abed
erse
nan
dce
rebra
l
dis
ord
erfo
rco
ntr
ol)
Auth
ors
’co
ncl
usi
ons:
Tra
bed
erse
nat
10
lM
had
super
ior
effi
cacy
and
safe
tyin
com
par
ison
to
80
lM
trab
eder
sen
or
chem
oth
erap
yat
2an
d3
yea
rfo
llow
-up
inte
rval
sbut
the
study
was
not
pow
ered
todet
erm
ine
ifth
isw
assi
gnifi
cant.
The
auth
ors
stat
eth
isfi
ndin
gim
pli
estr
abed
erse
n
des
erves
furt
her
clin
ical
dev
elopm
ent
inhig
h-g
rade
gli
om
a
Wen
(2011)
Phas
eII
mult
icen
ter
open
-lab
el,
single
agen
t,2
stag
etr
ial
of
AM
G102
(ril
otu
mum
ab),
afu
lly
hum
an
monocl
onal
anti
body
agai
nst
hep
atocy
tegro
wth
fact
or/
scat
ter
fact
or
(HG
F/S
F)
Pat
ient
popula
tion:
Adult
pat
ients
wit
hre
curr
ent
gli
obla
stom
aor
gli
osa
rcom
aw
ith
thre
eor
few
er
recu
rren
ces.
(n=
61
of
whic
h60
wer
etr
eate
d)
Tre
atm
ent
regim
en:
Pat
ients
rece
ived
AM
G102
10
(n=
40)
or
20
(n=
20)
mg/k
gby
intr
aven
ous
infu
sion
(over
30–60
min
)ev
ery
2w
eeks
III
Bev
aciz
um
abN
aı̈ve
:10
mg/k
gD
ose
PF
S-6
:17.9
%
Med
ian
PF
S:
4.1
wee
ks
Med
ian
OS
:10.9
month
s
20
mg/k
gD
ose
PF
S-6
:15.0
%;
Med
ian
PF
S:
4.7
wee
ks;
Med
ian
OS
:11.4
month
s
Pri
or
Bev
aciz
um
ab:
10
mg/k
gD
ose
PF
S-6
:5.3
%;
Med
ian
PF
S:
4.0
wee
ks;
Med
ian
OS
:3.6
month
s
20
mg/k
gD
ose
PF
S-6
:10.0
%;
Med
ian
PF
S:
4.1
wee
ks;
Med
ian
OS
:3.4
month
s
Res
ponse
:C
Ran
dP
R:
None
Toxic
ity:
Eig
hte
enpat
ients
(30
%)
had
seri
ous
toxic
ity
incl
udin
gco
nvuls
ion
(n=
4),
confu
sion
(n=
2),
edem
a(n
=2),
gra
de
3hypoca
lcem
ia(n
=1),
and
gra
de
3hypophosp
hat
emia
(n=
3)
Auth
ors
’co
ncl
usi
on:
AM
G102
monoth
erap
ydid
not
hav
esi
gnifi
cant
anti
tum
or
acti
vit
yin
this
pat
ient
popula
tion
Iwam
oto
(2011)
Apro
spec
tive,
phas
eI/
IIm
ult
icen
ter
tria
lof
rom
idep
sin,
ahis
tone
dea
cety
lase
inhib
itor
Pat
ient
popula
tion:
Adult
sw
ith
recu
rren
tm
alig
nan
tgli
om
a(n
=35
gli
obla
stom
apat
ients
inphas
eII
com
ponen
t;phas
eI
resu
lts
not
div
ided
by
his
tolo
gy)
Tre
atm
ent
regim
en:
Rom
idep
sin
was
intr
aven
ousl
yin
fuse
dover
4h
on
day
s1,
8,
and
15
of
a28-d
ay
cycl
e.D
uri
ng
the
phas
eI
port
ion,
pat
ients
wer
egiv
enei
ther
13.3
or
17.7
mg/m
2per
dose
.D
uri
ng
the
phas
eII
port
ion,
pat
ients
wer
egiv
enat
13.3
mg/m
2w
ith
one
reduct
ion
poss
ible
to10
mg/m
2in
case
of
toxic
ity
III
PF
S-6
ingli
obla
stom
ain
phas
eII
:3
%
Med
ian
PF
Sin
gli
obla
stom
ain
phas
eII
:8
wee
ks
Res
ponse
:C
Ran
dP
R:
None
Toxic
ity:
Six
pat
ients
(4G
BM
and
2an
apla
stic
gli
om
as)
dis
conti
nued
rom
idep
sin
ther
apy
due
to
toxic
ity
(4th
rom
bocy
topen
ia,
1el
evat
edal
anin
eam
inotr
ansf
eras
ele
vel
,an
d1
card
iac
abnorm
alit
y).
Nin
epat
ients
(22
%)
requir
eddose
reduct
ion.
Hem
atolo
gic
toxic
ity
and
fati
gue
wer
e
the
most
com
mon
gra
de
C3
adver
seev
ents
Auth
ors
’co
ncl
usi
ons:
Rom
idep
sin
isin
effe
ctiv
ein
this
dose
sched
ule
for
recu
rren
tgli
obla
stom
a
560 J Neurooncol (2014) 118:557–599
123
Ta
ble
1co
nti
nu
ed
Auth
or
(yea
r)D
escr
ipti
on
of
study
Dat
a
clas
s
Concl
usi
ons
de
Gro
ot
(2011)
Phas
eII
,m
ult
icen
ter
tria
lof
aflib
erce
pt
(VE
GF
trap
)
Pat
ient
popula
tion:
recu
rren
thig
h-g
rade
gli
om
apat
ients
pre
vio
usl
ytr
eate
dw
ith
tem
ozo
lom
ide
chem
ora
dia
tion.
(n=
58,
39
wit
hgli
obla
stom
a)
Tre
atm
ent
regim
en:
Afl
iber
cept
was
giv
en4
mg/k
gIV
on
day
1of
ever
y14-d
aycy
cle.
Atw
o-d
ay
win
dow
on
eith
ersi
de
of
the
trea
tmen
tcy
cle
was
allo
wed
III
The
foll
ow
ing
surv
ival
calc
ula
tions
wer
eav
aila
ble
for
gli
obla
stom
a:
PF
S-6
:7.7
%
Med
ian
PF
S:
12
wee
ks
Med
ian
OS
:39
wee
ks
Res
ponse
ingli
obla
stom
a
PR
:7
(18
%)
Toxic
ity:
6/3
9st
opped
trea
tmen
tfr
om
toxic
ity.
Gra
de
3an
d4
toxic
itie
sw
ere
num
erous
and
incl
uded
mai
nly
fati
gue,
hyper
tensi
on,
and
lym
phopen
ia,
but
no
gra
de
5to
xic
itie
sw
ere
obse
rved
Auth
ors
’co
ncl
usi
ons:
Afl
iber
cept
has
min
imal
acti
vit
yas
asi
ngle
agen
tin
recu
rren
tgli
obla
stom
a
Rudek
(2011)
Phas
eI,
mult
icen
ter
tria
lof
CO
L-3
inpat
ients
wit
hre
curr
ent
hig
hgra
de
gli
om
a
Pat
ient
popula
tion:
Pat
ients
wit
hpro
gre
ssiv
em
alig
nan
tgli
om
aw
ho
had
rece
ived
pri
or
radia
tion
ther
apy
(n=
33,
25
of
whic
hw
ere
gli
obla
stom
a).
Pat
ients
wer
ediv
ided
into
those
takin
gen
zym
e-
induci
ng
anti
seiz
ure
dru
gs
(EIA
ED
s),
and
those
who
wer
enot
Tre
atm
ent
regim
en:
CO
L-3
was
giv
enora
lly
once
dai
lyon
anunin
terr
upte
dsc
hed
ule
for
28
day
sper
cycl
e.D
ose
esca
lati
on
occ
urr
edbeg
innin
gat
25
mg/m
2in
25
mg/m
2in
crem
ents
up
toa
max
imum
100
mg/m
2.
Dose
sw
ere
rounded
dow
nto
the
nea
rest
10
mg
III
No
surv
ival
dat
aw
aspro
vid
edby
his
tolo
gy
Res
ponse
CR
and
PR
:N
one
for
gli
obla
stom
a
Toxic
ity:
Inth
eE
IAE
D(-
)ar
mat
the
100
mg/m
2/d
ayle
vel
,one
pat
ient
had
gra
de
3m
yal
gia
,an
done
had
gra
de
3fa
tigue
Inth
eE
IAE
D(?
)ar
m,
at50
mg/m
2/d
ay,
ther
ew
asone
gra
de
5C
NS
hem
orr
hag
eco
mbin
edw
ith
gra
de
3hypokal
emia
.B
oth
even
tsw
ere
asse
ssed
asunli
kel
yre
late
dto
CO
L-3
,an
ddose
esca
lati
on
conti
nued
wit
hno
furt
her
dose
lim
itin
gto
xic
itie
sobse
rved
inan
yoth
erpat
ient
Auth
ors
’co
ncl
usi
ons:
The
MT
Dw
as75
mg/m
2/d
ayin
the
EIA
D(-
)pat
ients
whil
eone
was
not
det
erm
ined
inE
IAE
D(?
)pat
ients
.T
her
ew
asnot
enough
single
-agen
tac
tivit
yto
war
rant
furt
her
study
inre
curr
ent
hig
h-g
rade
gli
om
a
Could
wel
l
(2011)
Pro
spec
tive,
mult
i-in
stit
uti
onal
phas
eI/
IItr
ial
of
synth
etic
hyper
icin
for
pro
gre
ssiv
em
alig
nan
t
gli
om
as
Pat
ient
popula
tion:
Pro
gre
ssiv
em
alig
nan
tgli
om
aw
ho
had
rece
ived
atle
ast
radia
tion
ther
apy
(n=
42
wit
h35
bei
ng
gli
obla
stom
as)
Tre
atm
ent
regim
en:
Hyper
icin
was
giv
enas
anora
lso
luti
on
atdose
sra
ngin
gfr
om
0.0
5to
0.5
0m
g/
kg
once
dai
lyfo
rup
toth
ree
month
s.D
ose
sw
ere
esca
late
dunti
lto
xic
ity
dev
eloped
III
Surv
ival
sfo
rgli
obla
stom
aal
one
not
report
ed
Res
ponse
PR
ingli
obla
stom
as:
1
Toxic
ity:
31/4
2pat
ients
had
adver
seev
ent
30/4
2pat
ients
had
skin
and
subcu
taneo
us
tiss
ue
dis
ord
ers:
Photo
sensi
tivit
y(4
2.9
%)
Ery
them
a(2
6.2
%)
Skin
burn
ing
sensa
tion
(14.3
%)
Ner
vous
syst
emdis
ord
ers
(35/4
2)
incl
udin
gco
nvuls
ions,
hyper
esth
esia
and
par
esth
esia
GI
side
effe
cts
(23.8
%)
Mil
dth
rom
bocy
topen
ia(1
pat
ient)
Alo
pec
ia(1
pat
ient)
Auth
ors
’co
ncl
usi
ons:
Hyper
icin
pro
duce
da
par
tial
resp
onse
inone
gli
obla
stom
a.M
ean
max
imum
tole
rate
ddose
for
the
enti
rest
udy,
incl
udin
glo
wer
gra
de
tum
ors
,w
as0.4
0±
0.0
98
mg/k
gdai
ly
J Neurooncol (2014) 118:557–599 561
123
Ta
ble
1co
nti
nu
ed
Auth
or
(yea
r)D
escr
ipti
on
of
study
Dat
a
clas
s
Concl
usi
ons
da
Fonse
ca
(2011)
Sin
gle
inst
ituti
on,
pro
spec
tive
phas
eI/
IItr
ial
of
monote
rpen
eper
illy
lal
cohol
inpat
ients
wit
h
pro
gre
ssiv
egli
obla
stom
a
Pat
ient
popula
tion:
Rec
urr
ent
gli
obla
stom
apat
ients
on
sym
pto
mat
ictr
eatm
ent
afte
rat
leas
tth
ree
rela
pse
sfo
llow
ing
surg
ery
and/o
rra
dia
tion
and
mult
imodal
chem
oth
erap
ysp
ecifi
cfo
r
gli
obla
stom
aw
ere
incl
uded
(n=
89).
They
wer
em
atch
edw
ith
his
tori
cal
contr
ols
coll
ecte
d
retr
osp
ecti
vel
yw
ho
had
support
ive
care
only
atre
curr
ence
(n=
52)
Tre
atm
ent
regim
en:
Per
illy
lal
cohol
(PO
H)
was
adm
inis
tere
dby
nas
alin
hal
atio
n4
tim
esdai
ly.
Init
iall
ypat
ients
rece
ived
0.3
%v/v
PO
H(5
5m
g)
tota
ling
220
mg/d
ay,
wit
hes
cala
tion
up
to
440
mg
dai
lyas
ali
mit
ing
dose
toav
oid
nas
aldis
com
fort
III
Med
ian
OS
:5.9
month
sin
pri
mar
ygli
obla
stom
aan
d11.2
month
sin
seco
ndar
ygli
obla
stom
a
Res
ponse
Not
report
ed
Toxic
ity:
nas
aldis
com
fort
(only
report
ed)
Auth
ors
’co
ncl
usi
on:
PO
Him
pro
ved
surv
ival
wit
hli
ttle
toxic
ity
inco
mpar
ison
tountr
eate
dco
ntr
ols
atth
ird
rela
pse
Lu-E
mer
son
(2011)
Ret
rosp
ecti
ve
study
of
das
atin
iban
dbev
aciz
um
abin
adult
sw
ith
pro
gre
ssiv
egli
obla
stom
a
Pat
ient
popula
tion:
Adult
pat
ients
wit
hhis
tolo
gic
ally
confi
rmed
gli
obla
stom
a(n
=14)
and
radio
gra
phic
ally
docu
men
ted
recu
rren
tdis
ease
.A
llhad
pri
or
trea
tmen
tw
ith
radio
ther
apy,
and
pri
or
fail
ure
of
bev
aciz
um
abth
erap
y.
Ther
ew
asno
lim
iton
the
num
ber
of
pre
vio
us
ther
apie
s
Tre
atm
ent
regim
en:
Das
atin
ib70–100
mg
twic
edai
ly,
inco
mbin
atio
nw
ith
bev
aciz
um
abunti
ltu
mor
pro
gre
ssio
nor
unac
cepta
ble
toxic
ity
III
PF
S-6
:0
%
Med
ian
PF
S:
28
day
s
Med
ian
OS
:78
day
s
Res
ponse
:
CR
and
PR
:0
Toxic
ity:
The
most
com
mon
toxic
itie
sin
cluded
fati
gue
(3),
dia
rrhea
(1),
and
thro
mbocy
topen
ia(2
).
Tw
opat
ients
(14
%)
stopped
das
atin
ibth
erap
ybec
ause
of
gra
de
1fe
ver
and
rigor
(1)
and
gra
de
4
hem
orr
hag
e(1
)
Auth
ors
’co
ncl
usi
on:
This
retr
osp
ecti
ve
anal
ysi
sdid
not
find
any
signifi
cant
acti
vit
yof
das
atin
ib,
in
com
bin
atio
nw
ith
bev
aciz
um
abin
hea
vil
ypre
trea
ted
pat
ients
wit
hpro
gre
ssiv
egli
obla
stom
a
Sat
horn
sum
etee
(2010)
Phas
eII
anal
ysi
sof
bev
aciz
um
aban
der
loti
nib
inpro
gre
ssiv
egli
obla
stom
a
Pat
ient
popula
tion:
Adult
pat
ients
wit
hpro
gre
ssiv
em
alig
nan
tgli
om
aw
ith
thre
eor
few
erpri
or
pro
gre
ssio
ns
(gli
obla
stom
an
=25)
Tre
atm
ent
regim
en:
Bev
aciz
um
ab(1
0m
g/k
g)
was
adm
inis
tere
din
trav
enousl
yev
ery
2w
eeks.
Erl
oti
nib
was
ora
lly
adm
inis
tere
d,
once
dai
lyfo
rea
ch42-d
aytr
eatm
ent
cycl
eat
200
mg/d
ayfo
r
pat
ients
not
on
CY
P3A
4en
zym
e-in
duci
ng
anti
epil
epti
cdru
gs
(EIA
ED
s)an
d500
mg/d
ayfo
r
pat
ients
on
EIA
ED
sas
esta
bli
shed
pre
vio
usl
y
III
PF
S-6
:26
%(f
or
pat
ients
trea
ted
more
than
3m
onth
saf
ter
radia
tion
ther
apy)
wee
ks
Med
ian
PF
S:
17
Med
ian
OS
:42
wee
ks
Res
ponse
CR
:1
PR
:11
Toxic
ity
(incl
udin
gal
lhis
tolo
gie
s)
Gra
de
3([
10
%in
ciden
ce):
Ras
h(3
9%
),fa
tigue
(16
%),
dia
rrhea
(11
%),
infe
ctio
n(1
1%
)
Gra
de
4:
Fat
igue,
stro
ke,
pulm
onar
yem
bolu
s,bac
teri
alm
enin
git
is(n
=1
each
)
Auth
ors
’co
ncl
usi
on:
The
com
bin
atio
npro
vid
edno
ben
efit
inpro
gre
ssio
nfr
eesu
rviv
alw
hen
com
par
edto
bev
aciz
um
abal
one
when
use
din
this
sett
ing
Rai
zer
(2010)
Phas
eII
,m
ult
icen
ter
study
of
erlo
tinib
inad
ult
sw
ith
recu
rren
tgli
obla
stom
a
Pat
ient
popula
tion:
Mult
iple
gro
ups
studie
sbut
incl
uded
pat
ients
wit
hre
curr
ent
gli
obla
stom
aw
ho
had
com
ple
ted
radia
tion
and
had
no
more
than
two
pri
or
rela
pse
san
dtw
opri
or
trea
tmen
ts
(n=
38)
Tre
atm
ent
regim
en:
Erl
oti
nib
150
mg/d
ayon
aco
nti
nuous
dai
lybas
is
III
PF
S-6
:3
%
Med
ian
PF
S:
2m
onth
s
Med
ian
OS
:6
month
s
Res
ponse
CR
and
PR
:N
one
Toxic
ity
Gra
de
3:
Ras
h(1
1),
Infe
ctio
nw
ithout
neu
tropen
ia(3
),F
atig
ue
(3)
and
num
erous
even
tsocc
urr
ing
only
once
or
twic
e
Gra
de
4:
Hypom
agnes
emia
(1)
Gra
de
5:
Sei
zure
(1)
Auth
ors
’co
ncl
usi
on:
Sin
gle
agen
ter
loti
nib
did
not
dem
onst
rate
effi
cacy
inth
issi
tuat
ion
562 J Neurooncol (2014) 118:557–599
123
Ta
ble
1co
nti
nu
ed
Auth
or
(yea
r)D
escr
ipti
on
of
study
Dat
a
clas
s
Concl
usi
ons
Iwam
oto
(2010)
Pro
spec
tive,
mult
i-in
stit
uti
onal
phas
eII
anal
ysi
sof
paz
opan
ibin
pro
gre
ssiv
egli
obla
stom
a
Pat
ient
popula
tion
Pat
ients
wit
h2
or
more
recu
rren
ces
of
gli
obla
stom
anot
trea
ted
wit
han
ti-V
EG
F/V
EG
FR
ther
apy
(n=
35)
Tre
atm
ent
regim
en
Paz
opan
ib800
mg/d
ayin
4w
eek
cycl
esw
ithout
inte
rrupti
on
III
PF
S-6
:3
%
Med
ian
PF
S:
12
wee
ks
Med
ian
over
all
surv
ival
(fro
mpaz
opan
ibtr
eatm
ent
init
iati
on):
l:35
wee
ks
Res
ponse
:P
R:
2
Toxic
ity
Gra
de
3–4
AL
Tel
evat
ion,
thro
mboti
cev
ents
(3ea
ch)
Lym
phopen
ia(2
)
Leu
kopen
ia,
thro
mbocy
topen
ia,
AS
Tel
evat
ion,
bra
inhem
orr
hag
e,fa
tigue:
(1ea
ch)
Auth
ors
’co
ncl
usi
on:
Sin
gle
agen
tpaz
opan
ibdid
not
pro
long
pro
gre
ssio
nfr
eesu
rviv
alin
this
popula
tion
but
did
dem
onst
rate
bio
logic
acti
vit
yas
dem
onst
rate
dby
radio
gra
phic
resp
onse
s
Kunw
ar(2
010)
Mult
iple
site
,m
ult
inat
ional
,pro
spec
tive,
random
ized
phas
eII
Ist
udy
of
convec
tion-e
nhan
ced
del
iver
yof
cintr
edek
inbes
udoto
x(C
B)
com
par
edw
ith
Gli
adel
waf
ers
(GW
)in
adult
pat
ients
wit
h
gli
obla
stom
am
ult
iform
eat
firs
tre
curr
ence
Pat
ient
popula
tion
Enro
llee
sw
ere
those
who
had
tum
ors
that
wer
eca
ndid
ates
for
gro
ssto
tal
rese
ctio
n.
Ran
dom
izat
ion
was
2:1
for
CB
:G
W
Enro
lled
:296
Tre
atm
ent
regim
en
CB
(0.5
mg/m
L;
tota
lfl
ow
rate
0.7
5m
L/h
)w
asad
min
iste
red
over
96
hvia
2–4
intr
apar
ench
ym
al
cath
eter
spla
ced
afte
rtu
mor
rese
ctio
n.
GW
(3.8
5%
/7.7
mg
carm
ust
ine
per
waf
er;
max
imum
8
waf
ers)
wer
epla
ced
imm
edia
tely
afte
rtu
mor
rese
ctio
n
[CB
:IL
13-P
E38Q
QR
,a
reco
mbin
ant
chim
eric
cyto
toxin
com
pose
dof
hum
anin
terl
eukin
-13
(IL
13)
fuse
dto
atr
unca
ted,
muta
ted
form
of
Pse
udom
onas
aeru
gin
osa
exoto
xin
A(P
E38Q
QR
)]
IM
edia
nsu
rviv
al(I
nte
nt
totr
eat
popula
tion)
CB
:36.4
wee
ks
GW
:35.3
wee
ks
(P=
0.4
76)
No
subcl
ass
anal
ysi
sre
vea
led
sele
ctiv
eben
efits
Toxic
ity
Sim
ilar
pro
file
sbet
wee
nth
etw
ogro
ups
exce
pt
for
pulm
onar
yem
boli
sm:
8%
(CB
)vs.
1%
(GW
),
(P=
0.0
14)
Auth
ors
’C
oncl
usi
on
Ther
ew
asno
surv
ival
dif
fere
nce
bet
wee
nC
Bad
min
iste
red
via
CE
Dan
dG
W
Rea
rdon
(2010)
Phas
eII
study
of
erlo
tinib
and
siro
lim
us
inpat
ients
wit
hre
curr
ent
gli
obla
stom
a
Pat
ient
popula
tion:
Pat
ients
wer
ere
quir
edto
hav
ehis
tolo
gic
ally
confi
rmed
GB
Mth
atw
as
radio
gra
phic
ally
pro
gre
ssiv
efo
llow
ing
pri
or
radia
tion
and
chem
oth
erap
y.
32
case
sen
roll
ed
Tre
atm
ent
regim
en
Str
atifi
cati
on:
±E
IAE
Ds
Conti
nuous
dai
lydosi
ng
for
up
totw
elve
28
day
cycl
es:
Str
atum
AE
IAE
D(-
):E
rloti
nib
150
mg
and
siro
lim
us
5m
gdai
ly.
n=
24
Str
atum
BE
IAE
D(?
):E
rloti
nib
450
mg
and
siro
lim
us
10
mg
dai
ly.
n=
8
III
PF
S-6
:3.1
%fo
ral
lpat
ients
Med
ian
PF
S:
6.9
wee
ks
over
all
Med
ian
PF
SS
trat
um
A:
8.4
wee
ks
Med
ian
PF
SS
trat
um
B:
4.0
wee
ks
(Avs.
BP
=0.0
3)
Med
ian
OS
:33.8
wee
ks
Res
ponse
:
No
CR
’sor
PR
’sobse
rved
Toxic
ity
Gra
de
C2
toxic
itie
sw
ere
rash
(59
%),
muco
siti
s(3
4%
),dia
rrhea
(31
%),
fati
gue
(28
%)
and
hyper
lipid
emia
(25
%).
Gra
de
4:
Thro
mbocy
topen
ia(n
=1)
Auth
ors
’co
ncl
usi
on:
This
regim
enhad
lim
ited
acti
vit
yw
ith
tole
rable
toxic
ity
J Neurooncol (2014) 118:557–599 563
123
Ta
ble
1co
nti
nu
ed
Auth
or
(yea
r)D
escr
ipti
on
of
study
Dat
a
clas
s
Concl
usi
ons
Wic
k(2
010)
Phas
eII
Ian
alysi
sof
enza
stau
rin
and
lom
ust
ine
inth
etr
eatm
ent
of
recu
rren
tgli
obla
stom
a
Pat
ient
popula
tion:
His
tolo
gic
ally
confi
rmed
gli
obla
stom
a(i
ncl
udin
ggli
osa
rcom
as);
mag
net
ic
reso
nan
ceim
agin
gev
iden
ceof
tum
or
pro
gre
ssio
naf
ter
radia
tion
and
chem
oth
erap
y;
no
more
than
two
2pri
or
chem
oth
erap
yre
gim
ens
could
hav
ebee
nuse
dbef
ore
enro
llm
ent.
Pat
ients
wer
eta
ken
off
EIA
ED
s14
or
more
day
sbef
ore
trea
tmen
tin
itia
tion.
Over
all
n=
266
Tre
atm
ent
regim
en(r
andom
ized
2:1
enza
stau
rin
tolo
must
ine)
:
Enza
stau
rin:
6-w
eek
cycl
esof
enza
stau
rin
500
mg/d
ay(1
,125-m
glo
adin
gdose
,day
1)
Lom
ust
ine:
6-w
eek
cycl
esof
100–130
mg/m
2,
day
1
IS
tudy
stopped
at266
pat
ients
when
itm
etcr
iter
iafo
rfu
tili
ty
PF
S-6
:
Enza
stau
rin:
11.1
%
Lom
ust
ine:
19.0
%
Med
ian
PF
S
Enza
stau
rin:
1.5
month
s
Lom
ust
ine:
1.6
month
s
Med
ian
over
all
surv
ival
:
Enza
stau
rin:
6.6
month
s
Lom
ust
ine:
7.1
month
s
All
outc
om
epar
amet
erdif
fere
nce
sdee
med
nonsi
gnifi
cant
Toxic
ity:
Enza
stau
rin:
Hem
atolo
gic
[G
rade
3:
thro
mbocy
topen
ia(0
.6%
)
Nonhem
atolo
gic
:F
atig
ue
(3.6
%),
thro
mbosi
s(1
.8%
),ed
ema
(1.2
%),
infe
ctio
n(1
.2%
)
Lom
ust
ine:
Hem
atolo
gic
[G
rade
3:
thro
mbocy
topen
ia(2
5%
),neu
tropen
ia(2
0.2
%),
leuco
pen
ia
(7.1
%)
Nonhem
atolo
gic
:In
fect
ion
(3.6
%)
Auth
ors
’co
ncl
usi
on:
Enza
stau
rin
has
less
toxic
ity
but
no
bet
ter
effi
cacy
than
lom
ust
ine
Cham
ber
lain
(2010)
Ret
rosp
ecti
ve
anal
ysi
sof
single
agen
tbev
aciz
um
abth
erap
yin
recu
rren
tgli
obla
stom
a
Pat
ient
popula
tion:
All
com
ple
ted
XR
Tan
dT
MZ
and
36
com
ple
ted
one
salv
age
alkyla
tor
regim
en
(n=
50)
Tre
atm
ent
regim
en:
Bev
aciz
um
ab10
mg/k
gev
ery
2w
eeks
III
PF
S-6
:42
%
Med
ian
TT
P:
1.0
month
s
Med
ian
Surv
ival
:8.5
month
s
Res
ponse
:P
R58
%
Toxic
ity:
fati
gue
(16
pat
ients
;4
gra
de
3),
leuco
pen
ia(9
;1
gra
de
3),
anem
ia(5
;0
gra
de
3),
hyper
tensi
on
(7;
1gra
de
3),
dee
pvei
nth
rom
bosi
s(4
;1
gra
de
3)
and
wound
deh
isce
nce
(2;
1gra
de
3)
Auth
ors
Concl
usi
on:
Bev
aciz
um
abal
one
dem
onst
rate
sef
fica
cyin
alkyla
tor
refr
acto
rygli
obla
stom
a
Gal
anis
(2009)
Phas
eII
anal
ysi
sof
vori
nost
atfo
rre
curr
ent
GB
M
Pat
ient
popula
tion:
Eli
gib
lepat
ients
had
his
tolo
gic
confi
rmat
ion
of
gra
de
4as
trocy
tom
aat
pri
mar
y
dia
gnosi
sor
recu
rren
cean
dre
ceiv
edno
more
than
one
pri
or
chem
oth
erap
yre
gim
enfo
rpro
gre
ssiv
e
or
recu
rren
tdis
ease
.T
his
could
be
firs
tor
late
rre
curr
ence
Tre
atm
ent
regim
en:
Vori
nost
at.
n=
66
III
PF
S-6
:15.2
%
Med
ian
Tim
eto
Pro
gre
ssio
n:
1.9
month
s
Med
ian
OS
:5.7
month
s
Res
ponse
:2
PR
Toxic
ity:
Gra
de[
3nonhem
atolo
gic
:26
%(f
atig
ue,
deh
ydra
tion,
hyper
nat
rem
ia).
Gra
de[
3
hem
atolo
gic
:26
%(m
ainly
thro
mbocy
topen
ia
Auth
ors
’co
ncl
usi
on:
‘‘M
odes
tsi
ngle
agen
tac
tivit
y’’
564 J Neurooncol (2014) 118:557–599
123
Ta
ble
1co
nti
nu
ed
Auth
or
(yea
r)D
escr
ipti
on
of
study
Dat
a
clas
s
Concl
usi
ons
Kre
isl
(2009)
Eval
uat
ion
of
the
acti
vit
yof
bev
aciz
um
abin
pat
ients
wit
hre
curr
ent
gli
obla
stom
a
Pat
ient
popula
tion:
Pat
ients
wit
hre
curr
ent
gli
obla
stom
a.(n
=48)
No
lim
itto
the
num
ber
of
pri
or
ther
apie
s
Tre
atm
ent
regim
en:
Fir
stst
age
of
ther
apy:
Bev
aciz
um
ab10
mg/k
gev
ery
2w
eeks
Sec
ond
stag
eof
ther
apy:
Aft
erpro
gre
ssio
ntr
eatm
ent
was
conver
ted
tobev
aciz
um
ab10
mg/k
gev
ery
2w
eeks
and
irin
ote
can
340
mg/m
2(p
atie
nts
on
EIA
ED
s)or
125
mg/m
2(p
atie
nts
not
on
EIA
ED
s).
19
case
sre
ceiv
edth
ese
cond
stag
eof
ther
apy
III
The
acti
vit
yin
thes
epat
ients
was
calc
ula
ted
for
the
tim
eth
eyw
ere
rece
ivin
gbev
aciz
um
abal
one
pro
vid
ing
som
euse
ful
dat
afo
rth
epurp
ose
of
this
guid
elin
e.S
om
edat
aco
uld
not
be
separ
ated
from
the
effe
cts
of
those
trea
ted
inth
ese
cond
stag
eof
ther
apy
afte
rpro
gre
ssio
non
bev
aciz
um
ab
alone
Pri
or
Ther
apy:
48
%of
pat
ients
had
[3
pri
or
chem
oth
erap
yre
gim
ens
PF
S-6
:29
%
Eff
ect
of
Fir
stS
tage
of
Ther
apy:
Med
ian
PF
S:
16
wee
ks
Eff
ect
of
Both
Sta
ges
of
Ther
apy:
OS
6m
onth
:57
%;
Med
ian
OS
:31
wee
ks;
Res
ponse
(McD
onal
d
Cri
teri
a)
Fir
stS
tage:
1C
R?
16
PR
:35
%
Sec
ond
Sta
ge:
No
obje
ctiv
ere
sponse
sw
ere
seen
inth
e19
pat
ients
trea
ted
wit
hth
ese
cond
stag
eof
ther
apy
Toxic
ity:
Thro
mboem
boli
cev
ents
(12.5
%),
hyper
tensi
on
(12.5
%),
hypophosp
hat
emia
(6%
),an
d
thro
mbocy
topen
ia(6
%)
Auth
ors
’co
ncl
usi
ons:
Sin
gle
agen
tbev
aciz
um
abhas
anti
tum
or
acti
vit
yin
pat
ients
wit
hre
curr
ent
gli
obla
stom
a
Quan
t(2
009)
Ret
rosp
ecti
ve
asse
ssm
ent
of
adult
pro
gre
ssiv
em
alig
nan
tgli
om
atr
eate
dw
ith
ase
cond
bev
aciz
um
ab
conta
inin
gre
gim
en
Pat
ient
popula
tion:
Pat
ients
who
pro
gre
ssed
on
abev
aciz
um
abco
nta
inin
gre
gim
enan
dw
ere
subse
quen
tly
trea
ted
wit
han
alte
rnat
ebev
aciz
um
ab-c
onta
inin
gre
gim
en(g
liobla
stom
an
=35)
Tre
atm
ent
regim
en:
Bev
aciz
um
abw
asco
mbin
edw
ith
eith
erca
rbopla
tin,
irin
ote
can,
carm
ust
ine,
lom
ust
ine,
etoposi
de,
or
erlo
tinib
III
Res
ponse
CR
and
PR
:N
one
All
oth
erre
sponse
par
amet
ers
wer
eca
lcula
ted
wit
hout
separ
atin
ghis
tolo
gie
s
Toxic
ity
Not
separ
ated
by
his
tolo
gy
or
trea
tmen
tag
ents
use
d
Auth
ors
Concl
usi
ons:
Those
pat
ients
wit
hgli
obla
stom
aw
ho
pro
gre
ssed
des
pit
ea
bev
aciz
um
ab-
conta
inin
gre
gim
endid
not
resp
ond
toth
ese
cond
bev
aciz
um
ab-c
onta
inin
gch
emoth
erap
euti
c
regim
en.
Insu
chpat
ients
,al
tern
ate
ther
apie
ssh
ould
be
consi
der
ed
Fri
edm
an
(2009)
Ran
dom
ized
,pro
spec
tive,
mult
icen
ter
nonco
mpar
ativ
eas
sess
men
tof
bev
aciz
um
abal
one
wit
h
bev
aciz
um
aban
dir
inote
can
ingli
obla
stom
aat
firs
tor
seco
nd
rela
pse
ina
mult
icen
ter
study
Pat
ient
popula
tion:
Pat
ients
wit
hhis
tolo
gic
ally
pro
ven
gli
obla
stom
aat
firs
t(8
0.8
%)
or
seco
nd
(19.2
%)
rela
pse
wit
him
agea
ble
tum
or
(n=
167).
7.8
%w
ere
seco
ndar
ygli
obla
stom
aan
dhad
his
tolo
gic
ally
confi
rmed
pro
gre
ssio
n
Tre
atm
ent
regim
en:
Pat
ients
wer
era
ndom
lyas
signed
toG
roup
1or
2:
Gro
up
1:
bev
aciz
um
ab10
mg/k
gal
one
ever
y2
wee
ks.
n=
85
Gro
up
2:
bev
aciz
um
ab10
mg/k
gw
ith
irin
ote
can
340
mg/m
2(w
ith
enzy
me-
induci
ng
anti
epil
epti
c
dru
gs)
or
125
mg/m
2(w
ithout
enzy
me-
induci
ng
anti
epil
epti
cdru
gs)
ever
y2
wee
ks.
n=
82
III
PF
S-6
:G
roup
1:
42.6
%;
Gro
up
2:
50.3
%;
Not
signifi
cantl
ydif
fere
nt
Med
ian
OS
:B
evac
izum
ab:
9.2
month
s;B
evac
izum
aban
dir
inote
can:
8.7
month
s;N
ot
signifi
cantl
y
dif
fere
nt
Res
ponse
:B
evac
izum
ab:
28.2
%;
CR
:1;
PR
:23
Bev
aciz
um
aban
dir
inote
can:
37.8
%:
CR
:2;
PR
:29;
Not
signifi
cantl
ydif
fere
nt
Med
ian
OS
:G
roup
1:
9.2
month
s;G
roup
2:
8.7
month
s
Toxic
ity:
Thir
ty-n
ine
pat
ients
(46.4
%)
inG
roup
1an
d52
pat
ients
(65.8
%)
inG
roup
2ex
per
ience
d
gra
de
3or
gre
ater
adver
seev
ents
.T
he
most
com
mon
wer
ehyper
tensi
on
(8.3
%)
and
convuls
ion
(6.0
%)
inG
roup
1an
dco
nvuls
ion
(13.9
%),
neu
tropen
ia(8
.9%
),an
dfa
tigue
(8.9
%)
inG
roup
2
Auth
ors
’co
ncl
usi
ons:
The
resu
lts
dem
onst
rate
dnota
ble
anti
tum
or
acti
vit
yof
single
-agen
t
bev
aciz
um
aban
dbev
aciz
um
abin
com
bin
atio
nw
ith
irin
ote
can
inpre
trea
ted
pat
ients
wit
h
gli
obla
stom
ain
firs
tor
seco
nd
rela
pse
.T
he
auth
ors
note
the
outc
om
esex
ceed
thei
rhis
tori
cal
info
rmat
ion
on
salv
age
chem
oth
erap
yw
hen
com
par
edto
bev
aciz
um
abal
one
and
irin
ote
can
alone
when
com
par
edto
bev
aciz
um
aban
dir
inote
can
(P\
0.0
001
inboth
inst
ance
s)
The
auth
ors
note
that
the
study
isnot
pow
ered
toac
hie
ve
am
eanin
gfu
loutc
om
eco
mpar
ison
and
cross
over
sw
ere
allo
wed
from
Gro
up
1to
Gro
up
2at
fail
ure
.C
om
par
ison
of
each
gro
up
to
publi
shed
his
tori
cal
dat
ain
this
pat
ient
popula
tion
yie
lds
clas
sII
Idat
a
J Neurooncol (2014) 118:557–599 565
123
Ta
ble
1co
nti
nu
ed
Auth
or
(yea
r)D
escr
ipti
on
of
study
Dat
a
clas
s
Concl
usi
ons
Ray
mond
(2008)
Phas
eII
study
of
imat
inib
inre
curr
ent
gli
om
as
Pat
ient
popula
tion:
Pat
ients
wit
hre
curr
ent
gli
om
asof
all
his
tolo
gie
s,n
=112
inal
l,51
of
whic
h
wer
egli
obla
stom
as
Tre
atm
ent
regim
en:
Init
iall
ya
once
dai
lyora
ldose
of
600
mg/d
ayes
cala
ted
to800
mg/d
ay(4
00
mg
twic
ea
day
)in
the
abse
nce
of
gra
de
2over
the
firs
t8
wee
ks
of
trea
tmen
t(n
=19
gli
obla
stom
as).
Invie
wof
good
tole
rance
,th
epro
toco
lw
asam
ended
toin
crea
seth
edose
of
imat
inib
to800
mg/
day
(400
mg
twic
ea
day
),w
ith
dose
esca
lati
on
to1,0
00
mg/d
ay(5
00
mg
twic
ea
day
)af
ter
8w
eeks
inth
eab
sence
of
gra
de
2to
xic
ity
(n=
31
gli
obla
stom
as)
III
The
auth
ors
pro
vid
eso
me
dat
aca
lcula
ted
for
gli
obla
stom
aal
one
PF
S-6
:16
%
6M
onth
OS
:50
%
Med
ian
OS
:5.9
month
s
Res
ponse
:P
R:
3(o
f51
gli
obla
stom
as)
Toxic
ity:
600
mg/d
aydose
:G
rade
3–4
([5
%in
ciden
ce)
Neu
tropen
ia6.6
%
Fat
igue
6.6
%
AL
Tel
evat
ion
6.6
%
800
mg/d
aydose
:G
rade
3–4
([5
%in
ciden
ce)
Neu
tropen
ia11
%
Feb
rile
neu
tropen
ia6.2
%
Auth
ors
’co
ncl
usi
ons:
The
over
all
resp
onse
rate
and
6-m
onth
PF
Sra
teac
hie
ved
are
insu
ffici
ent
to
sugges
tth
atim
atin
ibhas
clin
ical
lyuse
ful
acti
vit
yin
any
subty
pe
of
dif
fuse
gli
om
asw
hen
giv
enas
asi
ngle
agen
t
Rea
rdon
(2008)
Ran
dom
ized
phas
eII
study
of
cile
ngit
ide
inre
curr
ent
gli
obla
stom
a
Pat
ient
popula
tion:
Pat
ients
wit
hhis
tolo
gic
ally
confi
rmed
GB
Mth
atre
curr
edaf
ter
surg
ery,
XR
T,
and
no
more
than
one
chem
oth
erap
yre
gim
en(n
=81)
Tre
atm
ent
regim
en:
Pat
ients
wer
era
ndom
lyas
signed
tore
ceiv
eci
lengit
ide
atei
ther
500
(Arm
1,
n=
41)
or
2,0
00
mg
(Arm
2,
n=
40)
per
dose
.C
ilen
git
ide
was
infu
sed
intr
aven
ousl
yover
1h
twic
ew
eekly
,w
ith
atle
ast
72
hbet
wee
nin
fusi
ons.
Itw
asad
min
iste
red
in4
wee
ktr
eatm
ent
cycl
es
III
PF
S-6
:A
rm1:
10
%;
Arm
2:
15
%
Med
ian
TT
P:
Arm
1:
7.9
month
s;A
rm2:
8.1
month
s
Med
ian
OS
:A
rm1:
6.5
month
s;A
rm2:
9.9
month
s
Res
ponse
:P
R:
9%
(med
ian
17
month
sdura
tion,
wit
hno
dif
fere
nce
bet
wee
nar
ms)
Toxic
ity:
Gra
de
3–4
lym
phopen
ia:
9%
;G
rade
3–4
neu
tropen
ia:
1%
Nonhem
atolo
gic
:F
our
pat
ients
exper
ience
dgra
de
3nonhem
atolo
gic
toxic
itie
sposs
ibly
rela
ted
to
cile
ngit
ide.
Inth
e500-m
gar
m,one
pat
ient
had
tran
sam
inas
eel
evat
ion
and
one
pat
ient
exper
ience
d
arth
ralg
ia.
Inth
e2,0
00-m
gar
m,
one
pat
ient
dev
eloped
wei
ght
gai
nan
done
pat
ient
exper
ience
d
hea
dac
he
and
alte
red
men
tal
stat
us
Auth
ors
’co
ncl
usi
on:
The
exce
llen
tsa
fety
pro
file
and
modes
tac
tivit
yof
cile
ngit
ide
monoth
erap
y
note
din
the
study
are
enco
ura
gin
gbut
the
auth
ors
also
stat
eth
ecl
inic
alben
efit
of
single
-agen
t
ther
apy
for
targ
eted
ther
apeu
tics
among
unse
lect
edpat
ients
isli
mit
ed.
They
note
the
resp
onse
rate
and
PF
S-6
issi
mil
arto
tem
ozo
lom
ide
ther
apy
under
sim
ilar
circ
um
stan
ces
Pre
uss
er(2
008)
‘‘E
xplo
rato
ry’’
study
of
EG
FR
inhib
itors
inre
curr
ent
mal
ignan
tgli
om
a
Pat
ient
popula
tion:
Pat
ients
wit
hpro
gre
ssiv
em
alig
nan
tgli
om
aof
any
his
tolo
gy
incl
udin
g
gli
obla
stom
a(n
=21).
20/2
1had
rece
ived
radia
tion
and
all
had
rece
ived
pri
or
syst
emic
ther
apy
regim
ens
(ran
ge
1–5).
14/2
1pat
ients
had
gli
obla
stom
a
Tre
atm
ent
regim
en:
Erl
oti
nib
(n=
18):
pat
ients
\70
kg
rece
ived
100
mg/d
ay,
pat
ients
[70
kg
rece
ived
150
mg/d
ay.
Gefi
tinib
(n=
3):
250
mg/d
ay
III
Dat
ais
not
report
edby
his
tolo
gy
inth
ete
xt
how
ever
ata
ble
ispro
vid
edth
atin
cludes
each
pat
ient
and
allo
ws
for
som
eas
sess
men
t
Gli
obla
stom
are
sponse
PR
:2/1
4
Gli
obla
stom
aM
edia
nS
urv
ival
Tim
e:4.1
7m
onth
s
Auth
ors
’co
ncl
usi
on:
EG
FR
inhib
itors
seem
tobe
asso
ciat
edw
ith
ther
apeu
tic
effi
cacy
inonly
few
pat
ients
wit
hm
alig
nan
tgli
om
a.It
isnot
clea
rth
atth
etr
eatm
ent
pro
vid
edis
pro
spec
tive,
and
itis
not
clea
rw
hy
dif
fere
nt
EG
FR
inhib
itors
wer
euse
dfr
om
one
pat
ient
toan
oth
er,
thus
war
ranti
ng
des
ignat
ion
ascl
ass
III
dat
a
566 J Neurooncol (2014) 118:557–599
123
Ta
ble
1co
nti
nu
ed
Auth
or
(yea
r)D
escr
ipti
on
of
study
Dat
a
clas
s
Concl
usi
ons
Orl
ando
da
Fonse
ca
(2008)
Ast
udy
of
intr
anas
alper
illy
lal
cohol
adm
inis
trat
ion
inad
ult
sw
ith
recu
rren
tm
alig
nan
tgli
om
as
Pat
ient
popula
tion:
Pat
ients
wit
hpro
gre
ssiv
edis
ease
afte
rpri
or
surg
ery,
radio
ther
apy,
and
atle
ast
tem
ozo
lom
ide-
base
dch
emoth
erap
yw
ere
enro
lled
Over
all
n=
37
Gli
obla
stom
an
=29
Tre
atm
ent
regim
en:
0.3
%v/v
per
illy
lal
cohol
(55
mg)
4ti
mes
dai
lyby
intr
anas
aldel
iver
yto
tali
ng
220
mg/d
ay
III
Though
dubbed
phas
eI,
no
dose
esca
lati
on
occ
urr
ed.
Tim
ean
dre
ason
for
dis
conti
nuat
ion
of
ther
apy
not
clea
rly
outl
ined
PF
S-6
Gli
obla
stom
a:48.2
%
Res
ponse
Gli
obla
stom
aP
R:
1(3
.4%
)
Toxic
ity
No
toxic
ity,
dose
reduct
ion
or
dis
conti
nuat
ion
nee
ded
Auth
ors
Concl
usi
on:
Per
illy
lal
cohol
isw
ell
tole
rate
dan
dre
gre
ssio
nof
tum
or
size
inso
me
pat
ients
issu
gges
tive
of
anti
tum
or
acti
vit
y
This
was
apro
spec
tive
study
wit
hch
arac
teri
stic
sth
atar
enot
consi
sten
tw
ith
the
phas
eI
des
ign
sugges
ted
inth
epap
er.
The
min
imal
sum
mar
youtc
om
edat
aav
aila
ble
render
sth
iscl
ass
III
evid
ence
Fra
nce
schi
(2007)
Phas
eII
study
of
gefi
tinib
inpro
gre
ssiv
ehig
hgra
de
gli
om
as
Pat
ient
popula
tion:
Pat
ients
wit
hpro
gre
ssiv
ehig
hgra
de
gli
om
a(g
liobla
stom
a,an
apla
stic
astr
ocy
tom
a,an
apla
stic
oli
goden
dro
gli
om
aan
dan
apla
stic
oli
goas
trocy
tom
a)af
ter
surg
ery,
radio
ther
apy
and
no
more
than
one
cours
eof
chem
oth
erap
y
Over
all:
28
Gli
obla
stom
a:16
Tre
atm
ent
regim
en:
Gefi
tinib
was
adm
inis
tere
dora
lly
ata
dose
of
250
mg/d
ayunti
ldis
ease
pro
gre
ssio
nan
d/o
rsi
gnifi
cant
clin
ical
dec
line,
unac
cepta
ble
toxic
ity
or
the
pat
ient
dec
isio
nto
wit
hdra
w
III
Dat
aon
the
gli
obla
stom
apat
ients
isre
port
edse
par
atel
yin
this
study
and
note
dbel
ow
PF
S-6
:12.5
%
Res
ponse
CR
:0
PR
:0
Toxic
ity
Gra
de
3:
dia
rrhea
(n=
1)
and
neu
tropen
ia(n
=1)
Gra
de
4:
acute
pulm
onar
yed
ema
(n=
1),
pulm
onar
yth
rom
boem
boli
sm
(n=
1)
and
centr
alner
vous
syst
emhem
orr
hag
e(n
=1)
Auth
ors
’C
oncl
usi
on
The
PF
S-6
rate
was
too
low
toco
nsi
der
the
dru
gac
tive
inhig
hgra
de
gli
om
a
Lev
in(2
006)
Phas
eII
study
of
com
bin
atio
nch
emoth
erap
yw
ith
13-c
is-r
etin
oic
acid
(13-c
RA
)an
dce
leco
xib
inth
e
trea
tmen
tof
gli
obla
stom
a
Pat
ient
popula
tion:
Pat
ients
wit
hhis
tolo
gic
ally
pro
ven
supra
tento
rial
GB
Mth
athad
recu
rred
or
pro
gre
ssed
des
pit
era
dia
tion
ther
apy
(n=
25).
Pri
or
chem
oth
erap
yre
gim
ens
num
ber
ed0–3
Tre
atm
ent
regim
en:
13-c
RA
was
adm
inis
tere
dora
lly
asA
ccuta
ne
ata
dose
of
100
mg/m
2dai
lyin
div
ided
dose
sfo
r21
conse
cuti
ve
day
sfo
llow
edby
7dru
g-f
ree
day
s.C
elec
oxib
was
adm
inis
tere
d
ora
lly
ata
dose
of
400
mg
twic
edai
lyw
ith
13-c
RA
for
21
conse
cuti
ve
day
sfo
llow
edby
the
7-d
ay
rest
per
iod.
The
regim
enw
asre
pea
ted
unti
ltr
eatm
ent
fail
ure
or
the
dev
elopm
ent
of
signifi
cant
toxic
ity
III
Acc
rual
stopped
earl
ybec
ause
of
slow
accr
ual
Res
ponse
CR
,P
R:
0
PF
S-6
:19
%
Med
ian
PF
S:
8w
eeks
Toxic
ity
Gra
de
3
Skin
rash
/des
quam
atio
n,
pru
ritu
s,dry
skin
,xer
ost
om
a,hea
dac
he,
and
thro
mbocy
topen
ia:
1ea
ch
Auth
ors
’co
ncl
usi
on:
The
PF
Sra
tew
asth
esa
me
asth
e19
%6-m
onth
PF
Sra
tein
13-c
RA
alone
in
pat
ients
wit
hG
BM
[See
,2004].
Furt
her
use
of
the
com
bin
atio
nof
13-c
RA
wit
hce
leco
xib
isnot
war
rante
d
J Neurooncol (2014) 118:557–599 567
123
Ta
ble
1co
nti
nu
ed
Auth
or
(yea
r)D
escr
ipti
on
of
study
Dat
a
clas
s
Concl
usi
ons
Clo
ughse
y
(2006)
Phas
eII
study
of
tipif
arnib
inpat
ients
wit
hre
curr
ent
mal
ignan
tgli
om
adiv
ided
by
EIA
ED
s
Pat
ient
popula
tion:
Pat
ients
wit
hhis
tolo
gic
ally
confi
rmed
dia
gnosi
sof
pro
gre
ssiv
eor
recu
rren
t
mal
ignan
tgli
om
aaf
ter
radia
tion
wit
hm
easu
rable
dis
ease
wit
hup
totw
opri
or
rela
pse
s
Tre
atm
ent
regim
en:
Gro
up
A:
Pat
ients
not
takin
gE
IAE
Ds
wer
etr
eate
dw
ith
tipif
arnib
300
mg
bid
on
day
s1–21
ever
y4
wee
ks
(n=
46,
gli
obla
stom
an
=36)
Gro
up
B:
Pat
ients
takin
g
EIA
ED
sre
ceiv
edti
pif
arnib
600
mg
bid
on
day
s1–21
ever
y4
wee
ks
(n=
43,
gli
obla
stom
an
=31)
III
PF
S-6
Gli
obla
stom
a:G
roup
A:
16.7
%;
Gro
up
B:
6.5
%
Med
ian
PF
SG
liobla
stom
a:G
roup
A:
9w
eeks;
Gro
up
B:
6w
eeks
(P=
0.0
1)
Res
ponse
ingli
obla
stom
a:P
R:
Gro
up
A:
4;
Gro
up
B:
1
Toxic
ity:
Gro
up
A;
Gra
de
3–4
Hem
atolo
gic
:gra
nulo
cyto
pen
ia(n
=4),
leukopen
ia(n
=3),
lym
phocy
topen
ia(n
=1),
thro
mbocy
topen
ia(n
=1)
Gra
de
3–4
Nonhem
atolo
gic
:C
onst
ipat
ion,
dia
rrhea
,fa
tigue,
rash
(all
n=
1)
Gro
up
B:
Gra
de
3–4
Hem
atolo
gic
:none
Gra
de
3–4
Nonhem
atolo
gic
:H
eadac
he
(n=
2),
rash
(n=
2),
fati
gue
(n=
1)
Auth
ors
’co
ncl
usi
on:
The
ther
apeu
tic
ben
efit
from
single
-agen
tti
pif
arnib
ism
odes
t.F
utu
rest
udie
sin
gli
obla
stom
aw
ith
tipif
arnib
should
be
lim
ited
toth
ose
pat
ients
not
rece
ivin
gE
IAE
Ds
Wen
(2006)
Phas
eI
and
phas
eII
study
of
imat
inib
mes
yla
tein
recu
rren
tm
alig
nan
tgli
om
as
Pat
ient
popula
tion:
Pat
ients
wit
hhis
tolo
gic
ally
confi
rmed
mal
ignan
tgli
om
astr
eate
dw
ith
radia
tion
and
recu
rren
tby
imag
ing.
For
the
phas
eI
pat
ients
ther
eco
uld
be
no
more
than
3pri
or
tum
or
rela
pse
san
dfo
rphas
eII
no
more
than
2pri
or
tum
or
rela
pse
s
Phas
eI:
Over
all
n=
50;
Gro
up
A:
EIA
ED
s=
27;
Gro
up
B:
nonE
IAE
Ds
=23
(35
gli
obla
stom
asin
Gro
up
A?
B,
but
num
ber
of
gli
obla
stom
asby
gro
up
isnot
report
ed)
Phas
eII
:O
ver
all
n=
55
(all
nonE
IAE
D,
34
gli
obla
stom
as)
Tre
atm
ent
regim
en:
Phas
eI:
inte
rpat
ient
dose
esca
lati
on
schem
ebeg
innin
gat
400
mg/d
ayin
4w
eek
cycl
esti
llD
LT
’socc
urr
ed
Phas
eII
:P
atie
nts
rece
ived
imat
inib
mes
yla
te800
mg/d
ayin
itia
lly.
Four
gli
obla
stom
apat
ients
dev
eloped
hem
orr
hag
esan
dth
edose
was
reduce
dto
600
mg/d
ay
III
Max
imum
Tole
rate
dD
ose
nonE
IAE
Dpat
ients
:800
mg/d
ay
EIA
ED
pat
ients
:M
TD
not
reac
hed
.1200
mg/d
ayw
asm
axim
um
dose
use
d
Phas
eI
DL
Tin
nonE
IAE
Dpat
ients
:
neu
tropen
ia,
rash
,an
del
evat
edal
anin
eam
inotr
ansf
eras
e
Res
ponse
(gli
obla
stom
a)
Phas
eII
PF
S-6
:3
%
Res
ponse
ingli
obla
stom
a
PR
:2
inphas
eII
,1
inphas
eI
Toxic
ity:
Intr
atum
ora
lhem
orr
hag
es:
4in
phas
eII
gli
obla
stom
apat
ients
trea
ted
at800
mg/d
ay
Auth
ors
’co
ncl
usi
on
Rea
sons
for
poor
resp
onse
hypoth
esiz
edto
incl
ude
lim
ited
pen
etra
tion
of
the
dru
gac
ross
the
blo
od–
bra
inbar
rier
,an
dth
atin
hib
itio
nof
PD
GF
Ral
one
isin
suffi
cien
tto
pre
ven
tgro
wth
of
mal
ignan
t
gli
om
as.
Itm
aybe
asso
ciat
edw
ith
incr
ease
dtu
mor
hem
orr
hag
eri
sk
Doher
ty(2
006)
Pil
ot
study
of
gefi
tinib
or
erlo
tinib
and
siro
lim
us
inre
curr
ent
mal
ignan
tgli
om
as
Pat
ient
popula
tion:
Pat
ients
wit
ha
his
tolo
gic
dia
gnosi
sof
mal
ignan
tgli
om
atr
eate
dw
ith
atle
ast
radia
tion
ther
apy.
EIA
ED
sw
ere
not
allo
wed
.T
her
ew
asno
lim
itto
the
num
ber
of
pri
or
ther
apie
s.
(n=
28,
gli
obla
stom
a=
22)
Tre
atm
ent
regim
en:
Gefi
tinib
500
mg
or
erlo
tinib
150
mg
ora
lly
once
dai
lyin
com
bin
atio
nw
ith
siro
lim
us
ata
dose
of
6m
gora
lly
the
firs
tday
foll
ow
edby
4m
gora
lly
once
dai
lyth
erea
fter
.B
oth
med
icat
ions
wer
egiv
enco
nti
nuousl
yev
ery
day
in28
day
cycl
es
III
PF
S-6
gli
obla
stom
a:25
%
Res
ponse
ingli
obla
stom
a
PR
:4
(18
%)
Toxic
ity
Ras
h
Gra
de
3:
1(r
equir
ing
dis
conti
nuat
ion)
Infe
ctio
n
Gra
de
3:
3
All
pat
ients
rece
ivin
gco
nco
mit
ant
war
fari
nfo
rven
ous
thro
mboem
boli
cdis
ease
had
signifi
cant
elev
atio
nof
the
inte
rnat
ional
norm
aliz
edra
tio
(IN
R)
requir
ing
reduct
ion
inth
edose
of
war
fari
n
Auth
ors
’co
ncl
usi
on:
This
study
was
note
dto
hav
eal
lth
eli
mit
sof
its
pil
ot
nat
ure
but
was
sugges
ted
ithas
acti
vit
yco
mpar
edto
his
tori
cco
ntr
ol
PF
S-6
of
15
%fo
rgli
obla
stom
a
568 J Neurooncol (2014) 118:557–599
123
Ta
ble
1co
nti
nu
ed
Auth
or
(yea
r)D
escr
ipti
on
of
study
Dat
a
clas
s
Concl
usi
ons
Gal
anis
(2005)
Pro
spec
tive,
mult
i-in
stit
uti
onal
phas
eII
study
of
tem
siro
lim
us
inre
curr
ent
gli
obla
stom
apat
ients
Pat
ient
popula
tion:
Adult
pat
ients
wit
hpro
gre
ssiv
egli
obla
stom
aw
ho
hav
ere
ceiv
edno
more
than
pri
or
chem
oth
erap
yre
gim
en(n
=65)
Tre
atm
ent
regim
en:
Tem
siro
lim
us
250
mg
IVw
eekly
.A
trea
tmen
tcy
cle
was
defi
ned
as4
wee
ks
III
PF
S-6
:7.8
%
Med
ian
Tim
eto
Pro
gre
ssio
n:
2.3
month
s
Med
ian
over
all
surv
ival
:4.4
month
s
Res
ponse
CR
and
PR
:0
Toxic
ity
Hem
atolo
gic
Gra
de
3:
Over
all
11
%,
wit
hth
rom
bocy
topen
iain
9%
Gra
de
4:
None
Non-h
emat
olo
gic
:
Gra
de
3–4:
Over
all
51
%w
ith
hyper
chole
ster
ole
mia
11
%,
hyper
trig
lyce
ridem
ia
(8%
),hyper
gly
cem
ia(8
%),
rash
(8%
),an
dfa
tigue
(6%
)
Gra
de
5:
One
pneu
monia
and
one
pneu
monit
is
Auth
ors
concl
usi
on:
Tem
osi
roli
mus
isw
ell
tole
rate
din
this
popula
tion
and
longer
tim
eto
pro
gre
ssio
nin
those
wit
hso
me
radio
gra
phic
impro
vem
ent
and
inth
ose
wit
hhig
hbas
elin
etu
mor
level
sof
phosp
hory
late
dp70s6
kin
ase
Gro
ssm
an
(2005)
Phas
eII
study
of
the
anti
sense
oli
gonucl
eoti
de
apri
noca
rsen
dir
ecte
dat
pro
tein
kin
ase
C-a
lpha
Pat
ient
popula
tion:
Pat
ients
wit
han
apla
stic
astr
ocy
tom
a,an
apla
stic
oli
ogoden
dro
gli
om
a,or
gli
obla
stom
am
ult
iform
eth
athad
pro
gre
ssed
or
recu
rred
foll
ow
ing
radia
tion
ther
apy.
Pat
ients
may
hav
ehad
chem
oth
erap
y.
22
pat
ients
accr
ued
wit
h16
hav
ing
gli
obla
stom
a
Tre
atm
ent
regim
en:
Apri
noca
rsen
was
giv
enas
aco
nti
nuous
i.v.
infu
sion
over
21
day
s(a
t2
mg/k
g/
day
,w
ith
anopti
on
of
incr
easi
ng
the
infu
sion
rate
to3
mg/k
g/d
ayaf
ter
cycl
e2),
foll
ow
edby
a
seven
-day
trea
tmen
t-fr
eein
terv
al
III
Med
ian
TT
P:
36
day
s
Med
ian
Surv
ival
:3.4
month
s
Res
ponse
No
PR
or
CR
Toxic
ity
Thro
mbocy
top
enia
gra
de
3:
24
%
AL
Tgra
de
4:
5%
AS
Tgra
de
3:
5%
Nau
sea
gra
de
3:
5%
Vom
itin
ggra
de
3:
5%
Fat
igue
gra
de
3:
5%
Auth
ors
Concl
usi
on:
The
resu
lts
indic
ate
that
ther
eis
no
clin
ical
ben
efit
from
apri
noca
rsen
,as
pat
ients
who
wer
etr
eate
dra
pid
lydev
eloped
clin
ical
and
radio
gra
phic
evid
ence
consi
sten
tw
ith
tum
or
pro
gre
ssio
n
Chan
g(2
005)
Aphas
eII
anal
ysi
sof
CC
I-779
inpat
ients
wit
hre
curr
ent
gli
obla
stom
a
Pat
ient
popula
tion:
Pat
ients
wit
hhis
tolo
gic
ally
confi
rmed
gli
obla
stom
aat
init
ial
dia
gnosi
sor
by
surg
ery
atpro
gre
ssio
n.
Pri
or
radia
tion
nee
ded
tohav
ebee
nco
mple
ted
and
the
pat
ient
could
hav
e
no
more
than
2pri
or
rela
pse
s(n
=43
wit
h41
eval
uab
le)
Tre
atm
ent
regim
en:
CC
I-779
adm
inis
tere
dw
eekly
ata
dose
of
250
mg
intr
aven
ousl
yfo
rpat
ients
on
enzy
me-
induci
ng
anti
-epil
epti
cdru
gs
(EIA
ED
s).
Pat
ients
not
on
EIA
ED
sw
ere
init
iall
ytr
eate
dat
250
mg;
how
ever
,th
edose
was
reduce
dto
170
mg
bec
ause
of
into
lera
ble
side
effe
cts
inth
efo
rm
of
stom
atit
is
III
PF
S-6
:2
%;
Med
ian
TT
P:
9w
eeks
Res
ponse
:P
R:
2
Toxic
ity:
Ele
vat
edch
ole
ster
ol;
Gra
de
3:
9%
;G
rade
4:
7%
Ele
vat
edtr
igly
ceri
de:
Gra
de
3:
5%
;G
rade
4:
5%
Lym
phopen
ia:
Gra
de
3:
14
Anem
ia:
Gra
de
3:
5%
Sto
mat
itis
:G
rade
3:
5%
;G
rade
4:
5%
Auth
ors
Concl
usi
on:
No
evid
ence
of
effi
cacy
of
CC
I-779
alone
inpat
ients
wit
hre
curr
ent
gli
obla
stom
a
J Neurooncol (2014) 118:557–599 569
123
Ta
ble
1co
nti
nu
ed
Auth
or
(yea
r)D
escr
ipti
on
of
study
Dat
acl
ass
Concl
usi
ons
Ric
h(2
004)
Pro
spec
tive
phas
eII
study
of
gefi
tinib
inad
ult
sw
ith
recu
rren
tgli
obla
stom
a
Pat
ient
popula
tion:
Pat
ients
wit
hhis
tolo
gic
ally
confi
rmed
gli
obla
stom
aat
firs
tre
lapse
wit
hfr
esh
froze
ntu
mor
sam
ple
for
anal
ysi
sat
the
tim
eof
rela
pse
toco
nfi
rmre
curr
ent
dis
ease
.N
oim
agin
gre
sidual
requir
ed.N
och
emoth
erap
yor
radio
ther
apy
wit
hin
4w
eeks
of
study
entr
y(6
wee
ks
for
anit
roso
ure
a)
Tre
atm
ent
regim
en:
Gefi
tinib
atan
init
ial
ora
ldose
of
500
mg/d
ay.
Pat
ients
who
rece
ived
dex
amet
has
one
and/o
rE
IAE
Ds
and/o
roth
erC
YP
3A
4-i
nduci
ng
agen
tsw
ithout
toxic
itie
saf
ter
2w
eeks
of
rece
ivin
ggefi
tinib
had
the
gefi
tinib
dose
esca
late
dto
750
mg/d
ay.
Ifno
side
effe
cts
wer
enote
daf
ter
anad
dit
ional
2w
eeks,
the
dose
was
esca
late
dto
1,0
00
mg/d
ay
III
PF
S-6
:13
%
Med
ian
PF
S:
8.1
wee
ks
Res
ponse
CR
and
PR
:N
one
Toxic
ity
Ras
h
Gra
de
3:
5,
Gra
de
4:
3
Dia
rrhea
Gra
de
3:
5,
Gra
de
4:
2
Oth
erG
rade
3T
oxic
ity
Conju
nct
ivit
is(1
),A
LT
elev
atio
n(1
),A
ST
elev
atio
n(1
),D
eep
vei
nth
rom
bosi
s(2
),ce
rebra
led
ema
(1),
confu
sion
(1),
inco
nti
nen
ce(1
),hea
dac
he
(1),
musc
lew
eaknes
s(1
)
Oth
erG
rade
4T
oxic
ity
Sei
zure
(1),
intr
acer
ebra
lhem
orr
hag
e(1
)
Auth
ors
’co
ncl
usi
on:
Gefi
tinib
isw
ell
tole
rate
dan
dhas
acti
vit
yin
pat
ients
wit
hre
curr
ent
gli
obla
stom
a.T
he
auth
ors
go
on
tosp
ecula
teab
out
pote
nti
alad
van
tages
of
dose
modifi
cati
on
and
ther
apy
inco
mbin
atio
nw
ith
oth
erm
odal
itie
s
See (2
004)
Ret
rosp
ecti
ve
anal
ysi
sof
cis-
reti
noic
acid
inre
curr
ent
gli
obla
stom
a
Pat
ient
popula
tion:
Pat
ients
wit
hpri
or
his
tolo
gic
dia
gnosi
sof
gli
obla
stom
aan
dtr
eate
dw
ith
radia
tion
(med
ian
dose
of
60
Gy).
The
firs
t15
wer
etr
eate
das
par
tof
aphas
eII
pro
toco
lan
dth
ere
stof
pro
toco
l(n
=85
over
all)
.38
%fa
iled
two
or
more
pri
or
chem
oth
erap
yre
gim
ens
Tre
atm
ent
regim
en:
Of
the
firs
tth
ree
pat
ients
,one
was
trea
ted
wit
h60
mg/m
2/d
ay,
and
two
wer
etr
eate
dw
ith
80
mg/
m2/d
ayin
div
ided
dose
sfo
r21
conse
cuti
ve
day
s,fo
llow
edby
7dru
g-f
ree
day
s.T
he
rem
ainder
of
the
pat
ients
wer
etr
eate
dat
100
mg/m
2/d
ayfo
llow
edby
7dru
gfr
eeday
s
III
PF
S-6
:19
%
Med
ian
PF
S:
10.0
wee
ks
Med
ian
OS
:24.6
wee
ks
Res
ponse
PR
:3
(4%
)
Toxic
ity
Gra
de
3or
4to
xic
ity
dev
eloped
in14
pat
ients
(16.5
%),
incl
udin
g5
pat
ients
wit
hhyper
chole
ster
ole
mia
or
hyper
trig
lyce
ridem
ia(1
die
dof
acute
pan
crea
titi
s),
2
wit
hra
sh,
7w
ith
neu
tropen
iaor
leukopen
ia,
and
1w
ith
reti
nal
chan
ges
Auth
ors
’co
ncl
usi
on:
Res
ponse
sse
enin
this
retr
osp
ecti
ve
revie
war
esi
mil
arto
those
report
edw
ith
conven
tional
cyto
toxic
chem
oth
erap
yre
gim
ens.
The
side
effe
cts
are
tole
rable
,al
though
close
monit
ori
ng
isre
quir
edfo
rhyper
lipid
emia
Lim
its
yie
ldin
gcl
ass
III
stat
us
for
this
work
incl
ude
the
init
ial
3ca
ses
bei
ng
trea
ted
atlo
wer
dose
sth
anth
ere
stof
the
cohort
and
the
retr
osp
ecti
ve
nat
ure
of
the
maj
ori
tyof
the
rem
ainin
gca
ses
Puduval
li(2
004)
Phas
eII
study
of
fenre
tinid
efo
rpat
ients
wit
hre
curr
ent
mal
ignan
tgli
om
as
Pat
ient
popula
tion:
Pat
ients
wit
hsu
pra
tento
rial
mal
ignan
tgli
om
asw
ho
had
uneq
uiv
oca
ltu
mor
recu
rren
ceon
ast
able
ster
oid
dose
asdia
gnose
dby
mag
net
icre
sonan
ceim
agin
gsc
anaf
ter
radio
ther
apy
and
no
more
than
two
pri
or
chem
oth
erap
yre
gim
ens
(n=
23
inth
egli
obla
stom
aar
mw
ith
45
pat
ients
over
all)
Tre
atm
ent
regim
en:
The
dosa
ge
of
fenre
tinid
efo
rgli
obla
stom
aw
as600
mg/m
2bid
appro
xim
atel
y12
hap
art
on
day
s1–7
and
22–28
of
each
6-w
eek
per
iod,
const
ituti
ng
one
trea
tmen
tcy
cle
III
Anal
ysi
sw
asst
rati
fied
for
gli
obla
stom
a(2
2as
sess
able
)an
dan
apla
stic
gli
om
a
PF
S-6
gli
obla
stom
a:0
%
Med
ian
PF
Sgli
obla
stom
a:6
wee
ks
Med
ian
over
all
surv
ival
from
trea
tmen
tin
itia
tion
for
gli
obla
stom
a:16
wee
ks
Res
ponse
ingli
obla
stom
as
No
CR
or
PR
Toxic
ity
Gra
de
1to
xic
itie
sin
cluded
fati
gue,
hea
dac
he,
skin
chan
ges
and
dig
esti
ve
trac
tsy
mpto
ms
Gra
de
2to
xic
itie
sin
cluded
seiz
ure
san
dco
nfu
sion
One
epis
ode
of
intr
acra
nia
lhem
orr
hag
ew
asre
port
edan
done
leth
alca
seof
epis
taxis
ina
pat
ient
on
Coum
adin
was
obse
rved
Auth
ors
’co
ncl
usi
on:
Fen
reti
nid
edee
med
asin
acti
ve
atth
edosa
ge
use
d
570 J Neurooncol (2014) 118:557–599
123
Ta
ble
1co
nti
nu
ed
Auth
or
(yea
r)
Des
crip
tion
of
study
Dat
a
clas
s
Concl
usi
ons
Oudar
d
(2003)
Phas
eII
study
of
lonid
amin
ean
ddia
zepam
for
recu
rren
tgli
obla
stom
a
Pat
ient
popula
tion:
Pat
ients
wit
hhis
tolo
gic
ally
pro
ven
gli
obla
stom
aw
ith
imag
ing
evid
ence
of
tum
or
pro
gre
ssio
naf
ter
radia
tion
ther
apy
and
chem
oth
erap
y(n
=16
wit
h14
eval
uab
lefo
rre
sponse
)
Tre
atm
ent
regim
en:
Lonid
amin
e450
mg
dai
lyan
ddia
zepam
15
mg
dai
lyon
aco
nti
nuous
bas
is
III
Med
ian
TT
P:
8w
eeks
Med
ian
over
all
surv
ival
:15
wee
ks
Res
ponse
:N
oC
Ror
PR
Toxic
ity
No
hem
atolo
gic
toxic
ity
and
no
nonhem
atolo
gic
gra
de
4to
xic
ity.
Gra
de
3so
mnole
nce
in9
pat
ients
Auth
ors
’co
ncl
usi
on:
This
com
bin
atio
nhas
afa
vora
ble
safe
typro
file
but
resu
lted
inno
obje
ctiv
e
resp
onse
Mar
x
(2001)
Phas
eII
study
of
thal
idom
ide
inre
curr
ent
gli
obla
stom
as
Pat
ient
popula
tion:
Pat
ients
wit
hsu
pra
tento
rial
his
tolo
gic
ally
confi
rmed
gra
de
IVgli
om
a
(gli
obla
stom
a)an
dra
dio
logic
alev
iden
ceof
pro
gre
ssiv
edis
ease
afte
rfu
lldose
stan
dar
dfr
acti
onat
ion
exte
rnal
bea
mra
dio
ther
apy
(n=
42
wit
h38
eval
uab
le)
Tre
atm
ent
regim
en:
Thal
idom
ide
100
mg/d
ay,
incr
ease
dat
wee
kly
inte
rval
sby
100
mg
toa
max
imum
tole
rate
ddose
wit
ha
lim
itof
500
mg/d
ay
III
Med
ian
Max
imum
Tole
rate
dD
ose
:300
mg
Med
ian
TT
P:
11
wee
ks;
Med
ian
Surv
ival
:31
wee
ks;
1Y
ear
Surv
ival
Rat
e:35
%
Res
ponse
:P
R:
2
SD
:16
Toxic
ity:
Gra
de
3
Fat
igue:
3(8
%)
Const
ipat
ion:
2(5
%)
Edem
a:1
(3%
)
Xer
ost
om
a:1
(3%
)
Neu
ropat
hy
was
the
dose
lim
itin
gto
xic
ity
info
ur
pat
ients
Auth
ors
’co
ncl
usi
on:
Thal
idom
ide
has
som
ebio
logic
alac
tivit
yan
dm
ayim
pac
ton
the
qual
ity
of
life
of
pat
ients
wit
hre
curr
ent
gli
obla
stom
a.O
pti
mum
dosi
ng
wit
han
tian
gio
gen
icag
ents
isst
ill
under
inves
tigat
ion.
Though
this
was
label
eda
phas
eII
study,
asi
gnifi
cant
par
tof
the
des
ign
incl
uded
intr
apat
ient
dose
esca
lati
on
yie
ldin
ga
dat
am
ore
consi
sten
tw
ith
aphas
eI
study.
14/4
2ca
ses
rece
ived
1–2
chem
oth
erap
yre
gim
ens
pri
or
toen
roll
men
tpro
vid
ing
ahet
erogen
eous
study
popula
tion
Vla
ssen
ko
(2000)
Eval
uat
ion
of
SU
101
inpat
ients
wit
hre
curr
ent
mal
ignan
tgli
om
asw
ith
FD
GP
ET
and
Gd-D
TP
AM
RI
Pat
ient
popula
tion:
Ara
ndom
sele
ctio
nof
pat
ients
ina
larg
erphas
eII
clin
ical
tria
lof
SU
101
are
the
subje
cts
of
this
study.
All
had
under
gone
surg
ery
and
radia
tion
and
7/8
had
som
efo
rmof
chem
oth
erap
y(n
=8
wit
h5
gli
obla
stom
as)
Tre
atm
ent
regim
en:
SU
101
was
adm
inis
tere
din
trav
enousl
yas
a4-d
aylo
adin
gdose
at417–443
mg/m
2/
day
wit
hm
ainte
nan
ceth
erap
yev
ery
7–14
day
s
III
This
was
ast
udy
for
whic
ha
maj
or
thru
stw
asim
agin
gco
rrel
atio
nof
ther
apy
resp
onse
wit
hF
DG
PE
T
and
MR
I.H
ow
ever
,so
me
outc
om
edat
ais
pro
vid
ed
Mea
nT
TP
gli
obla
stom
a:12.4
wee
ks
Mea
nS
urv
ival
from
trea
tmen
tst
art
gli
obla
stom
a:25.8
wee
ks
Toxic
ity:
Toxic
ity
was
not
enum
erat
edan
dth
eau
thors
stat
eth
atin
all
pat
ients
inth
isP
ET
study,
ther
apy
rela
ted
toxic
ity
was
rever
sible
,an
ddea
thre
sult
edfr
om
tum
or
pro
gre
ssio
n
Auth
ors
Concl
usi
on:
The
study
was
susp
ended
by
the
sponso
rdue
tounex
pec
ted
mort
alit
ies
inth
e
larg
erphas
eII
study.
Corr
elat
ive
FD
Gst
udie
sw
ere
not
pre
dic
tive
of
tum
or
pro
gre
ssio
n
Bush
unow
(1999)
Stu
dy
of
goss
ypol
inre
curr
ent
mal
ignan
tgli
om
a
Pat
ient
popula
tion:
Pat
ients
wit
hpat
holo
gic
ally
confi
rmed
anap
last
icas
trocy
tom
aor
gli
obla
stom
a
whic
hhad
imag
ing
evid
ence
of
recu
rren
ceaf
ter
radia
tion
ther
apy
wit
hno
spec
ific
lim
itto
pri
or
chem
oth
erap
y(n
=27
wit
h15
gli
obla
stom
as)
Tre
atm
ent
regim
en:
Goss
ypol
10
mg
ora
lly
twic
ea
day
taken
1h
pri
or
toor
1h
afte
rm
eals
or
anta
cids
unti
lth
epat
ient
had
evid
ence
of
pro
gre
ssiv
edis
ease
or
dev
eloped
gre
ater
than
gra
de
2to
xic
ity
III
Res
ponse
ingli
obla
stom
a
PR
:2
Toxic
ity
(all
his
tolo
gie
s)
Gra
de
3
Hypokal
emia
:1
Auth
ors
’co
ncl
usi
ons:
Goss
ypol
isw
ell
tole
rate
dan
dhas
alo
w,
but
mea
sura
ble
,re
sponse
rate
ina
hea
vil
ypre
trea
ted,
poor-
pro
gnosi
sgro
up
of
pat
ients
wit
hre
curr
ent
gli
om
a.W
est
opped
our
study
bas
edon
our
findin
gof
alo
wre
sponse
rate
inth
ispoor-
pro
gnosi
s,unse
lect
edgro
up
of
pat
ients
Pre
trea
tmen
tpro
gre
ssio
nof
one
low
gra
de
gli
om
aca
sew
asas
sum
edto
hav
ebec
om
ea
mal
ignan
t
gli
om
abas
edon
imag
ing
wit
hout
his
tolo
gic
confi
rmat
ion.
Pre
trea
tmen
tch
emoth
erap
yw
as
het
erogen
eous
inte
rms
of
num
ber
of
rela
pse
san
dty
pes
of
agen
tsyie
ldin
gcl
ass
III
dat
a
J Neurooncol (2014) 118:557–599 571
123
Ta
ble
1co
nti
nu
ed
Auth
or
(yea
r)
Des
crip
tion
of
study
Dat
acl
ass
Concl
usi
ons
Kab
a
(1997)
Phas
eII
eval
uat
ion
of
all-
tran
s-re
tinoic
acid
inre
curr
ent
cere
bra
lgli
om
as
Pat
ient
popula
tion:
Pat
ients
wit
hre
curr
ent
pri
mar
ygli
om
asw
ho
had
com
ple
ted
radia
tion
ther
apy
(n=
36
wit
h21
gli
obla
stom
as)
19/2
1gli
obla
stom
ashad
rece
ived
som
efo
rmof
chem
oth
erap
y
pre
vio
usl
y
Tre
atm
ent
regim
en:
150
mg/m
2/d
ayof
all-
tran
s-re
tinoic
acid
giv
enora
lly
for
3w
eeks
foll
ow
edby
a
rest
per
iod
of
1w
eek.
Tw
o4
wee
kcy
cles
const
itute
d1
cours
eof
ther
apy.
Fourt
een
pat
ients
wer
e
trea
ted
atth
isdose
level
.T
hen
the
star
ting
dose
was
reduce
dto
120
mg/m
2in
subse
quen
tpat
ients
bec
ause
of
the
freq
uen
tocc
urr
ence
of
sever
ehea
dac
he
wit
hth
ehig
her
dose
III
Res
ponse
ingli
obla
stom
a
CR
and
PR
:N
one
TT
Pan
dS
urv
ival
:N
ot
report
edfo
rgli
obla
stom
aas
agro
up
Toxic
ity
(all
pat
ients
)
Gra
de
3
Hea
dac
he:
5
Hyper
trig
lyce
ridem
ia:
3
Nau
sea
and
vom
itin
g:
1
Fat
igue:
1
Confu
sion:
1
Auth
ors
’C
oncl
usi
on
All
-tra
ns-
reti
noic
acid
asa
single
agen
thas
no
signifi
cant
acti
vit
yag
ainst
recu
rren
tce
rebra
lgli
om
as
Could
wel
l
(1996)
Stu
dy
of
hig
hdose
tam
oxif
enin
recu
rren
tm
alig
nan
tgli
om
as
Pat
ient
popula
tion:
Pat
ients
wit
hm
alig
nan
tgli
om
asw
ith
dem
onst
rate
dcl
inic
alan
dra
dio
gra
phic
pro
gre
ssio
nfo
llow
ing
exte
rnal
bea
mra
dia
tion
ther
apy
(and
addit
ional
chem
oth
erap
yin
11;
imm
unoth
erap
yin
2)
(over
all
n=
32
eval
uab
lew
ith
20
gli
obla
stom
as)
Tre
atm
ent
regim
en:
Tam
oxif
en200
mg/d
ayin
mal
esan
d160
mg/d
ayin
fem
ales
giv
enw
ith
a
conti
nuous
twic
edai
lysc
hed
ule
III
Med
ian
over
all
surv
ival
from
init
ial
dia
gnosi
sgli
obla
stom
a:17.4
month
s
Med
ian
surv
ival
from
init
iati
on
of
tam
oxif
engli
obla
stom
a:7.2
month
s
Res
ponse
ingli
obla
stom
as:
4/2
0(2
0%
)T
reat
men
tre
sponse
was
defi
ned
asa
gre
ater
than
50
%
dec
reas
ein
volu
me
of
the
enhan
cing
lesi
on
volu
me
on
MR
Ian
da
dec
reas
ein
met
aboli
cac
tivit
y
(18F
dG
upta
ke)
on
PE
Tsc
ans
wit
hcl
inic
alneu
rolo
gic
alim
pro
vem
ent
(incl
udin
gK
arnofs
ky
score
s)
Toxic
ity
Dee
pven
ous
thro
mbosi
s(2
),nau
sea
(1),
hot
flas
hes
(1),
fati
gue
(2)
Auth
ors
’co
ncl
usi
on:
This
ther
apy
may
repre
sent
anal
tern
ativ
eor
adju
van
tto
exis
ting
chem
oth
erap
ies
for
thes
etu
mors
The
nonco
mpar
ativ
enat
ure
of
this
study
and
the
het
erogen
eous
nat
ure
of
the
pre
-enro
llm
ent
ther
apy
yie
lds
clas
sII
Idat
a
Yung
(1996)
Eval
uat
ion
of
13-c
is-R
etin
oic
Aci
d(C
RA
)in
recu
rren
tgli
obla
stom
a
Pat
ient
popula
tion:
Pat
ients
wit
hhis
tolo
gic
ally
pro
ven
mal
ignan
tgli
om
aan
duneq
uiv
oca
lev
iden
ceof
tum
or
recu
rren
ceor
dis
ease
pro
gre
ssio
nby
CT
or
MR
Isc
ans
afte
rfa
ilin
gpri
or
radia
tion
ther
apy
and
chem
oth
erap
y(1
–4
regim
ens)
(n=
50
wit
h43
eval
uab
leof
whic
h15
wer
egli
obla
stom
as)
Tre
atm
ent
regim
en:
CR
Aas
asi
ngle
agen
tora
lly
ata
dose
of
60–100
mg/m
2per
day
.T
hre
ew
eeks
of
trea
tmen
tw
ere
foll
ow
edby
1w
eek
of
rest
III
Med
ian
tim
eto
pro
gre
ssio
ngli
obla
stom
a:19
wee
ks
Med
ian
Surv
ival
Tim
egli
obla
stom
a:58
wee
ks
Res
ponse
ingli
obla
stom
a
CR
,P
R:
None
Toxic
ity
(all
his
tolo
gie
s)
Sid
eef
fect
sw
ere
des
crib
edas
‘‘in
gen
eral
mil
dto
moder
ate
and
tole
rable
.’’
and
no
gra
din
gor
tabula
r
form
atw
aspro
vid
ed.
Most
pat
ients
dev
eloped
‘‘dry
skin
,cr
acked
lips,
and
occ
asio
nal
ulc
ers
inora
l
muco
sa.’’
Ele
vat
ion
of
trig
lyce
rides
was
seen
info
ur
pat
ients
afte
r2–6
month
sof
ther
apy.
Tw
oof
the
four
pat
ients
also
dev
eloped
anel
evat
edch
ole
ster
ol
level
.O
ne
pat
ient
dev
eloped
mar
ked
elev
atio
nof
seru
mtr
igly
ceri
des
and
pri
mar
yac
ute
pan
crea
titi
san
dsu
ccum
bed
Auth
ors
’co
ncl
usi
on:
CR
Aap
pea
rsto
pro
vid
esi
gnifi
cant
ben
efit
wit
ha
mil
ddeg
ree
of
toxic
ity
for
this
gro
up
of
pat
ients
Four
dif
fere
nt
star
ting
dose
sw
ere
use
din
this
study
asit
pro
gre
ssed
mak
ing
the
ther
apy
more
dif
ficu
lt
toco
mpar
efr
om
one
case
toan
oth
er.
This
yie
lds
clas
sII
Idat
a
CB
cintr
edek
inbes
udoto
x,
GW
Gli
adel
waf
ers,
PF
S-6
pro
gre
ssio
nfr
eesu
rviv
alat
6m
onth
s,O
Sover
all
surv
ival
,T
TP
tim
eto
pro
gre
ssio
n,
EIA
ED
enzy
me-
induci
ng
anti
-epil
epti
cdru
g,
CR
com
ple
tere
sponse
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Rpar
tial
resp
onse
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LT
dose
lim
itin
gto
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axim
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Rep
ider
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or
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pto
r,cR
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CI-
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ethyl
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rof
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us
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xym
ethy
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e)ra
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gra
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l)-p
hen
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ide,
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uoro
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cose
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tron
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ogra
phy,
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PT
Agad
oli
niu
m-
die
thylt
riam
inep
enta
acet
icac
id
572 J Neurooncol (2014) 118:557–599
123
Burkhardt et al., reported a phase I, single center trial
assessing 14 patients with recurrent glioblastoma treated
with a single dose of superselective intra-arterial cerebral
infusion of bevacizumab after blood–brain barrier disrup-
tion (BBBD). BBBD was performed by giving a single
dose of mannitol (1.4 M) at 10 mL per 120 s, and then
bevacizumab was given with dose escalation from 2 to
15 mg/kg. Twelve of the fourteen patients went on to twice
monthly intravenous doses of bevacizumab and two con-
tinued monthly intra-arterial bevacizumab after BBBD.
Median progression free survival was 10 months, with
median survival 8.8 months (4 patients died prior to
imaging progression). The authors do not state the cause of
death in these four and cite weaknesses in imaging
assessment of progression by the updated Response
Assessment in Neuro-oncology criteria as an explanation
for the median progression free survival being longer than
median overall survival [21]. Eight patients had a partial
response. The authors conclude that this technique gives
‘‘encouraging’’ outcomes in comparison to trials of IV
bevacizumab and irinotecan and given study design yields
class III data [25].
Thalidomide Thalidomide was evaluated by Marx et al.
based on its anti-angiogenic effect. Although the authors
called the study, a phase II study the drug dose was esca-
lated in each patient. Doses of 100–500 mg/day were used.
In the 38 evaluable patients, the median tolerated dose was
300 mg/day. Median time to progression was 11 weeks,
median survival from treatment initiation was 31 weeks
and two cases of partial response were observed. This
provides Class III data. The authors note an optimal dosing
regimen was not identified but they felt that the agent had
activity and warranted further pursuit [26].
Pazopanib Iwamoto et al. conducted a phase II trial of
pazopanib, a selective multi-targeted receptor tyrosine
kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3,
PDGFR-a/b, and c-kit that blocks tumor growth and
inhibits angiogenesis, given at a dose of 800 mg daily, in
35 patients with recurrent glioblastoma. The study design
results in class III data. They reported a median progression
survival of 12 weeks, with progression free survival rate at
6 months of 3 %. Two patients had a partial response.
Median overall survival from pazopanib treatment initia-
tion was 35 weeks [27].
Aflibercept In a prospective phase II, multicenter trial, de
Groot et al., studied aflibercept in recurrent, high-grade
glioma patients. Aflibercept is a (a recombinant fusion
protein of the extracellular domains of VEGF fused to the
Fc portion of immunoglobulin G1 that binds with high
affinity to VEGF-A, VEGF-B and placental growth factor).
Aflibercept was given 4 mg/kg IV on day 1 of every
14-day cycle. Among glioblastoma patients, median PFS
was 12 weeks and median OS was 39 weeks. Seven of 39
glioblastoma patients achieved a partial response (18 %).
Six of 39 patients had to stop treatment from toxicity. The
authors conclude aflibercept has minimal activity as a
single agent in this patient population and this study yields
Class III data [28].
Anti-angiogenic agents combined with cytotoxic agents
Thalidomide and cytotoxic agents Fine et al. described
their experience with a phase II study of thalidomide and
BCNU in 6-week cycles. The thalidomide was escalated
within each patient as tolerated. Progression free survival at
6 months for the 38 glioblastomas was 27.03 %. The
median progression free survival for the glioblastomas was
104 days. Toxicities were as expected for BCNU. The
authors stated it was their impression that the combination
was more efficacious than either drug alone, but recom-
mended a confirmatory study (see Table 2) [29]. This and
the remainder of the studies combining anti-angiogenic
agents with cytotoxic agents yield class III data.
In an updated version of the report by Fine et al., a phase
II study of thalidomide and temozolomide was reported by
Groves et al. Intrapatient thalidomide escalation was
allowed from 400 to 1,200 mg/day [30]. In the 43 evalu-
able glioblastomas and gliosarcomas, progression free
survival at 6 months was 23 %, median time to progression
was 15 weeks and there were three partial responses. It was
the authors’ opinion that thalidomide minimally improved
disease control over temozolomide alone. This is based on
a historical overall progression free survival at 6 months
from studies of various agents of 15 % and from single
agent TMZ of 21 % [19, 31]. No statistical comparison was
carried out between the current and historical studies and
thus this is a class III study. In addition, they note the small
improvement of disease control observed was at the cost of
additional toxicity [30].
Sorafenib and temozolomide In a phase II study of daily
sorafenib (a small molecular inhibitor of several tyrosine
protein kinases such as VEGFR and PDGFR and Raf
kinases) and temozolomide at a single center, Reardon et al.,
studied adult patients with recurrent glioblastoma (n = 32).
Six-month progression free survival was 9.4 %, with median
progression free survival of 6.4 weeks. Partial response only
occurred in 1 patient (3 %). The authors conclude that this
dosing regimen, while reasonably well tolerated, has limited
activity in recurrent glioblastoma [32].
Bevacizumab and cytotoxic agents The meeting abstract
by Stark-Vance is an example of early experience with
J Neurooncol (2014) 118:557–599 573
123
bevacizumab and irinotecan. Although eleven of the 21
cases reported were glioblastomas, the responses and tox-
icities were not separated by histology and the report does
not qualify for inclusion in this guideline beyond men-
tioning it for historical interest [33].
This initial report was followed by a series of others
with progressively better design. Pope et al. retrospectively
reviewed their experience with iriniotecan, carboplatin or
etoposide with bevacizumab. Ten of the fourteen cases
were recurrent glioblastomas. Forty percent of these cases
demonstrated a partial response. The authors recognized
the limits of this report and emphasized the extent of
response despite the eclectic nature of the reported popu-
lation. This represented class III data [34].
In a formally designed phase II study, Vredenburgh
et al. administered bevacizumab at 10 mg/kg and irino-
tecan at 340 mg/m2 for patients on enzyme-inducing anti-
epileptic drugs and at 125 mg/m2 in those not on enzyme-
inducing anti-epileptic drugs. Each agent was administered
intravenously once every 2 weeks, i.e., days 1, 15, and 29
of a 6-week cycle. In the 23 glioblastomas included, the
progression free survival at 6 months was 30 %. Median
progression free survival was 20 weeks and median overall
survival was 40 weeks. There was one complete response
and 13 partial responses. There were two treatment related
deaths including one pulmonary embolus and one arterial
ischemic stroke. The authors concluded the regimen had
antitumor activity but at the cost of significant toxicity
[35].
In the next iteration for the same group, a comparison of
two slightly different regimens of bevacizumab and irino-
tecan Vredenburgh et al. compared all parameters, and
found them to have no statistical difference. Therefore,
they reported them as one group. The progression free
survival at 6 months was 46 %. The median progression
free survival was 24 weeks and the median overall survival
was 42 weeks. They concluded that the outcomes in this
group of 35 glioblastomas were better than historic controls
of cytoxic agents alone. No formal statistical comparison
was accomplished yielding class III data [20, 31, 36–38]
In the report alluded to above by Friedman et al., the
therapy of one of the two randomized groups was bev-
acizumab and irinotecan (n = 82). The 6-month progression
free survival was 50.3 % and median overall survival from
treatment initiation was 8.7 months. When compared to
historical reports of irinotecan therapy, these outcomes were
significantly better (P \ 0.0001) [39–42]. The response rate
was 37.8 % including two complete responses and 29 partial
responses. This combined therapy was associated with grade
three or greater toxicities with the most common being
convulsions (13.9 %), neutropenia (8.9 %), and fatigue
(8.9 %). %). The resultant data is methodically compared to
historical data, this produces class II data [22].
In consideration of alternative cytotoxic agents to be
combined with bevacizumab Reardon et al. provided their
experience with daily etoposide and standard dose bev-
acizumab in a population that included 27 progressive
glioblastomas. The progression free survival at 6 months
was 44.4 %. The median overall survival was 46.4 weeks.
Combined complete and partial response was 23 %. It is of
note that abstract and table numbers for these outcome
parameters are different in this paper. Neutropenia occur-
red in 24 % of cases and there was one death from pul-
monary embolism. The authors concluded the efficacy of
the combination was similar to bevacizumab alone but at
the cost of increased toxicity. No statistical analyses were
conducted compared to other published studies (making
this class III data), but the authors note for recurrent
glioblastoma patients, the 6-PFS rate and median overall
survival were higher than those reported with temozolo-
mide at first recurrence, as well as those reported in several
studies with etoposide and historical series of salvage
regimens [19, 20, 31, 43, 44]. Additionally, the outcomes
of this study did not differ significantly from those with
bevacizumab plus irinotecan in a single institution, phase 2
study [35, 45].
Desjardins et al. reported on the use of continuous low
dose temozolomide and biweekly bevacizumab in glio-
blastoma patients that included those with multiple recur-
rences and prior treatment regimens. They found a
progression free survival at 6 months of 18.8 % and
median overall survival rate of 37.1 weeks. Toxicity was as
expected for these agents. The authors noted activity in the
regimen, but observed it was less than in earlier reports of
the use of bevacizumab alone or with cytotoxics. They
suspected this was due to the greater degree of pretreatment
in this population of 32 cases [22, 38, 46].
Reardon et al., reported a phase II, open label, single
arm, single institution study using carboplatin, irinotecan,
and bevacizumab among progressive glioblastoma patients
who progressed on a regimen that had included bev-
acizumab. Six month progression free survival was 16 %,
with a median progression free survival of 2.3 months.
Median overall survival was 5.8 months. No patient met
criteria for radiographic response, but 20 achieved stable
disease. Nine dose reductions were carried out because of
toxicity. The authors concluded that, given the lack of
therapies available in this patient population, this combi-
nation had a modest antitumor effect with an acceptable
safety profile [47].
Reardon et al., performed a similar phase II, open label,
single arm trial using carboplatin, irinotecan, and bev-
acizumab at the same doses in bevacizumab-naı́ve, recur-
rent glioblastoma patients previously treated with radiation
and temozolomide. Grade three toxicities were significant
and included grade 3 anemia, thrombocytopenia,
574 J Neurooncol (2014) 118:557–599
123
Ta
ble
2C
om
bin
edta
rget
edth
erap
yan
dcy
toto
xic
chem
oth
erap
y
Auth
or,
yea
rD
escr
ipti
on
of
study
Dat
a
clas
s
Concl
usi
ons
Chin
nai
yan
etal
.,2012
Phas
eI,
mult
icen
ter
tria
lof
bev
aciz
um
ab,
irin
ote
can,
and
vori
nost
atin
recu
rren
tgli
obla
stom
a
Pat
ient
popula
tion:
Adult
pat
ients
wit
hhis
tolo
gic
ally
confi
rmed
gli
obla
stom
aor
gli
osa
rcom
atr
eate
d
wit
hra
dia
tion
and
tem
ozo
lom
ide
but
not
bev
aciz
um
abor
irin
ote
can.
(n=
19)
Tre
atm
ent
regim
en:
Bev
aciz
um
abw
asgiv
en(1
0m
g/k
gi.
v.)
wit
hir
inote
can
(125
mg/m
2i.
v.)
on
day
s
1an
d15
ever
y28
day
s.V
ori
nost
atw
asgiv
enin
a3
?3
dose
-esc
alat
ion
des
ign
wher
eit
was
giv
en
atdose
sbet
wee
n200
and
400
mg
per
day
on
day
s1–7
and
15–21
of
a28-d
aycy
cle,
asa
thre
e-ti
er
dosi
ng
schem
a.D
ue
toto
xic
ity,
the
thir
dti
erw
asad
just
edto
300
mg
twic
edai
lyon
day
s1–3
and
15–17
of
the
28-d
aycy
cle.
Ifm
ore
than
two
pat
ients
had
adose
-lim
itin
gto
xic
ity,th
edose
would
not
esca
late
III
Med
ian
PF
S:
3.6
month
s
Med
ian
OS
:7.3
month
s
Toxic
itie
s:G
rade
3an
d4
toxic
itie
sin
cluded
neu
tropen
ia(n
=1),
dia
rrhea
(n=
3),
muco
siti
s(n
=1),
stom
ach
pai
n(n
=1),
fati
gue
(n=
5),
CN
Sis
chem
ia(n
=2),
hyper
tensi
on/h
ypote
nsi
on
(n=
1),
or
senso
ryneu
ropat
hy
(n=
1)
Auth
ors
’co
ncl
usi
ons:
Irin
ote
can
com
monly
requir
eddose
reduct
ions
earl
yin
ther
apy.
Hig
h-d
ose
vori
nost
athad
anim
pro
ved
PF
San
dO
Sth
anlo
w-d
ose
,but
this
was
not
stat
isti
call
ysi
gnifi
cant
An
MT
Dof
vori
nost
atof
400
mg/d
ayfo
rth
isco
mbin
atio
nhas
bee
nes
tabli
shed
,al
though
ithas
poor
long-t
erm
tole
rabil
ity,
most
lydue
toth
ein
crea
sed
toxic
itie
sof
irin
ote
can
Rea
rdon
etal
.,2012
Pro
spec
tive,
single
inst
ituti
on,
phas
eII
tria
lof
carb
opla
tin,
irin
ote
can,
and
bev
aciz
um
abin
pat
ients
bev
aciz
um
abnaı̈
ve
pat
ients
wit
hpro
gre
ssiv
egli
obla
stom
a
Pat
ient
popula
tion:
Adult
pat
ients
wit
h(1
)pro
gre
ssiv
egli
obla
stom
ath
athad
rece
ived
pri
or
radia
tion
and
tem
ozo
lom
ide,
but
no
bev
aciz
um
abor
(2)
wit
hlo
wgra
de
gli
om
asth
athad
recu
rred
as
gli
obla
stom
aan
dth
enfa
iled
radia
tion
and
tem
ozo
lom
ide
Tre
atm
ent
regim
en:
Bev
aciz
um
abgiv
enat
10
mg/k
gin
trav
enousl
yev
ery
14
day
s.C
arbopla
tin
was
adm
inis
tere
dat
anA
UC
of
4on
day
one
of
each
28-d
aycy
cle.
Irin
ote
can
was
adm
inis
tere
don
day
s
1an
d14
at340
mg/m
2fo
rpat
ients
on
EIA
ED
san
dat
125
mg/m
2fo
rth
ose
not
on
EIA
ED
s
III
PF
S-6
:46.5
%
Med
ian
OS
:8.3
month
s
Res
ponse
:P
R:
13
Toxic
ity:
Gra
de
3
Anem
ia,
thro
mbocy
topen
ia,
neu
tropen
ia,
fati
gue,
infe
ctio
n,
and
nau
sea
in3
(8%
),8
(20
%),
10
(25
%),
5(1
3%
),4
(10
%),
and
3(8
%)
pat
ients
,re
spec
tivel
y
Hem
atolo
gic
gra
de
4:
Neu
tropen
iain
eight
pat
ients
(20
%)
and
thro
mbocy
topen
iain
four
pat
ients
(10
%)
Addit
ional
ly,
one
pat
ient
each
dev
eloped
gra
de
4gas
troin
test
inal
per
fora
tion
and
ven
ous
thro
mbosi
s
Ther
ew
asone
study
rela
ted
dea
thfr
om
anin
test
inal
per
fora
tion
Auth
ors
’co
ncl
usi
ons:
This
regim
enhas
sim
ilar
anti
-tum
or
acti
vit
yas
bev
aciz
um
abm
onoth
erap
y,
but
wit
hsi
gnifi
cantl
ygre
ater
toxic
ity
Des
jard
ins
etal
.,2012
Phas
eII
tria
lof
dai
lyte
mozo
lom
ide
and
biw
eekly
bev
aciz
um
abin
pro
gre
ssiv
egli
obla
stom
a
Pat
ient
popula
tion:
Adult
pat
ients
wit
hpro
gre
ssiv
egli
obla
stom
aw
ho
had
atle
ast
rece
ived
wit
hno
lim
itto
the
num
ber
of
pri
or
pro
gre
ssio
ns
or
ther
apie
s(n
=32)
Tre
atm
ent
regim
en:
Tem
ozo
lom
ide
50
mg/m
2dai
lyan
dbev
aciz
um
ab10
mg/k
gin
trav
enousl
yev
ery
14
day
s.E
ach
cycl
ew
as4
wee
ks
long
III
PF
S-6
:18.8
%
Six
month
OS
:62.5
%
Med
ian
OS
:37.1
wee
ks
Res
ponse
CR
:none
PR
:28
%
Toxic
ity:
Gra
de
3:
fati
gue
(3),
hyper
tensi
on,
dysp
nea
,dia
rrhea
,co
liti
s,deh
ydra
tion,
hem
orr
hoid
s(1
each
);G
rade
4:
pan
crea
titi
s(1
);G
rade
5:
pneu
monia
(1)
Auth
ors
Concl
usi
ons:
The
com
bin
atio
nof
dai
lyte
mozo
lom
ide
and
biw
eekly
bev
aciz
um
abw
asw
ell
tole
rate
d,
but
the
6-m
onth
PF
Sap
pea
red
tobe
infe
rior
topre
vio
usl
yre
port
sof
bev
aciz
um
abal
one
and
toth
eco
mbin
atio
nof
irin
ote
can
and
bev
aciz
um
abT
he
auth
ors
hypoth
esiz
eth
ism
aybe
due
to
the
popula
tion
be
rela
tivel
yhea
vil
ypre
trea
ted
Wal
ber
t
etal
.,2011
Pro
spec
tive,
single
inst
ituti
on,
open
-lab
elst
udy
wit
htw
oco
mbin
atio
ntr
eatm
ent
arm
sdif
feri
ng
by
eith
erte
mozo
lom
ide
or
lom
ust
ine
Pat
ient
popula
tion:
Adult
pat
ients
wit
hpro
gre
ssiv
em
alig
nan
tgli
om
adiv
ided
into
two
trea
tmen
tar
ms,
those
tem
ozo
lom
ide
naı̈
ve,
and
those
pre
vio
usl
ytr
eate
dw
ith
tem
ozo
lom
ide
(n=
74
wit
h43
gli
obla
stom
as)
Tre
atm
ent
regim
en:
All
pat
ients
rece
ived
6-t
hio
guan
ine
for
3day
sev
ery
28-d
aycy
cle
on
day
s1–3
(ora
lly
ever
y6
hfo
ra
tota
lof
12
dose
sat
80
mg/m
2),
capec
itab
ine
14
day
sev
ery
28-d
aycy
cle
on
day
s14–27
(ora
lly
ever
y12
hat
825
mg/m
2/d
ose
),an
dce
leco
xib
14
day
sev
ery
28-d
aycy
cle
on
day
s14–27
(ora
lly
ever
y12
hat
400
mg/d
ose
).P
atie
nts
inar
mI
wer
ete
mozo
lom
ide
naı̈
ve
and
rece
ived
tem
ozo
lom
ide
5day
sev
ery
28-d
aycy
cle
on
day
s4–8,
ora
lly
atbed
tim
eat
150
mg/m
2/
dose
.P
atie
nts
inar
mII
had
pre
vio
us
exposu
reto
tem
ozo
lom
ide,
but
not
lom
ust
ine
or
carm
ust
ine,
and
rece
ived
lom
ust
ine
1day
ever
y42-d
aycy
cle
on
day
4,
ora
lly
atbed
tim
eat
100
mt/
m2/d
ose
III
PF
S-6
14
%
Med
ian
OS
for
gli
obla
stom
a:32
wee
ks
Res
ponse
for
gli
obla
stom
a
CR
:1
PR
:4
(der
ived
by
com
bin
ing
the
dat
afr
om
Arm
s1
and
2re
vea
led
that
12
%of
the
gli
obla
stom
apat
ients
resp
onded
(1C
Ran
d4
PR
)
Toxic
ity:
lookin
gat
all
pat
ients
,17–18
%had
gra
de
3hem
atolo
gic
alto
xic
ity
and
6%
had
gra
de
4
hem
atolo
gic
alto
xic
ity
Auth
ors
’co
ncl
usi
ons:
Com
bin
atio
nal
ther
apy
wit
h6-t
hio
guan
ine,
capec
itab
ine
and
cele
coxib
plu
s
lom
ust
ine
or
tem
ozo
lom
ide
does
not
appea
rto
be
more
effe
ctiv
eth
anoth
eral
kyla
ting
agen
t
sched
ule
sfo
rpat
ients
wit
hre
curr
ent
gli
obla
stom
a
J Neurooncol (2014) 118:557–599 575
123
Ta
ble
2co
nti
nu
ed
Auth
or,
yea
rD
escr
ipti
on
of
study
Dat
a
clas
s
Concl
usi
ons
Rea
rdon
etal
.,2011
Open
-lab
el,
single
inst
ituti
on,
phas
eII
study
of
met
ronom
icte
mozo
lom
ide
plu
sbev
aciz
um
abvs.
met
ronom
icet
oposi
de
plu
sbev
aciz
um
ab
Pat
ient
popula
tion:
Rec
urr
ent
gli
obla
stom
apat
ients
who
had
pro
gre
ssed
on
pri
or
bev
aciz
um
ab
ther
apy.
(n=
23)
Tre
atm
ent
regim
en:
Bev
aciz
um
abw
asgiv
enat
10
mg/k
gIV
ever
y14
day
s.P
atie
nts
rece
ivin
g
met
ronom
icte
mozo
lom
ide
rece
ived
50
mg/m
2/d
ayora
lly
on
aco
nti
nuous
dosi
ng
sched
ule
(n=
10).
Pat
ients
inth
em
etro
nom
icet
oposi
de
arm
took
50
mg/m
2of
etoposi
de
dai
lyfo
r21
conse
cuti
ve
day
sof
each
28
day
cycl
e(n
=13)
III
PF
S-6
TM
Z:
None
PF
S-6
etoposi
de:
7.7
month
s
Med
ian
PF
ST
MZ
:4.1
month
s
Med
ian
PF
Set
oposi
de:
8.1
month
s
Res
ponse
No
com
ple
teor
par
tial
resp
onse
s
Inth
ete
mozo
lom
ide
arm
,9
of
10
pat
ients
had
pro
gre
ssiv
edis
ease
at2
month
s,w
hil
e9
of
12
pat
ients
pro
gre
ssed
inth
eet
oposi
de
arm
at2
month
s
Toxic
ity:
Gra
de
3or
hig
her
toxic
itie
sin
cluded
neu
tropen
ia(n
=1),
fati
gue
(n=
2),
and
infe
ctio
n
(n=
1)
Auth
ors
’co
ncl
usi
ons:
The
study
was
ended
earl
yat
inte
rim
anal
ysi
sfo
rfu
tili
tydue
toea
rly
pro
gre
ssio
nin
both
trea
tmen
tar
ms
Rea
rdon
etal
.,2011
Pro
spec
tive,
single
inst
ituti
on
phas
eII
tria
lof
carb
opla
tin,
irin
ote
can,
and
bev
aciz
um
abfo
rre
curr
ent
gli
obla
stom
a
Pat
ient
popula
tion:
Adult
pat
ients
wit
hpro
gre
ssiv
egli
obla
stom
ath
athad
rece
ived
pri
or
radia
tion
and
tem
ozo
lom
ide,
foll
ow
edby
som
efo
rmof
bev
aciz
um
abth
erap
y,
and
had
then
pro
gre
ssed
.(n
=25)
Tre
atm
ent
regim
en:
Bev
aciz
um
abgiv
enat
10
mg/k
gin
trav
enousl
yev
ery
14
day
s.C
arbopla
tin
was
adm
inis
tere
dat
anA
UC
of
4on
day
one
of
each
28-d
aycy
cle.
Irin
ote
can
was
adm
inis
tere
don
day
s
1an
d14
at340
mg/m
2fo
rpat
ients
rece
ivin
gE
IAE
Ds
and
at125
mg/m
2fo
rth
ose
not
on
EIA
ED
s
III
PF
S-6
:16
%
Med
ian
PF
S:
2.3
month
s
Med
ian
OS
:5.8
month
s
Res
ponse
:
No
pat
ient
met
crit
eria
for
radio
gra
phic
resp
onse
Toxic
ity:
Gra
de
3or
4
Neu
tropen
ia(n
=8),
thro
mbocy
topen
ia(n
=3),
anem
ia(n
=2),
fati
gue
(n=
3),
hyper
tensi
on
(n=
2)
Auth
ors
’co
ncl
usi
ons:
Car
bopla
tin,
irin
ote
can,
and
bev
aciz
um
abis
asso
ciat
edw
ith
modes
tan
titu
mor
ben
efit
and
adeq
uat
esa
fety
inm
oder
atel
ypre
trea
ted
GB
Mpat
ients
who
hav
epro
gre
ssed
on
pri
or
bev
aciz
um
abth
erap
y
Rea
rdon
etal
.,2011
Pro
spec
tive,
single
inst
ituti
on,
phas
eII
study
of
sora
fenib
wit
hdai
lyte
mozo
lom
ide
for
pro
gre
ssiv
e
gli
obla
stom
a
Pat
ient
popula
tion:
Adult
pat
ients
wit
hre
curr
ent
gli
obla
stom
afo
llow
ing
pri
or
ther
apy
(n=
32)
Tre
atm
ent
regim
en:
Sora
fenib
(an
ora
lV
EG
FR
-2,
Raf
,P
DG
FR
,c-
KIT
and
Flt
-3in
hib
itor)
was
giv
en
ora
lly
at400
mg
twic
edai
ly.
Tem
ozo
lom
ide
was
giv
enora
lly
at50
mg/m
2dai
ly.
Dosi
ng
was
conti
nuous
wit
ha
cycl
edes
ignat
edas
4w
eeks
III
PF
S-6
:9.4
%
Med
ian
PF
S:
6.4
wee
ks
Med
ian
OS
:41.5
wee
ks
Res
ponse
:P
R:
1
Toxic
ity:
Gra
de
4;
Am
yla
sean
dli
pas
eel
evat
ion
(n=
2).
Gra
de
3;
Am
yla
sean
dli
pas
eel
evat
ion
(4),
anore
xia
(1),
dysp
nea
(2),
fati
gue
(2),
hyper
bil
irubin
emia
(1),
hyper
tensi
on
(1),
hypokal
emia
(2),
hypophosp
hat
emia
(2),
infe
ctio
n(1
),nau
sea
(1),
neu
tropen
ia(1
),er
yth
rodyse
sthes
ia(6
),
tran
sam
inas
eel
evat
ion
(1)
Auth
ors
’co
ncl
usi
ons:
This
dosi
ng
regim
enis
wel
lto
lera
ted,
but
has
lim
ited
acti
vit
yin
recu
rren
t
gli
obla
stom
a
Has
selb
alch
etal
.,2010
Pro
spec
tive
phas
eII
anal
ysi
sof
cetu
xim
abw
ith
bev
aciz
um
aban
dir
inote
can
inpat
ients
wit
hfi
rst
recu
rren
ceof
pri
mar
ygli
obla
stom
a
Pat
ient
popula
tion:
Pat
ients
wit
hfi
rst
pro
gre
ssio
nof
pri
mar
ygli
obla
stom
aw
ithin
6m
onth
sof
com
ple
ting
stan
dar
dra
dia
tion
and
tem
ozo
lom
ide
ther
apy.
WH
OP
erfo
rman
cest
atus
0–2
Enro
lled
:43
Eval
uab
le:
32
Tre
atm
ent
regim
en:
The
firs
t10
pat
ients
rece
ived
bev
aciz
um
ab5
mg/k
gea
ch2
wee
ks,
but
this
was
incr
ease
dto
10
mg/k
gaf
ter
anin
teri
msa
fety
anal
ysi
s.T
he
irin
ote
can
dose
was
bas
edon
whet
her
pat
ients
wer
eta
kin
gen
zym
e-in
duci
ng
anti
epil
epti
cdru
gs
or
not:
340
and
125
mg/m
2,
resp
ecti
vel
y.
Cet
uxim
ab400
mg/m
2as
alo
adin
gdose
was
foll
ow
edby
250
mg/m
2w
eekly
adm
inis
tere
dIV
III
PF
S-6
:33
%
Med
ian
PF
S:
16
wee
ks
Med
ian
OS
:29
wee
ks
(95
%C
I:23–37
wee
ks)
Res
ponse
rate
was
report
edas
26
%:
CR
:2
PR
:9
Auth
ors
Concl
usi
ons
and
Com
par
isons:
Res
ult
sar
eli
ttle
dif
fere
nt
than
his
tori
cal
contr
ols
for
bev
aciz
um
aban
dir
inote
can
alone
No
form
alst
atis
tica
lco
mpar
ison
was
carr
ied
out
bet
wee
nth
isst
udy
and
those
the
auth
ors
dee
med
appro
pri
ate
com
par
isons
yie
ldin
gcl
ass
III
dat
a
576 J Neurooncol (2014) 118:557–599
123
Ta
ble
2co
nti
nu
ed
Auth
or,
yea
rD
escr
ipti
on
of
study
Dat
a
clas
s
Concl
usi
ons
Zhan
get
al.,
2009
Ret
rosp
ecti
ve
anal
ysi
sof
the
use
of
bev
aciz
um
aban
da
cyto
toxic
agen
tin
asi
ngle
inst
ituti
on
in
pat
ients
wit
hre
curr
ent
gli
obla
stom
a
Pat
ient
popula
tion:
Pat
ients
wit
hpri
or
dia
gnosi
sof
mal
ignan
tgli
om
aw
ho
had
com
ple
ted
init
ial
chem
ora
dio
ther
apy.
Six
case
sac
crued
wit
hfi
ve
gli
obla
stom
as
Tre
atm
ent
regim
en:
Bev
aciz
um
abw
asad
min
iste
red
at10
mg/k
gin
trav
enousl
yev
ery
2w
eeks
and
the
choic
eof
conco
mit
ant
chem
oth
erap
euti
cag
ent
was
bas
edon
the
num
ber
of
recu
rren
ces
and
pri
or
chem
oth
erap
y.F
or
gli
obla
stom
apat
ients
thre
epat
ients
rece
ived
conco
mit
ant
tem
ozo
lom
ide
(50
mg/
m2/d
ay)
ora
lly,
one
pat
ient
wit
hir
inote
can
(125
mg/m
2ev
ery
2w
eeks)
and
one
pat
ient
wit
h
topote
can
(1.2
mg/m
2/d
ay)
intr
aven
ousl
y
III
Dat
apre
sent
inta
bula
rfo
rmfr
om
whic
hso
me
par
amet
ers
can
be
extr
acte
dby
elim
inat
ing
anap
last
ic
astr
ocy
tom
adat
a
Med
ian
PF
S:
10
wee
ks
Res
ponse
CR
:3
PR
:1
Toxic
itie
s:A
llpat
ients
dev
eloped
gra
de
1m
yel
oto
xic
ity,
two
pat
ients
wit
hep
ista
xis
,an
done
pat
ient
wit
hm
ild
dia
rrhea
Auth
ors
Concl
usi
on:
Anti
angio
gen
ictr
eatm
ents
wit
hbev
aciz
um
abar
est
rikin
gly
effe
ctiv
ean
dw
ell
tole
rate
dopti
ons
for
pat
ients
wit
hre
curr
ent
mal
ignan
tgli
om
as
Rea
rdon
etal
.,2009
Phas
eII
study
of
recu
rren
tm
alig
nan
tgli
om
atr
eatm
ent
wit
hbev
aciz
um
aban
ddai
lyet
oposi
de
Pat
ient
popula
tion:
His
tolo
gic
ally
confi
rmed
recu
rren
tm
alig
nan
tgli
om
aaf
ter
pri
or
radia
tion
and
chem
oth
erap
y(\
3pri
or
recu
rren
ces)
.P
revio
usl
ylo
wgra
de
lesi
ons
wer
eco
nfi
rmed
tobe
mal
ignan
t
wit
hre
pea
tsu
rger
y
Enro
lled
:59
case
sw
ith
27
bei
ng
gli
obla
stom
a
Tre
atm
ent
regim
en:
10
mg/k
gbev
aciz
um
abbiw
eekly
and
50
mg/m
2et
oposi
de
dai
lyfo
r21
conse
cuti
ve
day
sof
each
28
day
cycl
e
III
Gli
obla
stom
a:
PF
S-6
:44.4
%
Res
ponse
Rat
e:(C
R?
PR
):23
%
Med
ian
Surv
ival
46.4
wee
ks
Toxic
ity
Gra
de[
3ad
ver
seev
ents
:
Neu
tropen
ia(2
4%
),th
rom
bosi
s(1
2%
),in
fect
ion
(8%
)an
dhyper
tensi
on
(3%
).A
sym
pto
mat
ic,
gra
de
1in
trac
rania
lhem
orr
hag
e:2
case
s
Dea
thdue
topulm
onar
yem
boli
sm:
1ca
se
Auth
ors
Concl
usi
on:
The
com
bin
atio
nof
bev
aciz
um
aban
det
oposi
de
pro
vid
esef
fica
cysi
mil
ar
resp
onse
tobev
aciz
um
abm
onoth
erap
ybut
wit
hin
crea
sed
toxic
ity
van
den
Ben
t
etal
.,2009
Ara
ndom
ized
phas
eII
anal
ysi
sof
erlo
tinib
ver
sus
TM
Zor
carm
ust
ine
(BC
NU
)in
recu
rren
t
gli
obla
stom
a
Pat
ient
popula
tion
(n=
110):
Indiv
idual
sw
ith
recu
rren
tgli
obla
stom
aaf
ter
radia
tion
ther
apy.
They
could
hav
ehad
no
pri
or
chem
oth
erap
yfo
rre
curr
ent
dis
ease
or
am
axim
um
of
only
one
pri
or
chem
oth
erap
yre
gim
engiv
enas
adju
van
ttr
eatm
ent
Tre
atm
ent
regim
en:
Pat
ients
wer
era
ndom
ized
bet
wee
ner
loti
nib
and
the
contr
ol
arm
.If
random
ized
to
the
contr
ol
arm
,th
eyw
ere
random
ized
bet
wee
nT
MZ
and
BC
NU
Arm
1:
Erl
oti
nib
(n=
54);
Sta
rted
at150
mg
dai
ly,
wit
hdose
esca
lati
on
to200
mg
dai
lyif
no
or
min
imal
toxic
ity
was
exper
ience
d,
inpat
ients
who
wer
enot
on
EIA
ED
s,an
dat
300
mg
dai
ly,
wit
h
dose
esca
lati
on
in50-m
gin
crem
ents
up
to500
mg
dai
lyif
no
or
min
imal
toxic
ity,
for
pat
ients
on
EIA
ED
s
Arm
2:
TM
Z(c
ontr
ol,
n=
27);
star
ted
at200
mg/m
2on
day
s1–5
ever
y4
wee
ks
inch
emoth
erap
y-
naı̈
ve
pat
ients
or
at150
mg/m
2on
day
s1–5
ever
y4
wee
ks
afte
rpri
or
adju
van
tch
emoth
erap
y,
wit
h
dose
esca
lati
on
to200
mg/m
2in
the
abse
nce
of
signifi
cant
toxic
ity.
Arm
3:
BC
NU
(contr
ol,
n=
29):
Giv
enin
itia
lly
ata
dose
level
of
80
mg/m
2on
day
s1–3
ever
y8
wee
ks
for
am
axim
um
of
five
cycl
es
Arm
2&
3n
=56
III
PF
S-6
:A
rm1:
Erl
oti
nib
11.4
%;
Arm
2&
3(T
MZ
and
BC
NU
com
bin
ed)
24
%
Med
ian
PF
S:
Arm
1E
rloti
nib
:1.8
month
s;A
rm2&
3(C
ontr
ol)
2.4
month
s
Med
ian
OS
:A
rm1
Erl
oti
nib
:7.7
month
s;A
rm2&
3(C
ontr
ol)
7.3
month
s
Res
ponse
:A
rm1
Erl
oti
nib
:P
R3.7
%,
SD
16.7
%;
Arm
2&
3(C
ontr
ol)
PR
9.6
%,
SD
34.6
%
Toxic
ity:
Skin
toxic
ity
was
the
most
freq
uen
tad
ver
seef
fect
of
erlo
tinib
Auth
ors
’co
ncl
usi
on:
Erl
oti
nib
has
no
mea
nin
gfu
lac
tivit
yin
recu
rren
tgli
obla
stom
aco
mpar
edto
stan
dar
dcy
toto
xic
agen
ts.
The
study,
though
random
ized
,w
asnot
pow
ered
todet
ect
signifi
cance
in
the
smal
loutc
om
edif
fere
nce
snote
d
This
dat
ais
also
wea
ken
edby
ahom
ogen
eous
contr
ol
arm
and
aport
ion
of
the
pat
ient
popula
tion
trea
ted
wit
hra
dia
tion
only
afte
rin
itia
lhis
tolo
gic
confi
rmat
ion.
Thus,
this
yie
lds
clas
sII
Iev
iden
ce
J Neurooncol (2014) 118:557–599 577
123
Ta
ble
2co
nti
nu
ed
Auth
or,
yea
rD
escr
ipti
on
of
study
Dat
a
clas
s
Concl
usi
ons
Pouls
enet
al.,
2009
Ret
rosp
ecti
ve
asse
ssm
ent
of
bev
aciz
um
abplu
sir
inote
can
inth
etr
eatm
ent
pat
ients
wit
hpro
gre
ssiv
e
mal
ignan
tbra
intu
mors
Pat
ient
popula
tion
Pat
ients
wit
hpro
gre
ssiv
em
alig
nan
tgli
om
a(n
=52)
wit
hal
lre
ceiv
ing
[2
pri
or
inte
rven
tions
Gli
obla
stom
a:n
=27
Tre
atm
ent
regim
en
Bev
aciz
um
ab10
mg/k
gev
ery
2w
eeks
and
irin
ote
can
340
mg/m
2fo
rpat
ients
EIA
ED
san
d125
mg/
m2
for
pat
ients
not
rece
ivin
gE
IAE
Ds
was
adm
inis
tere
d60
min
pri
or
tobev
aciz
um
ab
III
Dat
afr
om
gli
obla
stom
asw
asca
lcula
ted
separ
atel
yas
note
d:
PF
S-6
:40
%
Med
ian
PF
S:
22
wee
ks
Med
ian
OS
:28
wee
ks
Res
ponse
CR
:4
(15
%)
PR
:4
(15
%)
Fre
quen
cyan
dle
ngth
of
resp
onse
wer
enot
dif
fere
nt
bet
wee
nan
tico
nvuls
ant
gro
ups
when
dose
das
note
dan
dth
ere
sult
sw
ere
report
edto
get
her
Toxic
ity:
Stu
dy
trea
tmen
tw
asst
opped
bec
ause
of
toxic
ity
info
ur
pat
ients
:one
each
from
gra
de
5
dia
rrhea
,gra
de
3ce
rebra
lhem
orr
hag
e,gra
de
3ca
rdia
car
rhyth
mia
(atr
ial
fibri
llat
ion)
and
gra
de
3
inte
stin
alper
fora
tion
Auth
ors
’co
ncl
usi
on:
An
opti
mis
tic
inte
rpre
tati
on
was
pro
vid
ednoti
ng
‘‘dura
ble
resp
onse
sca
nbe
obta
ined
wit
hth
isre
gim
en.’’
Zunig
aet
al.,
2009
Ret
rosp
ecti
ve
anal
ysi
sof
bev
aciz
um
aban
dir
inote
can
ther
apy
inre
curr
ent
hig
hgra
de
gli
om
as
Pat
ient
popula
tion
Pat
ients
inth
elo
cal
dat
abas
ew
ith
recu
rren
thig
hgra
de
gli
om
a(n
=51)
Pat
ients
init
iall
ydia
gnose
d
wit
hlo
w-g
rade
gli
om
asbut
late
rdev
elopin
ghis
tolo
gic
ally
pro
ven
Gra
de
III
or
IVgli
om
asw
ere
incl
uded
inth
isst
udy.
Pat
ients
who
had
pre
vio
usl
yre
ceiv
edir
inote
can
or
anan
ti-a
ngio
gen
icdru
g
also
wer
eco
nsi
der
edin
elig
ible
Gli
obla
stom
a:n
=37
Tre
atm
ent
regim
en:
Bev
aciz
um
ab10
mg/k
gev
ery
2w
eeks
and
irin
ote
can
340
mg/m
2fo
rpat
ients
EIA
ED
san
d125
mg/m
2fo
rpat
ients
not
rece
ivin
gE
IAE
Ds
III
Dat
afo
rgli
obla
stom
aw
asca
lcula
ted
separ
atel
yas
foll
ow
s:
PF
S-6
:63.7
%
Med
ian
PF
S:
7.6
month
s
Six
month
OS
:78
%
Med
ian
OS
:11.5
month
s
Res
ponse
:
CR
:5.4
1%
PR
:62.1
6%
Toxic
ity
Six
pat
ients
(11.7
6%
)re
quir
eddis
conti
nuat
ion
of
trea
tmen
tin
cludin
gone
wit
hen
d-s
tage
renal
fail
ure
,one
wit
hgas
troin
test
inal
per
fora
tion
and
four
wit
hse
ver
enau
sea
and
vom
itin
g
Auth
ors
’co
ncl
usi
on:
This
regim
enis
effe
ctiv
ein
impro
vin
gP
FS
and
med
ian
OS
,an
dis
not
wit
hout
seri
ous
toxic
ity,
and
does
not
pre
clude
recu
rren
ce
Nord
enet
al.,
2008
Ret
rosp
ecti
ve
anal
ysi
sof
bev
aciz
um
aban
da
conven
tional
chem
oth
erap
yin
recu
rren
tm
alig
nan
t
gli
om
as
Pat
ient
popula
tion:
All
pat
ients
had
pri
or
trea
tmen
tw
ith
radio
ther
apy
and
tem
ozo
lom
ide,
and
most
wit
hat
leas
tone
addit
ional
chem
oth
erap
euti
c.T
her
ew
asno
lim
itto
the
num
ber
of
pri
or
ther
apie
s
(med
ian
=2)
Over
all
n=
55
Gli
obla
stom
an
=33
Tre
atm
ent
regim
en:
Bev
aciz
um
ab10
mg/k
gev
ery
2w
eeks
(exce
pt
for
one
pat
ient
that
rece
ived
5m
g/
kg)
PL
US
Irin
ote
can
(125
mg/m
2ev
ery
2w
eeks
for
pat
ients
not
on
EIA
ED
san
d340
mg/m
2ev
ery
2w
eeks
for
pat
ients
on
EIA
ED
s)(n
=47)
OR
Car
bopla
tin
(AU
Cof
5–6)
(n=
6)
OR
Car
must
ine
(200
mg/m
2ev
ery
6w
eeks)
(n=
1)
OR
Tem
ozo
lom
ide
(150–200
mg/m
2fo
r5
day
sev
ery
4w
eeks)
(n=
1)
III
Dat
aon
gli
obla
stom
afo
rm
ost
par
amet
ers
isnot
pro
vid
edse
par
atel
y
PF
S-6
gli
obla
stom
a:42
%
At
pro
gre
ssio
non
this
Tre
atm
ent
regim
ench
angin
gth
ecy
toto
xic
agen
tonly
2/2
3pat
ients
had
pro
longat
ion
of
PF
S
Toxic
ity:
Gra
de
4:
Colo
nper
fora
tion
(n=
1)
and
pulm
onar
yem
boli
sm(n
=4)
Gra
de
3:
Dee
pven
ous
thro
mbosi
s(n
=1)
Tw
oas
ym
pto
mat
icbra
inhem
orr
hag
esan
dtw
oca
ses
of
impai
red
cran
ioto
my
wound
hea
ling
Auth
ors
’co
ncl
usi
on:
Com
bin
atio
nth
erap
yw
ith
bev
aciz
um
aban
dch
emoth
erap
yis
wel
l-to
lera
ted
and
acti
ve
agai
nst
recu
rren
tm
alig
nan
tgli
om
as.
At
recu
rren
ce,
conti
nuin
gbev
aciz
um
aban
dch
angin
g
the
chem
oth
erap
yag
ent
pro
vid
edlo
ng-t
erm
dis
ease
contr
ol
inonly
asm
all
subse
tof
pat
ients
.
Bev
aciz
um
abm
ayal
ter
the
recu
rren
cepat
tern
of
mal
ignan
tgli
om
asby
suppre
ssin
gen
han
cing
tum
or
recu
rren
cem
ore
effe
ctiv
ely
than
itsu
ppre
sses
non-e
nhan
cing,
infi
ltra
tive
tum
or
gro
wth
578 J Neurooncol (2014) 118:557–599
123
Ta
ble
2co
nti
nu
ed
Auth
or,
yea
rD
escr
ipti
on
of
study
Dat
a
clas
s
Concl
usi
ons
Kan
get
al.,
2008
Sin
gle
inst
ituti
on
retr
osp
ecti
ve
revie
wof
pat
ients
wit
hpro
gre
ssiv
egli
om
astr
eate
dw
ith
bev
aciz
um
ab
and
irin
ote
can
Pat
ient
popula
tion
Pat
ients
wit
hin
itia
lhig
h-g
rade
gli
om
aor
those
wit
hpre
vio
us
low
-gra
de
dis
ease
wit
hcl
inic
alor
his
tolo
gic
ally
-pro
ven
hig
h-g
rade
dis
ease
who
pro
gre
ssed
wer
ein
cluded
(n=
27)
Gli
obla
stom
a:n
=12
atin
itia
ldia
gnosi
s
Tre
atm
ent
regim
en
Irin
ote
can
at340
mg/m
2in
trav
enousl
yw
asgiv
enfo
rpat
ients
on
EIA
ED
.Ir
inote
can
at125
mg/m
2w
as
giv
enfo
rpat
ients
not
rece
ivin
gE
IAE
D.
Tre
atm
ents
wer
egiv
enon
day
s1
and
15,
and
repea
ted
ever
y28
day
s.B
evac
izum
abat
10
mg/k
gw
asgiv
enon
day
s1
and
15
of
each
cycl
ean
d
adm
inis
tere
dbef
ore
irin
ote
can
III
Som
epar
amet
ers
wer
eca
lcula
ted
for
pat
ients
wit
hgli
obla
stom
aat
init
ial
dia
gnosi
san
dar
ere
port
ed
her
e
PF
S-6
:17
%
Med
ian
PF
S:
3.8
month
s
Med
ian
OS
:7.1
month
s
6m
onth
OS
:75
%
Toxic
ity
Obse
rved
ingli
obla
stom
apat
ients
:
Ter
min
atin
gth
erap
y:
hem
aturi
a,dee
pven
ous
thro
mbosi
s(n
=2),
cough,
PE
(n=
2)
Not
term
inat
ing
ther
apy:
post
oper
ativ
ehem
orr
hag
e(l
oca
tion
not
outl
ined
),th
rom
bocy
topen
ia
Auth
ors
’co
ncl
usi
on:
Irin
ote
can
and
bev
aciz
um
abis
ahig
hly
acti
ve
ther
apeu
tic
com
bin
atio
n.
The
auth
ors
note
thes
ere
sult
sm
aybe
bia
sed
by
smal
lsa
mple
size
and
sele
ctio
nbia
s.T
his
and
the
retr
osp
ecti
ve
nat
ure
of
the
anal
ysi
syie
lds
clas
sII
Idat
a
de
Gro
ot
etal
.,2008
Phas
eII
study
of
carb
opla
tin
and
erlo
tinib
inpat
ients
wit
hre
curr
ent
gli
obla
stom
a
Pat
ient
popula
tion
Pat
ients
wit
hre
curr
ent
gli
obla
stom
aw
ith
no
more
than
two
pri
or
rela
pse
san
don
no
EIA
Eds
(n=
43
asse
ssab
lepat
ients
)
Tre
atm
ent
regim
en
Car
bopla
tin
intr
aven
ousl
yon
day
1of
ever
y28-d
aycy
cle
and
dai
lyer
loti
nib
at150
mg/d
ayw
asdose
esca
late
dto
200
mg/d
ay,
asto
lera
ted
III
PF
S-6
:14
%
Med
ian
PF
S:
9w
eeks
Med
ian
OS
:30
wee
ks
Res
ponse
PR
:1
Toxic
ity
Abdom
inal
pai
ngra
de
4:
1
Neu
tropen
iaG
rade
3:
13,
Gra
de
4:
2
Lym
phopen
iaG
rade
3:
17,
Gra
de
4:
3
Thro
mbocy
topen
iaG
rade
3:
12,
Gra
de
4:
3
Anem
iaG
rade
3:
3
Fat
igue
Gra
de
3:
9,
Gra
de
4:
1
Dea
thduri
ng
trea
tmen
t:1
Auth
ors
’co
ncl
usi
on:
This
phas
eII
tria
lev
aluat
ing
the
effi
cacy
of
erlo
tinib
and
carb
opla
tin
did
not
show
anO
Sben
efit
inunse
lect
edpat
ients
wit
hre
curr
ent
gli
obla
stom
a
Puduval
li
etal
.,2008
Phas
eII
study
of
thal
idom
ide
and
irin
ote
can
inre
curr
ent
gli
obla
stom
a
Pat
ient
popula
tion:
Pat
ients
wit
hre
curr
ent
his
tolo
gic
ally
pro
ven
supra
tento
rial
gli
obla
stom
aor
gli
osa
rcom
aco
mple
ting
radia
tion
and
wit
hup
totw
ore
lapse
s(n
=33,
eval
uab
len
=32)
Pri
or
tem
ozo
lom
ide:
27
Pri
or
nit
roso
ure
as:
8
Tre
atm
ent
regim
en:
6-w
eek
cycl
esw
ith
125
mg/m
2ir
inote
can
wee
kly
for
4w
eeks
foll
ow
edby
2w
eeks
off
trea
tmen
tT
hal
idom
ide
was
adm
inis
tere
dco
ncu
rren
tly
for
ato
tal
of
42
day
sbeg
innin
g
at100
mg
of
thal
idom
ide
dai
lyan
din
crea
sed
wee
kly
asto
lera
ted
to400
mg/d
ay.
All
pat
ients
wer
e
kep
toff
EIA
ED
s
III
PF
S-6
:25
%
Med
ian
PF
S:
13
wee
ks
Med
ian
OS
:36
wee
ks
Res
ponse
:C
R:
1;
PR
:1
Toxic
ity:
Leu
kopen
ia/N
eutr
open
ia:
Gra
de
3:
18;
Gra
de
4:
2
Lym
phopen
ia:
Gra
de
4:
1
Sei
zure
:G
rade
4:
1
Dia
rrhea
,ab
dom
inal
cram
ps:
Gra
de
3:
14
Ven
ous
thro
mboem
boli
sm:
Gra
de
4:
1
Auth
ors
Concl
usi
on:
The
com
bin
atio
nof
irin
ote
can
and
thal
idom
ide
show
spro
mis
ing
acti
vit
yag
ainst
recu
rren
tgli
obla
stom
ain
pat
ients
not
rece
ivin
gE
IAE
Ds
Not
all
pat
ients
had
bee
ntr
eate
dw
ith
radia
tion,
and
concu
rren
tan
dsu
bse
quen
tte
mozo
lom
ide,
lim
itin
gco
mpar
abil
ity
tocu
rren
tly
trea
ted
pat
ients
J Neurooncol (2014) 118:557–599 579
123
Ta
ble
2co
nti
nu
ed
Auth
or,
yea
rD
escr
ipti
on
of
study
Dat
a
clas
s
Concl
usi
ons
Gro
ves
etal
.,
2007
Phas
eII
tria
lof
tem
ozo
lom
ide
plu
sth
alid
om
ide
for
pro
gre
ssiv
egli
obla
stom
a
Pat
ient
popula
tion:
Pat
ients
wit
hhis
tolo
gic
ally
pro
ven
dia
gnosi
sof
gli
obla
stom
aor
gli
osa
rcom
aw
ith
uneq
uiv
oca
lpro
gre
ssio
nby
mag
net
icre
sonan
ceim
agin
gan
dno
more
than
one
trea
tmen
tw
ith
chem
oth
erap
yfo
rre
curr
ence
(n=
44,
wit
h43
eval
uab
le)
Tre
atm
ent
regim
en:
Tem
ozo
lom
ide
150–
200
mg/m
2/d
ayon
day
s1–5
of
each
28-d
aycy
cle
and
Thal
idom
ide
400
mg
atbed
tim
e(d
ays
1–28)
and
incr
ease
dto
1,2
00
mg
asto
lera
ted
III
PF
S-6
:23
%
Mea
nti
me
topro
gre
ssio
n:
15
wee
ks
Res
ponse
PR
:3
Toxic
ity
Gra
de
3an
d4
Neu
tropen
ia:
15
Confu
sion,
dec
reas
edco
nsc
iousn
ess,
moto
rch
anges
,dep
ress
ion,
wea
knes
s,sy
nco
pe,
seiz
ure
:10
Thro
mbosi
s:8
Gas
troin
test
inal
:4
Ele
vat
edli
ver
enzy
mes
,hypokal
emia
,hyponat
rem
ia:
4
Thro
mbocy
topen
ia:
2
Hea
dac
he:
1
Skin
:1
Auth
ors
’co
ncl
usi
on:
Thal
idom
ide
min
imal
lyau
gm
ents
TM
Zef
fect
but
the
poss
ible
ben
efit
com
esat
the
pri
ceof
anin
crea
sein
gra
de
3an
d4
toxic
itie
s
Kes
ari
etal
.,
2007
Phas
eII
anal
ysi
sof
conti
nuous
low
-dose
dai
ly(m
etro
nom
ic)
chem
oth
erap
y
Pat
ient
popula
tion
Pat
ients
wit
hhis
tolo
gic
ally
pro
ven
recu
rren
tin
trac
rania
lm
alig
nan
tgli
om
a.T
her
ew
asno
lim
iton
the
num
ber
of
pri
or
trea
tmen
tre
gim
ens
Over
all
n=
48
Gli
obla
stom
an
=28
Tre
atm
ent
regim
en
Eto
posi
de
[35
mg/m
2(m
axim
um
,100
mg/d
ay)
dai
lyfo
r21
day
s],
alte
rnat
ing
ever
y21
day
sw
ith
cycl
ophosp
ham
ide
[2m
g/k
g(m
axim
um
,100
mg/d
ay)
dai
lyfo
r21
day
s],
inco
mbin
atio
nw
ith
dai
ly
thal
idom
ide
(beg
un
ata
dose
of
50–200
mg
ora
lly
atbed
tim
eat
the
trea
ting
physi
cian
’sdis
cret
ion
and
esca
late
dby
50
mg
ever
yw
eek
toa
max
imum
of
1,2
00
mg
dai
ly)
and
cele
coxib
(beg
un
ata
dose
of
200
mg
twic
edai
lyan
din
crea
sed
to400
mg
twic
edai
lyin
pat
ients
wei
ghin
gm
ore
than
50
kg)
III
PF
S6:
9%
Med
ian
PF
S:
11
wee
ks
Med
ian
over
all
surv
ival
:21
wee
ks
Res
ponse
CR
:0
PR
:1
(his
tolo
gy
not
spec
ified
)
Toxic
ity
Const
ipat
ion
Gra
de
3:
3(6
%)
Gra
de
4:
2(4
%)
Leu
kopen
iaor
Neu
tropen
ia
Gra
de
4:
4
Tre
mor
Gra
de
3:
1
Fiv
even
ous
thro
mboem
boli
cev
ents
wer
enote
din
this
study
Auth
ors
’co
ncl
usi
on:
This
four
dru
g,ora
lm
etro
nom
icre
gim
endid
not
signifi
cantl
yim
pro
ve
OS
inth
is
hea
vil
ypre
trea
ted
gro
up
of
pat
ients
who
wer
egen
eral
lynot
elig
ible
for
conven
tional
pro
toco
ls
The
bro
adra
nge
of
poss
ible
dose
com
bin
atio
ns
inth
isgro
up
of
pat
ients
mak
esm
eanin
gfu
lco
mpar
ison
tohis
tori
cal
or
any
oth
erdat
adif
ficu
ltat
bes
tan
dyie
lds
clas
sII
Idat
a
580 J Neurooncol (2014) 118:557–599
123
Ta
ble
2co
nti
nu
ed
Auth
or,
yea
rD
escr
ipti
on
of
study
Dat
a
clas
s
Concl
usi
ons
Vre
den
burg
h
etal
.,2007
Phas
eII
study
of
bev
aciz
um
aban
dir
inote
can
inre
curr
ent
gli
obla
stom
a
Pat
ient
popula
tion
Adult
sw
ith
his
tolo
gic
ally
pro
ven
gli
obla
stom
ahav
ing
alre
ady
rece
ived
radia
tion
ther
apy
and
tem
ozo
lom
ide.
All
had
exper
ience
dtu
mor
pro
gre
ssio
n,
and
had
mea
sura
ble
dis
ease
on
MR
I.n
=35
Tre
atm
ent
regim
en
Cohort
1(n
=23):
Bev
aciz
um
ab10
mg/k
gan
dir
inote
can
ever
y2
wee
ks.
Irin
ote
can
340
mg/m
2fo
r
pat
ients
on
EIA
ED
san
d125
mg/m
2in
those
not
on
EIA
ED
s
Cohort
2(n
=12):
Bev
aciz
um
ab15
mg/k
gin
trav
enousl
yev
ery
21
day
s,an
dth
eir
inote
can
was
adm
inis
tere
don
day
s1,
8,
22,
and
29
of
a42-d
aycy
cle.
The
irin
ote
can
was
dose
dat
350
mg/m
2fo
r
pat
ients
rece
ivin
gE
IAE
Ds
and
125
mg/m
2fo
rpat
ients
not
rece
ivin
gan
tiep
ilep
tic
dru
gs
or
rece
ivin
g
non-E
IAE
Ds
III
Ther
ew
ere
no
stat
isti
cal
dif
fere
nce
sbet
wee
nth
etw
oco
hort
san
dth
eir
dat
ais
report
edto
get
her
PF
S-6
:46
%;
Med
ian
PF
S:
24
wee
ks;
6m
onth
Over
all
Surv
ival
:77
%
Med
ian
OS
:42
wee
ks;
Res
ponse
Rat
e:P
R:
20
Toxic
ity:
Rep
ort
edas
reas
ons
for
dis
conti
nuat
ion
of
ther
apy
Thro
mboem
boli
cco
mpli
cati
ons:
4
Gra
de
2pro
tein
uri
a:2:
Gra
de
2fa
tigue:
4
Sep
sis:
1
CN
Shem
orr
hag
e:1
Leg
ulc
ers:
1
Req
uir
edsu
rger
yfo
runre
late
dre
asons:
3
Auth
ors
Concl
usi
on:
The
study
show
edim
pro
vem
ent
inth
eP
FS
-6co
mpar
edw
ith
that
of
his
tori
cal
contr
ols
and
ahig
hre
sponse
rate
.T
her
ew
ere
no
earl
yC
NS
hem
orr
hag
es,
but
ther
ew
asa
sugges
tion
of
anin
crea
sed
risk
of
thro
mboem
boli
cco
mpli
cati
ons
Vre
den
burg
h
etal
.,2007
Phas
eII
study
of
bev
aciz
um
aban
dir
inote
can
inre
curr
ent
gli
obla
stom
a
Pat
ient
popula
tion
Pat
ients
wit
hhis
tolo
gic
ally
pro
ven
gra
de
III
or
IVgli
om
ath
atw
aspro
gre
ssiv
eor
recu
rren
taf
ter
radia
tion
wer
eel
igib
lefo
rth
est
udy
n=
32
wit
h23
gli
obla
stom
as
Tre
atm
ent
regim
en
Eac
hag
ent
was
adm
inis
tere
din
trav
enousl
yonce
ever
y2
wee
ks:
day
s1,
15,
and
29
of
a6-w
eek
cycl
e
Bev
aciz
um
abw
asgiv
enat
10
mg/k
gan
dir
inote
can
at340
mg/m
2fo
rpat
ients
on
EIA
ED
san
dat
125
mg/m
2in
those
not
on
EIA
ED
s
III
PF
S-6
gli
obla
stom
a:30
%
Med
ian
PF
Sgli
obla
stom
a:20
wee
ks
Med
ian
OS
gli
obla
stom
a:40
wee
ks
Res
ponse
Rat
eG
liobla
stom
a:C
R:
1;
PR
:13
Toxic
ity:
Tre
atm
ent-
asso
ciat
eddea
ths
Pulm
onar
yem
bolu
s:1
Art
eria
lis
chem
icst
roke:
1
Thro
mboem
boli
cco
mpli
cati
ons:
Pulm
onar
yem
boli
:2;
Dee
pven
ous
thro
mbus:
1;
Art
eria
lis
chem
ic
stro
ke:
1;
Irin
ote
can
anap
hyla
xis
:1
Toxic
ity
was
not
dif
fere
nt
in
pat
ients
rece
ivin
gE
IAE
Ds
and
those
not
rece
ivin
gE
IAE
Ds
Auth
ors
’co
ncl
usi
on:
The
com
bin
atio
nof
bev
aciz
um
aban
dir
inote
can
resu
lted
inan
titu
mor
acti
vit
y
agai
nst
recu
rren
tgra
de
III-
IVtu
mors
but
wit
hsi
gnifi
cant
toxic
ity
Pope
etal
.,
2006
Sin
gle
inst
ituti
on,
retr
osp
ecti
ve
imag
ing
anal
ysi
sof
mal
ignan
tgli
om
astr
eate
dw
ith
bev
aciz
um
aban
d
cyto
toxic
chem
oth
erap
y
Pat
ient
popula
tion:
Pat
ients
wit
hre
curr
ent
gra
de
III
and
gra
de
IVgli
om
astr
eate
dw
ith
bev
aciz
um
ab
and
chem
oth
erap
yat
UC
LA
who
had
abas
elin
eM
RI
obta
ined
wit
hin
14
day
sof
init
iati
ng
trea
tmen
t,st
able
or
dec
reas
ing
ster
oid
dose
wit
hin
10
day
sof
bas
elin
eM
RI,
no
incr
ease
inst
eroid
dose
duri
ng
trea
tmen
tfr
om
bas
elin
eM
RI,
fail
edpre
vio
us
radia
tion
and
chem
oth
erap
y,
evid
ence
of
tum
or
pro
gre
ssio
nat
leas
t4
wee
ks
bey
ond
com
ple
tion
of
pre
vio
us
radia
tion,an
dsi
gned
inst
ituti
onal
revie
wboar
dap
pro
ved
conse
nt
n=
14
wit
h10
gli
obla
stom
as
Tre
atm
ent
regim
en:
Ingli
obla
stom
asbev
aciz
um
abplu
sir
inote
can
(7),
carb
opla
tin
(2)
or
etoposi
de
(1).
Dose
sar
enot
spec
ified
III
Res
ponse
(gli
obla
stom
a)
PR
:4
(40
%)
Toxic
ity
Not
dis
cuss
edin
gli
obla
stom
aal
one
Auth
ors
’co
ncl
usi
on:
The
hig
hper
centa
ge
of
pat
ients
who
show
edan
imag
ing
resp
onse
(nea
rly
one-
hal
fta
kin
gin
toac
count
all
mal
ignan
tgli
om
as)
tobev
aciz
um
ab/c
hem
oth
erap
yin
the
curr
ent
study
isre
mar
kab
le
J Neurooncol (2014) 118:557–599 581
123
Ta
ble
2co
nti
nu
ed
Auth
or,
yea
rD
escr
ipti
on
of
study
Dat
a
clas
s
Concl
usi
ons
Tan
get
al.,
2006
Phas
eII
study
of
carb
opla
tin
and
chro
nic
hig
h-d
ose
tam
oxif
enin
pat
ients
wit
hre
curr
ent
mal
ignan
t
gli
om
a
Pat
ient
popula
tion
Pat
ients
hav
ing
had
surg
ery
and
his
tolo
gic
alco
nfi
rmat
ion
of
recu
rren
tm
alig
nan
tas
trocy
tom
aaf
ter
init
ial
trea
tmen
tw
ith
pri
mar
ysu
rger
yan
dra
dia
tion
ther
apy.
They
wer
eex
cluded
ifth
eyhad
rece
ived
any
chem
oth
erap
yor
radia
tion
ther
apy
for
recu
rren
tdis
ease
(over
all
n=
27,
gli
obla
stom
a/
gli
osa
rcom
an
=17)
Tre
atm
ent
regim
en
Car
bopla
tin
was
adm
inis
tere
dat
400
mg/m
2as
a2
hin
trav
enous
infu
sion
on
day
1of
each
28-d
ay
cycl
e.T
amoxif
enw
asad
min
iste
red
ora
lly
ata
dose
of
20
mg
bid
esca
lati
ng
to80
mg
bid
inw
om
en
and
100
mg
bid
for
men
over
aper
iod
of
1m
onth
.P
atie
nts
who
show
edno
evid
ence
of
tum
or
pro
gre
ssio
nfo
llow
ing
6cy
cles
conti
nued
tore
ceiv
eta
moxif
enunti
lpro
gre
ssiv
edis
ease
or
up
totw
o
yea
rsaf
ter
the
last
cycl
eof
carb
opla
tin
III
Med
ian
tim
eto
pro
gre
ssio
ngli
obla
stom
a:2.8
6m
onth
s
Med
ian
over
all
surv
ival
gli
obla
stom
a:5.8
5m
onth
s
Res
ponse
s:not
separ
ated
by
his
tolo
gy
Toxic
ity
(all
his
tolo
gie
s)
Gra
de
3–4
Fat
igue:
5
Anore
xia
:3
Nau
sea:
3
DV
T,
erec
tile
dysf
unct
ion,
hea
dac
he,
hyper
gly
cem
ia,
psy
chosi
s,ra
sh,
thro
mbocy
topen
ia:
1
Auth
ors
’co
ncl
usi
on:
The
com
bin
atio
nof
carb
opla
tin
and
tam
oxif
enis
wel
lto
lera
ted.
Obvio
us
clin
ical
syner
gy
bet
wee
nca
rbopla
tin
and
tam
oxif
enw
asnot
iden
tifi
ed.
The
auth
ors
consi
der
tam
oxif
en
alone
asse
cond-l
ine
trea
tmen
topti
on
for
pat
ients
wit
hre
curr
ent
mal
ignan
tgli
om
as
Rea
rdon
etal
.,2005
Phas
eII
study
of
imat
inib
mes
yla
tean
dhydro
xyure
ain
adult
sw
ith
recu
rren
tgli
obla
stom
a
Pat
ient
popula
tion
Pat
ients
wit
hhis
tolo
gic
ally
confi
rmed
gli
obla
stom
apro
gre
ssin
gaf
ter
radia
tion
ther
apy
and
tem
ozo
lom
ide
Over
all
n=
33
Str
atum
A:
not
on
EIA
ED
s(n
=18)
Str
atum
B:
on
EIA
ED
s(n
=15)
Tre
atm
ent
regim
en
The
imat
inib
mes
yla
tedose
was
500
mg
twic
ea
day
for
pat
ients
on
EIA
ED
san
d400
mg
once
aday
for
those
not
on
EIA
ED
son
aco
nti
nuous,
dai
lysc
hed
ule
.H
ydro
xyure
a(5
00
mg
twic
ea
day
)w
as
adm
inis
tere
dora
lly
on
aco
nti
nuous,
dai
lysc
hed
ule
III
PF
S-6
Str
atum
A:
17
%
Str
atum
B:
40
%(P
=0.0
217
vs.
Str
atum
A)
Over
all:
27
%
Med
ian
PF
S
Str
atum
A:
8.5
wee
ks
Str
atum
B:
16.6
wee
ks
Over
all:
14.4
wee
ks
Res
ponse
CR
:1
(3%
)
PR
:2
(6%
)
Toxic
ity
Gra
de
3:
neu
tropen
ia(1
6%
),th
rom
bocy
topen
ia(6
%),
and
edem
a(6
%)
Auth
ors
’co
ncl
usi
on:
Imat
inib
mes
yla
teplu
shydro
xyure
ais
wel
lto
lera
ted
and
asso
ciat
edw
ith
dura
ble
anti
tum
or
acti
vit
yin
som
epat
ients
wit
hre
curr
ent
GB
M
Dre
sem
an
etal
.,2005
Ret
rosp
ecti
ve
anal
ysi
sof
imat
inib
and
hydro
xyure
ain
recu
rren
tgli
obla
stom
a
Pat
ient
popula
tion
Gli
obla
stom
apat
ients
wit
hse
cond
dis
ease
pro
gre
ssio
n,
refr
acto
ryto
radia
tion
ther
apy
and
then
chem
oth
erap
y(t
emozo
lom
ide
plu
snit
roso
ure
a),
and
wit
hno
oth
ertr
eatm
ent
opti
on
avai
lable
to
them
.n
=30
Tre
atm
ent
regim
en
Imat
inib
400
mg
once
dai
lyan
dhydro
xyure
a500
mg
twic
edai
lyon
aco
nti
nuous
bas
is
III
PF
S-6
:32
%
Med
ian
OS
:19
wee
ks
Res
ponse
CR
:1
PR
:5
CR
?P
R:
20
%
Toxic
ity
Gra
de
3–4:
None
Auth
ors
’co
ncl
usi
on:
This
trea
tmen
tco
mbin
atio
nyie
lded
ben
efit
intr
eatm
ent
refr
acto
rypat
ients
wit
h
no
gra
de
3–4
toxic
ity.
Thes
ere
sult
sar
eco
mpar
able
wit
hpubli
shed
studie
sin
inves
tigat
ional
tria
ls
wit
hre
curr
ent
or
rela
pse
dgli
obla
stom
apat
ients
582 J Neurooncol (2014) 118:557–599
123
Ta
ble
2co
nti
nu
ed
Auth
or,
yea
rD
escr
ipti
on
of
study
Dat
a
clas
s
Concl
usi
ons
Rea
rdon
etal
.,2005
Phas
eII
anal
ysi
sof
irin
ote
can
and
cele
coxib
for
recu
rren
tm
alig
nan
tgli
om
a
Pat
ient
popula
tion:
His
tolo
gic
ally
confi
rmed
dia
gnosi
sof
mal
ignan
tgli
om
ath
atw
asre
curr
ent
as
defi
ned
by
the
pre
sence
of
uneq
uiv
oca
lpro
gre
ssiv
edis
ease
afte
rpri
or
radio
ther
apy
and
any
num
ber
of
chem
oth
erap
yre
gim
ens
(n=
37
wit
h34
bei
ng
gli
obla
stom
a)
Tre
atm
ent
regim
en:
Irin
ote
can
was
giv
enduri
ng
wee
ks
1,
2,
4,
and
5of
each
6-w
eek
trea
tmen
tcy
cle
ata
dose
of
350
mg/m
2fo
rpat
ients
rece
ivin
gE
IAE
Dan
dat
adose
of
125
mg/m
2fo
rth
ose
pat
ients
not
rece
ivin
gE
IAE
D.
Cel
ecoxib
was
adm
inis
tere
dora
lly
ata
dose
of
400
mg
on
aco
nti
nuous
bas
is
twic
edai
ly.
Pat
ients
rece
ived
up
toei
ght
trea
tmen
tcy
cles
III
PF
S-6
:27.5
%
Med
ian
TT
Pgli
obla
stom
a:11.1
wee
ks
Med
ian
OS
gli
obla
stom
a31.1
wee
ks
Res
ponse
PR
:5
gli
obla
stom
as
Toxic
ity
Non-E
IAE
DP
atie
nts
Hem
atolo
gic
Gra
de
3–4:
8%
Gra
de
3D
iarr
hea
:7
%
EIA
ED
Pat
ients
Hem
atolo
gic
Gra
de
3–4:
0
Gra
de
3D
iarr
hea
:8
%
Auth
ors
’co
ncl
usi
on:
Inth
ecu
rren
tst
udy,
irin
ote
can
plu
sce
leco
xib
can
be
adm
inis
tere
dsa
fely
toget
her
atfu
lldose
level
san
dw
asas
soci
ated
wit
hcl
ear
anti
tum
or
acti
vit
yas
mea
sure
dby
both
radio
gra
phic
resp
onse
and
PF
S
Pra
dos
etal
.,
2003
Pro
spec
tive,
random
ized
,double
-bli
nded
,m
ult
i-in
stit
uti
onal
phas
eII
study
of
RM
P-7
wit
hca
rbopla
tin
inre
curr
ent
mal
ignan
tgli
om
a
Pat
ient
popula
tion:
Adult
sw
ith
recu
rren
tgli
obla
stom
am
ult
iform
eor
anap
last
icgli
om
ahav
ing
fail
ed
radia
tion
ther
apy.
The
pat
ient
may
hav
ehad
pri
or
chem
oth
erap
y.
(n=
122
wit
h121
bei
ng
eval
uab
lew
ith
40/6
1bei
ng
gli
obla
stom
ain
the
RM
P-7
gro
up
and
40/6
0bei
ng
gli
obla
stom
ain
the
pla
cebo
gro
up)
Tre
atm
ent
regim
en:
Pat
ients
wer
era
ndom
ized
ina
1:1
rati
oto
rece
ive
carb
opla
tin
and
eith
erR
MP
-7
or
pla
cebo.
Car
bopla
tin
(dose
dto
achie
ve
anar
eaunder
the
curv
eof
5m
g/m
L9
tim
efo
rpat
ients
who
had
rece
ived
pri
or
chem
oth
erap
y,
or
7m
g/m
L9
tim
efo
rth
ose
who
had
not)
was
giv
en
intr
aven
ousl
yev
ery
4w
eeks,
foll
ow
edby
intr
aven
ous
infu
sion
of
eith
erR
MP
-7or
pla
cebo
(300
ng/
kg)
IIM
edia
nT
TP
Gli
obla
stom
a
RM
P-7
:8.6
wee
ks
Pla
cebo:
8.1
wee
ks
Med
ian
Surv
ival
Gli
obla
stom
a
RM
P-7
:24.0
wee
ks
Pla
cebo:
21.1
wee
ks
Toxic
ity
Gra
de
3–4
hem
atolo
gic
toxic
ity
equal
bet
wee
ngro
ups
and
ata
level
expec
ted
for
carb
opla
tin.
Vas
odil
atat
ion,
hea
dac
he,
nau
sea,
abdom
inal
pai
n,
and
tach
yca
rdia
,ty
pic
alfo
ra
his
tam
ine
like
reac
tion,
wer
em
ore
freq
uen
tly
seen
inth
eR
MP
-7gro
up
Auth
ors
Concl
usi
on:
No
dif
fere
nce
sw
ere
note
dfo
rti
me
tow
ors
enin
gof
neu
ropsy
cholo
gic
al
asse
ssm
ents
,fu
nct
ional
indep
enden
ce,
or
qual
ity
of
life
asse
ssm
ents
wit
hour
wit
hout
RM
P-7
.R
MP
-
7did
not
impro
ve
the
effi
cacy
of
carb
opla
tin
Jaec
kle
etal
.,
2003
Phas
eII
study
of
TM
Zan
d13-c
is-r
etin
oic
acid
inpro
gre
ssiv
em
alig
nan
tgli
om
a
Pat
ient
popula
tion
Pat
ients
wit
hpro
gre
ssio
nof
am
alig
nan
tgli
om
aaf
ter
surg
ery
and
radia
tion
and\
2pri
or
chem
oth
erap
y
regim
ens,
eith
eras
adju
van
ttr
eatm
ent
or
atre
curr
ence
(n=
88
wit
h40
gli
obla
stom
as)
Tre
atm
ent
regim
en
TM
Z150
(for
pat
ients
who
had
pri
or
chem
oth
erap
y)
or
200
(for
pat
ients
who
wer
ech
emoth
erap
y
naı̈
ve)
mg/m
2/d
ay,
day
s1–5,
and
cRA
100
mg/m
2/d
ay,
day
s1–21,
ever
y28
day
s
III
Cal
cula
tions
wer
epro
vid
edfo
rth
e40
gli
obla
stom
as
PF
S-6
:32
%
Med
ian
PF
S:
16
wee
ks
Over
all
6M
onth
Surv
ival
:65
%
Med
ian
Over
all
Surv
ival
:35
wee
ks
Res
ponse
ingli
obla
stom
as:
PR
:2
(5%
)
Toxic
ity
The
most
com
mon
gra
de
3–4
toxic
itie
sw
ere
gra
nulo
cyto
pen
ia(1
.8%
),th
rom
bocy
topen
ia(1
.4%
),
and
hyper
trig
lyce
ridem
ia(1
.2%
).G
rade
3el
evat
ion
inA
LT
was
obse
rved
in5.7
%
Auth
ors
’co
ncl
usi
on:
The
trea
tmen
tex
ceed
edth
eau
thors
goal
of
20
%in
crea
sein
PF
S-6
over
his
tori
cal
info
rmat
ion
(Yung
etal
.,2000)
for
succ
ess.
The
resu
lts
from
this
tria
lsu
gges
tth
atth
e
com
bin
atio
nof
TM
Zan
d13-c
is-r
etin
oic
acid
may
be
am
ore
acti
ve
regim
enin
recu
rren
tm
alig
nan
t
gli
om
asth
anT
MZ
alone
J Neurooncol (2014) 118:557–599 583
123
Ta
ble
2co
nti
nu
ed
Auth
or,
yea
rD
escr
ipti
on
of
study
Dat
a
clas
s
Concl
usi
ons
Fin
eet
al.,
2003
Aphas
eII
inves
tigat
ion
of
thal
idom
ide
and
carm
ust
ine
inpat
ients
wit
hre
curr
ent
hig
hgra
de
gli
om
as
Pat
ient
popula
tion
Pat
ients
wit
hre
curr
ent
mal
ignan
tgli
om
aaf
ter
radia
tion.
Up
to2
pri
or
chem
oth
erap
yre
gim
ens
wer
e
allo
wed
(n=
40
wit
hgli
obla
stom
a=
38)
Tre
atm
ent
regim
en
Thal
idom
ide
800
mg/d
ayfo
rth
efi
rst
2w
eeks,
whic
hw
ases
cala
ted
by
200
mg
ever
y2
wee
ks
unti
la
final
dose
of
1,2
00
mg/d
ayw
asre
ached
,or
unti
lth
epat
ient
exper
ience
ddose
-lim
itin
gto
xic
ity.
BC
NU
was
adm
inis
tere
das
anin
trav
enous
infu
sion
for
1h
ata
dose
of
200
mg/m
2ev
ery
6w
eeks.
Cycl
esw
ere
defi
ned
asev
ery
6w
eeks
III
PF
S-6
Gli
obla
stom
a:27.0
3%
Med
ian
PF
SG
liobla
stom
a:104
day
s
Toxic
ity
Gra
de
4
Neu
tropen
ia:
3
Thro
mbocy
topen
ia:
1
Gra
de
3
Confu
sion:
3
Som
nole
nce
:1
Const
ipat
ion:
1
Auth
ors
’co
ncl
usi
on:
The
dat
adem
onst
rate
that
thal
idom
ide
inco
mbin
atio
nw
ith
BC
NU
isw
ell
tole
rate
dan
dhas
anti
tum
or
acti
vit
yin
pat
ients
wit
hgli
obla
stom
a.T
he
com
bin
atio
nse
ems
tobe
more
acti
ve
than
eith
erag
ent
alone,
but
that
concl
usi
on
awai
tsa
confi
rmat
ory
tria
l
Bra
ndes
etal
.,1999
Aphas
eII
anal
ysi
sof
pro
carb
azin
ean
dhig
hdose
tam
oxif
enin
recu
rren
tm
alig
nan
tgli
om
as
Pat
ient
popula
tion
Pat
ients
wit
hknow
ngli
obla
stom
aor
anap
last
icas
trocy
tom
aan
ddocu
men
ted
imag
ing
recu
rren
cew
ho
had
under
gone
surg
ery
and
radio
ther
apy,
and
alre
ady
had
bee
ntr
eate
dw
ith
(Gro
up
A,
n=
34)
at
leas
tone
chem
oth
erap
yre
gim
enth
atin
cluded
nit
roso
ure
aor
(Gro
up
B,
n=
19)
ase
cond
line
regim
enof
carb
opla
tin
and
tenip
osi
de
(n=
53
wit
h51
eval
uab
lein
cludin
g28
gli
obla
stom
as)
Tre
atm
ent
regim
en
Pro
carb
azin
e100
mg/m
2/d
ayplu
sta
moxif
en100
mg/d
ayin
repea
ted
30-d
ayco
urs
esw
ith
a30-d
ay
inte
rval
bet
wee
nco
urs
es
III
Med
ian
TT
PG
liobla
stom
a:13
wee
ks
Med
ian
Surv
ival
Tim
eG
liobla
stom
a:27
wee
ks
Res
ponse
Gli
obla
stom
a
CR
:1
(3.5
%)
PR
:8
(28.6
%)
Toxic
ity
(all
his
tolo
gie
s)
Gra
de
3
Leu
kopen
ia(1
)
Thro
mbocy
topen
ia(2
)
Gas
troin
test
inal
(3)
Ven
ous
Thro
mbosi
s(5
)
Dea
ths:
Intr
aven
tric
ula
rhem
orr
hag
e(1
),pulm
onar
yem
boli
sm(3
)
Auth
ors
Concl
usi
on:
This
ther
apy
was
not
asso
ciat
edw
ith
anin
crea
sed
tim
eto
pro
gre
ssio
nor
med
ian
surv
ival
tim
eco
mpar
edto
his
tori
cal
dat
aw
ith
pro
carb
azin
eor
tam
oxif
enal
one
(Rodri
guez
1989;
Ver
tosi
ck1992;
Could
wel
l1996)
Addit
ional
ly,
they
note
this
seri
esis
too
smal
lto
allo
wan
y
defi
nit
eco
ncl
usi
on,
but
show
edtr
ansi
ent
dis
ease
contr
ol
asdet
erm
ined
by
resp
onse
Hoch
ber
g
etal
.1997
Phas
eI-
IIst
udy
of
BC
NU
and
fluoso
lin
recu
rren
tm
alig
nan
tgli
om
a
Pat
ient
popula
tion
Pat
ient
imag
ing
evid
ence
of
recu
rren
tm
alig
nan
tgli
om
aaf
ter
radia
tion
ther
apy
only
(n=
84
wit
h
pro
gre
ssiv
etu
mor
of
whic
h38
wer
egli
obla
stom
as)
Tre
atm
ent
regim
en
Flu
oso
lw
asin
fuse
din
agra
ded
fash
ion
(1m
L/m
info
r5
min
,th
en5
mL
/min
for
addit
ional
5m
inan
d
final
ly10
mL
/min
).F
luoso
ldose
level
ste
sted
wer
e150,
275,
400
and
600
mL
/m2.
Aft
erth
e
infu
sion,
100
%oxygen
(10–15
L/m
in)
was
giv
enfo
r5
hth
rough
ati
ghtl
yfi
ttin
gnonre
bre
ather
mas
k.
Thir
tym
inute
saf
ter
the
star
tof
oxygen
,B
CN
U(i
ntr
aven
ous
200
mg/m
2)
was
giv
enover
60–120
min
.T
her
apy
was
repea
ted
ever
y6
wee
ks
for
six
cycl
esor
unti
ldis
ease
pro
gre
ssio
n
III
Mea
nT
ime
toP
rogre
ssio
ngli
obla
stom
a:10.9
wee
ks
Med
ian
surv
ival
gli
obla
stom
a:26.7
wee
ks
Toxic
ity
(all
his
tolo
gie
s)
Gra
de
3–4
Leu
kopen
ia:
6,
thro
mbocy
topen
ia:
10,
elev
ated
liver
enzy
mes
:31,
hypote
nsi
on:
1,
mis
cell
aneo
us:
7
(IV
site
pai
n:
2,
arm
tender
nes
s:2,
nau
sea
and
vom
itin
g:
1,
dec
reas
edif
fusi
on
of
lung
carb
on
dio
xid
e:1,
pulm
onar
yem
boli
sm:
1)
Auth
or
Concl
usi
on:
The
com
bin
atio
nof
BC
NU
and
fluoso
lat
the
test
eddose
sis
asa
fean
dw
ell
tole
rate
dth
erap
yan
dm
ayen
han
ceth
eef
fect
iven
ess
of
BC
NU
.T
he
pla
nned
fluoso
ldose
for
futu
re
studie
sis
400
mL
/m2
PF
Spro
gre
ssio
nfr
eesu
rviv
al,
PF
S-6
pro
gre
ssio
nfr
eesu
rviv
alat
6m
onth
s,C
Ico
nfi
den
cein
terv
al,
CR
com
ple
tere
sponse
,P
Rpar
tial
resp
onse
,O
Sover
all
surv
ival
,T
TP
tim
eto
pro
gre
ssio
n,
MST
med
ian
surv
ival
tim
e,T
MZ
tem
ozo
lom
ide,
BC
NU
carm
ust
ine,
1,
3-b
is(2
-chlo
roet
hyl)
-1-n
itro
soure
a,E
IAE
Ds
enzy
me-
induci
ng
anti
-epil
epti
cdru
gs,
SD
stan
dar
ddev
iati
on,
PE
pulm
onar
yem
bolu
s,IV
intr
aven
ous
584 J Neurooncol (2014) 118:557–599
123
neutropenia, fatigue, infection, and nausea in 3 (8 %), 8
(20 %), 10 (25 %), 5 (13 %), 4 (10 %), and 3 (8 %)
patients, respectively. Hematologic grade four toxicities
included neutropenia in eight patients (20 %) and throm-
bocytopenia in four patients (10 %). Additionally, one
patient each developed grade 4 gastrointestinal perforation
and venous thrombosis. Eleven patients (28 %) discontin-
ued therapy due to toxicity and 17 additional patients
(43 %) required dose modification. There was one study
related death from an intestinal perforation. The 6-month
progression free survival was 46.5 %, and the median
overall survival was 8.3 months. Thirteen patients had a
partial response (33 %), and 21 patients had stable disease
(53 %). The authors conclude the regimen has similar anti-
tumor activity as bevacizumab monotherapy, but signifi-
cantly greater toxicity, so further study is not warranted
[48].
In a phase I, multicenter trial of bevacizumab, irino-
tecan, and vorinostat (or suberoylanilide hydroxamic acid
is a histone deacetylases inhibitor with a broad spectrum of
epigenetic activities), Chinnaiyan et al., studied adult
patients with glioblastoma or gliosarcoma at time of
recurrence after histologic confirmation, radiation and
temozolomide who had not received treatment with bev-
acizumab or irinotecan. Bevacizumab was given (10 mg/kg
i.v.) with irinotecan (125 mg/m2 i.v.) on days 1 and 15
every 28 days. Vorinostat was given in a 3 ? 3 dose-
escalation design where it was given at doses between 200
and 400 mg per day on days 1–7 and 15–21 of a 28-day
cycle, as a three-tier dosing schema. Due to toxicity, the
third tier was adjusted to 300 mg twice daily on days 1–3
and 15–17 of the 28-day cycle. If more than two patients
had a dose-limiting toxicity, the dose would not escalate.
Median progression free survival was 3.6 months and
median overall survival was 7.3 months. There was a trend
to improved outcomes with higher doses of vorinostat.
Grade 3 and 4 toxicities included neutropenia, diarrhea,
mucositis, stomach pain, fatigue, CNS ischemia, hyper-
tension, hypotension, and sensory neuropathy. Irinotecan
commonly required dose reductions early in therapy due to
toxicity. The authors also looked at biomarkers and found
that IGFBP-5 and PDGF-AA were markers of improved
PFS and recurrence, respectively. This study established a
maximum tolerated dose for vorinostat of 400 mg/day on
days 1–7 and 15–21 of a 28 day cycle for this combination,
although it has poor long-term tolerability, and the authors
recommended irinotecan be removed from the combination
for any future studies [49].
Reardon et al., studied temozolomide or etoposide in
combination with bevacizumab in a single institution phase
II evaluation of recurrent glioblastoma patients who pro-
gressed on prior bevacizumab monotherapy (n = 24). Six
month progression free survival in the temozolomide
cohort was 0 months, and in the etoposide group was
7.7 months. Nine out of ten patients in the temozolomide
cohort progressed within 2 months of therapy, as did nine
out of twelve patients in the etoposide cohort. The study
was ended at interim analysis due to lack of efficacy [32].
Retrospective analyses of bevacizumab and cytotoxic
agents A number of interesting retrospectively produced
reports on the use of bevacizumab and various cytotoxic
agents are available and discussed below. Though infor-
mative, each represents class III data. A small single
institution retrospective study of 12 glioblastomas treated
with bevacizumab and irinotecan was reported by Kang
et al. Interestingly the progression free survival at 6 months
was 17 % and the median progression free survival was
3.8 months. The median overall survival was 7.1 months.
Responses by histology were not reported. Though the
outcome data was considerably poorer than seen in the
Vredenburgh et al. and Friedman et al. studies, the authors
described the regimen as highly active (see Table 2) [22,
35, 50].
Norden et al. summarized their experience with bev-
acizumab and three cytotoxic agents, irinotecan, carbo-
platin or carmustine. Thirty-three of the cases were
recurrent glioblastoma. Little data was present for glio-
blastoma alone and the 6-month progression free survival
was 42 %. This paper provides considerable insight into
the use of bevacizumab in the recurrent setting but its value
in this guideline is limited by its retrospective nature and
lack of separation of glioblastoma data from that of other
histologies in most result reporting [51].
In another retrospective study of bevacizumab and iri-
notecan, Zuniga et al. report on its effect in 37 progressive
glioblastomas. Progression free survival at 6 months was
63.7 % and the median progression free survival was
7.6 months. The median overall survival from treatment
initiation was 11.5 months. Complete response occurred in
5.41 % and partial response occurred in 62.16 %. Six
patients required discontinuation of treatment including
one with end-stage renal failure, one with gastrointestinal
perforation and four with severe nausea and vomiting. The
authors concluded the therapy is effective but at the price
of serious toxicity in some individuals (see Table 2) [52].
In yet another retrospective analysis of bevacizumab and
irinotecan (dosed for the presence or absence of enzyme-
inducing antiepileptic drugs), Poulsen et al. reported their
experience with 27 progressive glioblastomas. They noted
no difference in treatment effect between patients on or off
enzyme inducing antiepileptic drugs and thus they reported
the results together. The 6-month progression free survival
was 40 % and the median progression free survival was
22 weeks. The median overall survival was 28 weeks.
There were four complete responses and four partial
J Neurooncol (2014) 118:557–599 585
123
responses. In the authors’ opinion, durable responses could
be obtained with this regimen [53].
In a small retrospective, single institution report Zhang
et al. report on five progressive glioblastomas treated with
bevacizumab and temozolomide (n = 3), or irinotecan
(n = 1) or topotecan (n = 1). Data from the tables could
be extracted for glioblastomas. The median progression
free survival was 10 weeks and there were three complete
responses and one partial response. The authors describe
antiangiogenic therapy as strikingly effective, but the het-
erogeneity of treatments and retrospective nature of the
data yield class III data [54].
Quant et al. evaluated 54 patients with recurrent
malignant gliomas (n = 35, glioblastoma) who progressed
on a bevacizumab-containing regimen and were then
treated with an alternate bevacizumab-containing regimen.
They reported a median progression free survival of
135 days on the first bevacizumab-containing regimen, and
35 days on the second bevacizumab-containing regimen,
with progression free survival rate at 6 months of 37 and
3 %, respectively. Median overall survival after discon-
tinuing the second regimen was 82 days. The results were
not stratified by grade of glioma except for responses. The
authors concluded that patients with glioblastoma who
progressed despite a bevacizumab-containing regimen did
not respond to the second bevacizumab-containing che-
motherapeutic regimen [55].
Anti-angiogenic agents combined with other targeted
agents
Sathornsumetee et al. reported the results of a phase II trial
that evaluated the combination of bevacizumab and erl-
otinib (an epidermal growth factor receptor inhibitor) in 25
patients with recurrent glioblastoma. The progression free
survival rate at 6 months was 25 % and median overall
survival was 42 weeks. The authors concluded that, while
this combination was well-tolerated, there was no associ-
ated benefit in PFS when compared to historic controls (see
Table 1) [22, 23, 56].
Lu-Emerson et al., performed a retrospective analysis of
recurrent glioblastoma patients treated with dasatinib a
SRC, BCR-ABL, c-KIT, EPHA2, and PDGFRb inhibitor,
in combination with bevacizumab after bevacizumab fail-
ure at a single institution (n = 14). Patients were given
dasatinib 70–100 mg twice daily in combination with
bevacizumab 10 mg/kg every 2 weeks. There were no
radiographic responses only one patient with stable disease.
One patient had a grade 4 cerebral hemorrhage. The
authors conclude dasatinib in combination with bev-
acizumab does not appear to have activity in heavily pre-
treated Glioblastoma (see Table 1) [57].
Antiangiogenic therapies summary
Based on comparison to historical data, one study provides
a well-documented set of class III data that bevacizumab
alone or in combination with iriniotecan is superior to
standard cytotoxic agents in this patient population [22].
This conclusion is supported by another prospective study
of bevacizumab alone that qualifies as class III data [23].
These two publications were important pieces of evidence
in what eventually led to FDA approval of bevacizumab for
glioblastoma in the recurrent setting [58, 59]. Prospective
analyses of bevacizumab combined with cytotoxic agents
such irinotecan, carboplatin and etoposide did not show
clear benefit over treatment with bevacizumab alone. A
number of retrospective studies were supported the possi-
ble therapeutic value of bevacizumab and confirmed the
agent is not without toxicity. Thalidomide has been studied
as an antiangiogenic agent with admitted marginal effect in
the published reports.
Given the scientific foundation for the use of antian-
giogenic agents in the setting of progressive glioblastoma,
the application of antiangiogenic agents in brain tumor
treatment is far from settled science. Ideal timing and
dosage of the agents alone and in combined regimens to
maximize efficacy, and minimize toxicity and inconve-
nience remains to be established. If use of these agents
could be guided by identified markers of response to anti-
angiogenic agents response rates and durability could
possibly improve. Finally, toxicities of this regimen are
quite real, require discontinuation of the antiangiogenic
agents and when this is necessary seems to be associated
with substantial and rapid tumor progression [18, 35, 60].
Targeted therapy-specific molecules or signaling pathways
Wide varieties of agents with reasonable scientific back-
ground or positive experience in other tumor sites have
been brought into the theater of progressive glioblastoma
treatment. Those publications meeting the eligibility cri-
teria for this guideline are described below.
Retinoids Because of their reported diverse biologic
effects in malignant conditions, including regulating the
synthesis of enzymes, growth factors, and binding proteins
various retinoids have been studied in the therapy of pro-
gressive glioblastoma. Yung et al. treated patients from this
population the first 3 weeks out of each 4-week cycle with
13-cis-retinoic acid at 60–100 mg/m2 per day. No complete
or partial responses were noted in glioblastomas and their
median time to progression was 19 weeks [61].
Analysis of the alternative form of this agent, all-trans-
retinoic acid was been assessed in a 21 recurrent glio-
blastomas. The regimen included 150 mg/m2/day in weeks
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1–3 and 5–7 of each 8-week cycle. After a number of cases
(number not specified in glioblastomas) of grade 3 head-
ache, hypertriglyceridemia, and constitutional symptoms
the dose was decreased to 120 mg/m2/day. No objective
responses were observed and time to progression and sur-
vival was not calculated for glioblastoma alone. The
authors concluded that all-trans-retinoic acid had no
activity in this disease process [62].
Fenretinide induces apoptosis in malignant glioma
models in vitro. To determine if this could be translated to
the human situation, Puduvalli et al. provided it to patients
with recurrent glioblastomas at a dose of 600 mg/m2 bid
approximately 12 h apart on days 1–7 and 22–28 of each
6-week period. In the 22 cases, the progression free sur-
vival at 6 months was zero. The median progression free
survival was 6 weeks and the median survival from treat-
ment initiation was 16 weeks. The authors concluded that
fenretinide had no activity at the doses studied [63].
In further analysis of 13-cis-retinoic acid, See et al.
evaluated eighty-five patients with recurrent glioblastoma.
Fifteen were part of a phase II study. The remainder were
collected and analyzed in a retrospective manner. The first
three cases were treated with 60 mg/m2/day for the 21 of
each 28-day cycle. Thereafter, the dose was increased to
100 mg/m2/day. They report a 6-month progression free
survival of 19 %. Median progression free survival was
10 weeks and median overall survival from treatment ini-
tiation was 24.6 weeks. Grade three and four toxicity was
experienced by 16.5 % of patients. The findings of this
class III study are in line with the prior experience noted
above [64].
Jaeckle et al. provided a report focused on 13-cis-reti-
noic acid to which temozolomide was added in a study with
40 recurrent glioblastomas. The 6-month progression free
survival of the combination was 32 % and the median
progression free survival was 16 weeks. The overall
6-month survival was 65 % and the median overall sur-
vival was 35 weeks. Though the prior measurement of
treatment effect were considered positive as it exceeded
prior reported outcomes for temozolomide alone, there
were only 2 partial responses (5 %) in glioblastomas [31,
65].
The combination of 13-cis-retinoic acid with another
targeted agent, celecoxib was reported in a phase II pro-
spective study of 25 progressive glioblastomas by Levin
et al. Although this study included more than the targeted
agent, the focus is on 13-cis-retinoic acid and included for
cohesion of the scientific foundation. 13-cis-retinoic acid
was administered orally at a dose of 100 mg/m2 daily in
divided doses and celecoxib was administered orally at a
dose of 400 mg twice daily for 21 consecutive days fol-
lowed by seven drug-free days. The progression free sur-
vival at 6 months was 19 % and median progression free
survival was 8 weeks. No responses were observed. The
authors point out the progression free survival rate at
6 months is the same as reported with 13-cis-retinoic acid
alone reported by See et al. noted above and that further
investigation of this combination is not warranted [64, 66].
This and the other retinoic acid studies mentioned previ-
ously provide class III evidence.
Hypericin Couldwell et al. reported a phase I/II study of
synthetic hypericin in recurrent high grade glioma in a
cohort that included 35 glioblastomas. Its antitumor
mechanism is probably multifactorial including inhibition
of protein kinase C activity, and binding of heat shock
protein 90 resulting in the disruption of several down-
stream growth pathways. Hypericin was given as an oral
solution at doses ranging from 0.05 to 0.50 mg/kg once
daily for up to 3 months. Doses were escalated until tox-
icity developed. The agent induced one partial response in
the glioblastoma patients. Survivals were not calculated for
glioblastoma alone, mean maximum tolerated dose was
0.40 ± 0.098 mg/kg daily. The authors conclude that
hypericin may be worthwhile studying in combination with
other agents [67]. Because this study only reports on one
partial response in glioblastoma and gives no data on
glioblastoma survival alone, it only marginally meets cri-
teria for inclusion in this guideline and yields Class III
data.
Tamoxifen The use of tamoxifen (an inhibitor protein
kinase C signal transduction in glioma cell lines) alone has
been explored by Couldwell et al. They provided the agent
on a continuous basis and obtained a median survival from
treatment initiation of 7.2 months. Responses were repor-
ted as 20 % in glioblastoma but measured with a combi-
nation of clinical improvement, reduction of tumor size on
MRI and decreased metabolic activity on PET making the
quantity difficult to compare to other reports. The resultant
data is class III in nature [68].
Gossypol A study of gossypol, a polyphenolic compound
proposed to deplete cellular energy by inhibition of several
intracellular dehydrogenases, was carried out in a popula-
tion that included 15 recurrent glioblastomas by Bushunow
et al. With a dose of 10 mg daily, the authors report two
partial responses with minimal toxicity. The authors stop-
ped the study based on low response rate. Prior therapy was
very heterogeneous over the population and one case did
not have histologic proof of glioblastoma yielding class III
data [69].
SU101 Vlassenko et al. have carried out a study of
SU101 (N-[(4-trifluoromethyl)-phenyl]-5-methylisoxazole-
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4-carboxamide, leflunomide), a cytostatic agent that
inhibits the platelet-derived growth factor (PDGF) medi-
ated signaling events, including receptor tyrosine phos-
phorylation, DNA cycle progression, and cell proliferation,
in recurrent malignant gliomas with the main focus being
it’s effect of imaging. However, some outcome data was
provided on the five glioblastomas included in the study.
Mean time to progression was 12.4 weeks and mean sur-
vival from initiation of therapy was 25.8 weeks. Toxicity
was not enumerated but the study was suspended by the
sponsor due to an unexpected mortality in the first 30 days
of treatment [70]. Class III evidence is provided by this
study.
Lonidamine and diazepam Based on the hypothesis that
lonidamine (an inhibitor of aerobic glycolysis in cancer
cells) and diazepam would act to inhibit two distinct
mitochondrial sites involved in cellular energy metabolism
on glioblastoma, Oudard et al. were able to assess 14 cases
of recurrent glioblastoma. Median time to progression was
11 weeks and median survival from treatment initiation
was 15 weeks. Though there was no significant toxicity, no
responses were observed and this yields class III evidence.
[71].
CCI-779 (temsirolimus) To assess the value of mTOR
pathway inhibition in progressive glioblastoma, Chang
et al. reported their experience from a prospective phase II
study of the rapamycin analog CCI-779. The drug was
provided intravenously at a dose of 250 mg weekly in
patients on enzyme-inducing anti-epileptic drugs. This was
the starting dose for patients not on enzyme-inducing anti-
epileptic drugs and this was ultimately stepped down to
170 mg weekly due to problems with stomatitis. In forty-
one cases, the authors reported a progression free survival
rate at 6 months of 2 %. The median time to progression
was 9 weeks and two partial responses were observed. The
authors concluded this agent had no activity alone in pro-
gressive glioblastomas [72].
Galanis et al. conducted a phase II trial of temsirolimus
dosed at 250 mg given intravenously weekly in 65 patients
with recurrent glioblastoma. The median time to progres-
sion was 2.3 months, median overall survival was
4.4 months, and progression free survival rate at 6 months
was 7.8 %. There were no objective responses [73]. Both
of these studies of temsirolimus produced class III data.
Aprinocarsen In an effort to translate the promising sci-
ence behind aprinocarsen, an antisense oligonucleotide
directed at protein kinase C-alpha, Grossman et al.
assessed its effect in progressive malignant gliomas, 16 of
which were glioblastomas. This phase II therapy entailed a
21 day continuous infusion of the agent beginning with
2 mg/kg/day with the option of intrapatient dose escalation.
In the glioblastomas, median time to progression was
36 days. Median survival from therapy initiation was
3.4 months and no responses were observed. It was con-
cluded that this agent delivered no clinical benefit and the
study produced class III data [74].
Imatinib As malignant gliomas are known to overexpress
various tyrosine kinases, imatinib mesylate, a potent
inhibitor of platelet derived growth factor receptor alpha
and beta (PDGFRa, PDGFRb) has been hypothesized to be
useful in the therapy malignant gliomas. In data from a
phase I and then phase II study of this agent, Wen et al.
evaluated sixty-nine glioblastoma patients (35 in phase I
and 34 in phase II). In the phase II study, progression free
survival at 6 months was 3 %. One partial response was
observed in the phase I study and two partial responses
were observed in the phase II study. The dose in the phase
II study was reduced from 800 to 600 mg/day after five
cases if intracranial hemorrhage. The authors concluded the
poor efficacy of the agent might be related to lack of tumor
penetration, inadequacy of biologic effect on glioblastoma
of blockage of the platelet derived growth factor pathway
alone, and raised concern over the frequent intratumoral
hemorrhage rate [75].
Another assessment of imatinib was carried out by
Raymond et al. Two cohorts were treated: one starting at
600 mg/day and escalating to 800 mg/day if no grade 2
toxicity occurred over the first 8 weeks (including 19
glioblastomas). This was tolerated well enough that the
investigators moved the dosing to starting at 800 mg/day
and escalating to 1,000 mg/day if no grade 2 toxicity
occurred over the first 8 weeks including 31 glioblasto-
mas). Combining the two cohorts, the 6-month progression
free survival was 16 % and overall 6-month survival from
treatment initiation was 50 %. Median overall survival
from treatment initiation was 5.9 months. In the larger
dose, the rate of grade 3–4 neutropenia and febrile neu-
tropenia was 11 and 6.2 %, respectively. As was the case
with Wen et al., they concluded the agent had insufficient
single agent activity to warrant further pursuit [75, 76]. In
both of the studies of imatinib, the evidence meets class III
criteria.
Tipifarnib Cloughsey et al. reported a phase II prospec-
tive analysis of the farnesyltransferase inhibitor tipifarnib
in recurrent malignant gliomas. The cases were divided
into those not taking enzyme-inducing antiepileptic drugs
(Group A received tipifarnib 300 mg bid on days 1–21
every 4 weeks) and those taking enzyme-inducing antiep-
ileptic drugs (Group B who received tipifarnib 600 mg bid
on days 1–21 every 4 weeks). The progression free sur-
vival at 6 months in Group A was 16.7 % (in 36
588 J Neurooncol (2014) 118:557–599
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glioblastomas) and in Group B, it was 6.5 % (in 31 glio-
blastomas). Median progression free survival was 9 weeks
in Group A and 6 weeks in Group B. Partial responses
were observed in four glioblastomas in Group A and one
glioblastoma in Group B. Low frequencies of a variety of
hematologic and nonhematologic toxicities were observed.
The authors optimistically described the activity of tipi-
farnib as modest and recommended future studies be lim-
ited to those not on enzyme-inducing antiepileptic drugs
[77]. This is class III data.
COL-3 (6-demethyl-6-deoxy-4-dedimethylaminotetracy-
cline) Rudek et al., studied COL-3 as a single agent in a
phase I, multicenter trial for recurrent high-grade glioma
(n = 33, 25 of which were glioblastoma). COL-3 is a non-
antimicrobial chemically modified tetracycline that targets
multiple aspects of matrix metalloproteinases regulation.
Patients were given COL-3 orally once daily on an unin-
terrupted schedule for 28 days per cycle. Dose escalation
occurred beginning at 25 mg/m2 in 25 mg/m2 increments
up to a maximum 100 mg/m2. Patients were divided into
based on the use of enzyme inducing antiseizure drugs
(EIAED). Survival results were not divided by pathology,
and only 27 patients were evaluable for response. However,
it is stated that there were no responders among the glio-
blastoma patients, and that three glioblastoma patients had
stable disease. All were in the EIAED (?) arm. A maxi-
mum tolerated dose was identified in patients on EIAED
(-) regimens but the authors conclude that further studies
are not warranted for COL-3 as a single agent [78]. This
represents class III data for the purposes of this guideline.
AMG 102 (rilotumumab) Wen et al., report on a phase II
multicenter, open-label, 2-stage trial of AMG 102 in
heavily pretreated recurrent glioblastoma patients
(n = 61). Patients received AMG 102 either 10 or 20 mg/
kg by IV infusion every 2 weeks. Progression free survival
at 6 months ranged from 5.3 to 17.9 % depending on AMG
102 dosing and bevacizumab exposure. There were no
complete or partial responses. Seven patients had best
response of stable disease. The authors concluded that
AMG 102 did not demonstrate significant antitumor
activity in this trial [79].
Trabedersen In a phase IIb, prospective, multinational
open-label, randomized, control trial, Bogdahn et al.,
studied the TGF-beta inhibitor trabedersen in adults with
recurrent high grade glioma (n = 103 for glioblastoma of
which 95 were evaluable for treatment effect). Patients
were divided into one of three groups: temozolomide or
PCV (for TMZ refractory patients) control, trabedersen at
10 lM, and trabedersen at 80 lM. In the control groups,
most common toxicities were marrow suppression
disorders. For the trabedersen groups, most toxicities were
nervous system disorders. Six month progression free
survival was 14, 12, and 15 % for 10 lM trabedersen,
80 lM trabedersen, and control, respectively. Median OS
was 7.2, 10.8, and 10.0 months for 10 lM trabedersen,
80 lM trabedersen, control, respectively. The authors
conclude that trabedersen had superior efficacy and safety
at 10 lM than at 80 lM or than control, especially at
longer follow-up intervals and that this agent deserves
further study [80]. Though designed to possibly produce
class II data enrollment was inadequate for being able to
tell significant differences between the groups for glio-
blastoma, thus yielding class III data.
EGFR inhibitors In an open label phase II trial of gefi-
tinib in 57 patients with recurrent glioblastoma, Rich et al.
observed a median progression free survival of 8.1 weeks,
and progression free survival at 6 months of 13 %. They
did not observe any objective response, however only 21 %
of their patients had measurable disease at the time of study
entry [81].
The use of EGFR inhibition by way of gefitinib was
studied by Franceschi et al. in a prospective phase II study
that included 16 glioblastomas. The drug was administered
at 250 mg/day on a continuous basis. Progression free
survival as 6 months was 12.5 %. No responses were
observed. The authors concluded that the 6-month pro-
gression free rate and response rate were too low to warrant
additional evaluation as a solo therapeutic agent in this
population [82].
Preusser et al. reported on the ‘‘exploratory’’ use of
erlotinib or gefitinib in a series that included 14 recurrent
glioblastomas. In general, data for the glioblastomas was
not reported separately but a summary table of patients
included was available allowing a median survival from
treatment initiation calculation of 4.17 months. The
authors conclude there may be efficacy with these agents in
few patients, but in general they have poor clinical effect. It
only provides class III data, as it is not clear that is it
prospective [83].
A randomized, prospective phase II analysis of erlotinib
(n = 54) versus temozolomide (n = 27) or carmustine
(n = 29) in progressive glioblastomas was reported by van
den Bent et al. No difference in outcome between the two
cytotoxic agents was observed and they were reported
together. The progression free survival at 6 months was
11.4 % in the erlotinib group and 24 % in the cytotoxic
agent group. The median progression free survival was
1.8 months in the erlotinib group and 2.4 months in the
cytotoxic agent group. The median overall survival was
7.7 months in the erlotinib group and 7.3 months in the
cytotoxic agent group. The partial response rate in the
erlotinib group was 3.7 % and in the cytotoxic agent group
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123
was 9.6 %. The authors concluded single agent erlotinib
had no meaningful activity in this setting. The study was
not powered to detect significant survival differences and
yields class III data [84].
Raizer et al. conducted a phase II trial using erlotinib
including patients with recurrent glioblastoma (n = 38,
evaluable). The progression free survival rate at 6 months
for this group was 3 %, median progression free survival
was 2 months and median overall survival was 6 months.
There were no objective responses [85].
The lack of efficacy despite what appears to be strong
supporting scientific data is clearly frustrating and has led
to careful reconsideration and recommendations for future
exploration of treatment based on EGFR biology [86].
Each of the studies of EGFR inhibitors noted here yield
class III data.
Monoterpene perillyl alcohol This agent is hypothesized
to involve effects on the TGF-b and/or the Ras signaling
pathway. Twenty-nine glioblastomas were included in the
series of patients that had failed surgery, radiation and at
least one temozolomide-based therapy reported by Orlando
da Fonseca et al. Administration was novel with for nasal
sprays a day, each containing 55 mg (0.3 % v/v perillyl
alcohol) for a total of 220 mg/day. Progression free sur-
vival at 6 months for the glioblastomas was reported at
48.2 %. One partial response was observed and they claim
no toxicity was observed [87].
This same group more recently reported a phase I/II
single center trial in recurrent glioblastoma patients only on
symptomatic treatment after at least three relapses fol-
lowing surgery and/or radiation and multimodal chemo-
therapy specific for glioblastoma. 89 patients were matched
with historical controls collected retrospectively who
received supportive care only at recurrence. POH was
administered similar to the previous study, but with esca-
lation up to 440 mg daily. POH was well tolerated, with
only some nasal discomfort reported at higher doses.
Median overall survival was 5.9 months in comparison to
2.3 months in the historical control cohort. The authors
also found an increased survival benefit among patients
with a basal ganglia location of disease or those with
secondary recurrent glioblastoma. These findings, though
interesting are not significant in that the study was not
powered to find differences in these subgroups and thus this
study represents class III data [88].
Cilengitide To assess the effect of the putative inhibitor
of the infiltrative component tumor cell function Reardon
et al. looked at two doses of cilengitide in eighty-one
recurrent glioblastoma patients. The agent was provided in
a randomized manner at 500 mg twice a week (Arm 1) or
2,000 mg twice a week (Arm 2) on a continuous basis.
Progression free survival at 6 months was 10 % in Arm 1
and 15 % in Arm 2. The median time to progression was
7.9 and 8.1 weeks in those same arms, respectively.
Median overall survival from treatment initiation was 6.5
and 9.9 months, respectively. Partial response rate was 9 %
overall with no difference between arms. The maximum
grade 3–4 toxicity was lymphopenia at 9 %. The authors
concluded cilengitide had limited activity as a single agent.
They note that the response rate is similar to that observed
by Yung et al. with temozolomide alone, but suggest cil-
engitide may be more useful when used in combination
with other agents. Though this was a randomized study
between different doses, no concurrent or historical com-
parison to other therapies was provided yielding class III
data [31, 89].
An additional phase II, double arm, multi-center trial of
cilengitide was performed by Gilbert et al., this trial gave
cilengitide either as a high dose (2,000 mg) or low dose
(500 mg) on days-8, -4, and -1 prior to tumor resection in
patients with recurrent glioblastoma with surgically
resectable lesions. The study ended because of slow
accrual. Thirty patients were enrolled. Drug was clearly
measurable in the resected tumor specimens. Six-month
progression free survival was 12 % with a mean progres-
sion free survival of 8 weeks. Treatment effect was mod-
est, but was deemed to not warrant further investigation of
cilengitide as a single agent [90]. As with the Reardon
study, this yields class III data.
Suberoylanilide hydroxamic acid Galanis et al. reported
their experience with suberoylanilide hydroxamic acid
(vorinostat), a histone deacetylase inhibitor with multiple
potential mechanism of action in a phase II multi-institu-
tional study. The 66 recurrent glioblastomas enrolled
received 200 mg orally twice a day for 14 days, followed
by a 7-day rest period until progression. The observed
progression free survival at 6 months was 15.2 %. Median
time to progression was 1.9 months and median overall
survival from the initiation of therapy was 5.7 months. The
results are class III in nature, and are similar to the data in
reviews of older cytotoxic agents the authors concluded
there was modest activity [19, 91].
Enzastaurin To assess the value of enzastaurin, an oral
serine/threonine kinase inhibitor, hypothesized to target
both the protein kinase C and the PI3K/AKT pathways23
to induce apoptosis and suppress proliferation and tumor-
induced angiogenesis, Wick et al. carried out a multi-
institutional, prospective randomized study between this
agent and lomustine using 6-week cycles. A total of 266
progressive glioblastoma patients were enrolled and ran-
domized 2:1 enzastaurin (n = 174) to lomustine (n = 92).
The study was ended after those 266 patients when the data
590 J Neurooncol (2014) 118:557–599
123
met criteria for stoppage due to futility rules. The pro-
gression free survival at 6 months for enzastaurin was
11.1 % and for lomustine was 19.0 %. The median pro-
gression free survivals for enzastaurin and lomustine were
1.5 and 1.6 months, respectively. The median overall sur-
vival after initiation of enzastaurin or lomustein was 6.6
and 7.1 months, respectively. None of the differences were
significant. This study was well done and meets criteria for
a class I study that provides data that enzastaurin is no
more efficacious than lomustine, but with nearly one tenth
the hematologic toxicity than the nitrogen mustard [92, 93].
Though this is a properly done study it is negative in nature
and provides no guidance as to the therapy that would be
superior. The results for both agents are inferior to those
reported by Yung with temozolomide (in temozolomide
naı̈ve patients) though neither enzastaurin or lomustine
have been tested head to head with temozolomide [9]. Thus
no formal recommendation about either can be provided.
Cintredekin besudotox Assessment of cintredekin be-
sudotox (IL13-PE38QQR, a recombinant chimeric cyto-
toxin composed of human interleukin-13 (IL13) fused to a
truncated, mutated form of Pseudomonas aeruginosa exo-
toxin A or PE38QQR) was carried out in a prospective
randomized multi-institutional phase III study. The agent
was delivered via surgically implanted catheters around a
tumor resection bed and delivered over a period of 96 h. This
therapy was compared to BCNU-impregnated wafer
implantation. The median survival in the intent to treat
population for cintredekin besudotox was 36.4 weeks and
for the BNCU-impregnated wafer group was 35.3 weeks
(P = 0.476) No subclass analysis revealed selective bene-
fits. Additionally there was an eight-fold increase in risk of
pulmonary embolism in the cintredekin besudotox group.
This provides class I data showing no benefit of cintredekin
besudotox over BCNU-wafer use. This study did not sub-
stantiate the promise of the agent reported in preliminary
studies suggesting potential value [94, 95]. Though this is a
properly done study it is negative in nature and provides no
guidance as to the therapy that would be superior. In the
section on cytotoxic chemotherapy in this set of guidelines,
BCNU impregnated wafers are recognized in a level II
recommendation. The results for cintredekin besudotox are
not superior and do not warrant a recommendation.
TLN-4601 A phase II study of 20 glioblastoma patients at
first recurrence was carried out by Mason et al. studying the
Ras-MAPK signaling pathway inhibitor TLN-4601. This
consisted of a 14 day constant infusion followed by a 7 day
rest period on a repeated basis. No complete or partial
responses were observed and the progression free survival
rate at 6 months was 0. Based on these results, the study,
initially planned for forty patients, and was curtailed at 20
cases with recommendations to not explore this agent
further until its underlying biology was better understood
[96]. This is Class III data
Romidepsin A phase I/II multicenter trial of romidepsin, a
histone deacetylase inhibitor, was performed in adults with
recurrent malignant glioma. Among the 35 glioblastoma
patients in the phase II portion of the study, 6 month pro-
gression free survival was 3 %, with a median progression
free survival of 8 weeks. There were no radiographic
responses. At the end of this class III data presentation, the
authors conclude that romidepsin in ineffective in this dose
schedule for recurrent malignant glioma [97].
Combination therapy with more than one targeted therapy
Vorinostat and bortezomib Friday et al., report a phase
two, single arm study of vorinostat, a histone deacetylase
inhibitor, and bortezomib, a reversible proteasome inhibi-
tor, in recurrent glioblastoma in 37 patients. Vorinostat was
given at a dose of 400 mg orally once daily on days 1–14
of a 21-day cycle. Bortezomib was given at a dose of
1.3 mg/m2 on days 1, 4, 8, and 11 of a 21-day cycle. They
had a 6 month progression free survival of 0 %. There
were no responses [98].
EGFR and mTOR inhibition A pilot retrospective study
of EGFR inhibition and mTOR inhibition was carried out
by Doherty et al. A population of 22 progressive glio-
blastoma patients received daily gefitinib (500 mg) or erl-
otinib (150 mg) and sirolimus 6 mg the first day and 4 mg
daily thereafter. The progression free survival at 6 months
was 25 %. Partial responses were observed in 18 %. Rash
and infection were the most often observed toxicities. The
authors state the outcome was similar to the historical
studies reported in the review by Wong et al. where the
6 month progression free survivals were in the range of
15 % [19, 99]. This yields Class III data.
Looking at a similar combination Reardon et al. reported
a phase II study of erlotinib and sirolimus. The enrollees
were stratified based on anticonvulsant use. Those not on
enzyme-inducing antiepileptic drugs (stratum A) received
erlotinib 150 mg and sirolimus 5 mg daily (n = 24) and
those on enzyme-inducing antiepileptic drugs (stratum B)
received erlotinib 450 mg and sirolimus 10 mg daily
(n = 8). They report a median progression free survival of
6.9 weeks overall, 8.4 weeks in stratum A and 4.0 weeks
in stratum B (A vs. B P = 0.03). Estimated progression
free survival at 6 months was 3.1 % overall and not
reported by stratum. No responses were observed. The
authors generously concluded the combination had limited
activity in unselected recurrent glioblastoma patients [100].
This provides Class III data
J Neurooncol (2014) 118:557–599 591
123
Combination therapy with a targeted therapy and cytotoxic
therapy
Assorted agent combinations Reports on multiple com-
binations of targeted agents with cytotoxic agents meet
inclusion criteria and are noted below. All yield class III
data.
Fluosol and BCNU To assess the potential value of
improved oxygenation in sensitizing recurrent malignant
gliomas to a cytoxic therapy Hochberg et al. reported on
their phase I-II experience with Fluosol (a dissolving
medium for oxygen hypothesized to improve tumor oxy-
genation) infusion followed by oxygen therapy during
BCNU infusion. For the 38 patients with glioblastomas,
median time to progression was 10.9 months and median
survival was 26.7 months. The authors concluded that there
is value to this technique and proposed a dosing strategy
for future studies [101].
RMP-7 and carboplatin RMP-7 is a synthetic bradykinin
agonist reported to enhance carboplatin delivery in pre-
clinical models. In a prospective, randomized, phase II
study of this agent compared to placebo, administered
monthly with carboplatin, Prados et al. found a median
time to progression for the glioblastoma population of
8.6 weeks with in the RMP-7 group and 8.1 weeks in the
placebo group. The median overall survival for the glio-
blastomas was 24.0 and 21.1 weeks for the same groups,
respectively. By their calculations, these differences were
not significant. The accrual goals in this well designed
study were not intended to detect survival differences by
histologic subgroup, yielding class II data [102].
Celecoxib and irinotecan Celecoxib is hypothesized to be
useful in human disease by acting as an inhibitor of
cyclooxygenase (COX)-2, the inducible isoform of pros-
taglandin H synthase associated with many forms of can-
cer. In 34 patients with recurrent glioblastomas, Reardon
et al. reported on the effect of continuous celecoxib at
400 mg/day with irinotecan in weeks 1, 2, 4 and 5 of each
6-week cycle. The observed a progression free survival rate
at 6 months of 27.5 % and median time to progression of
11.1 weeks. Median overall survival from treatment initi-
ation was 31.1 weeks. Five partial responses were
observed. The authors concluded that the combination was
better than either agent alone, measured by progression free
period or response or imaging [103].
Imatinib and hydroxyurea A retrospective review of
experience with this combination has been provided by
Deseman et al. In 30 progressive glioblastomas treated with
continuous daily dosing of each agent a 6-month
progression free survival of 32 % was observed. The
median overall survival from treatment initiation was
19 weeks. One complete response and five partial respon-
ses were observed and the authors state there were no grade
3 or 4 toxicities. In their discussions, they observed that
their selected series had outcomes exceeding salvage
therapies with standard cytotoxic agents [19, 31, 104–106].
In another report of the same combination, Reardon
et al. stratified based on absence (stratum A) of or presence
(stratum B) of enzyme-inducing anti-epileptic drugs. Pro-
gression free survival at 6 months was 17 % in stratum A,
40 % in stratum B and 27 % overall. The medium pro-
gression free survival was 8.5 weeks in stratum A,
16.6 weeks in stratum B and 14.4 weeks overall. Overall,
they observed one complete response and two partial
responses and concluded the combination produces mean-
ingful and durable disease control compared to prior
reports. They provide commentary on, but not statistical
comparison to, historical data is mentioned by way of two
studies for patients with recurrent glioblastoma. Specifi-
cally, Yung et al. administered temozolomide alone at first
relapse achieved a median PFS of 12.4 weeks, a 6-month
PFS rate of 21 % and a 5 % radiographic response rate
[31]. Wong et al. reported a median PFS of 9 weeks and a
6-month PFS rate of 15 % with eight consecutive salvage
regimens [19]. This yields class III data [103].
Tamoxifen combinations
Tamoxifen and procarbazine Brandes et al. reported a
phase II study of tamoxifen (100 mg/day) and procarbazine
(100 mg/m2/day) for 30 days followed by a 30-day rest in a
group of patients that included 28 recurrent glioblastomas.
Median time to progression for the glioblastomas was
13 weeks and median survival time from initiation of
treatment in the glioblastomas was 27 weeks. The response
rates in the glioblastomas included a complete response in
one (3.5 %) and partial response in eight (28.6 %). The
authors stated the results of this study were relatively
similar to prior a study of procarbazine alone noting a
response rate of 14 %, and two studies of tamoxifen alone
showing mainly disease stabilization(but that were exe-
cuted with different doses and amounts of pretreatment).
No statistical comparison was actually carried out, leaving
this as class II data [68, 107–109].
Tamoxifen and carboplatin To assess whether the addi-
tion of a cytotoxic agent to tamoxifen would improve its
efficacy Tang et al. reported on its use with carboplatin.
The carboplatin was administered at 400 mg/m2 every
4 weeks and tamoxifen was administered continuously:
20 mg bid escalating to 80 mg bid in women and 100 mg
bid for men. In the 17 patients with gliosarcomas or
592 J Neurooncol (2014) 118:557–599
123
glioblastomas, the median time to progression was
2.9 months and the median overall survival was
5.9 months. Responses were not reported by histology. The
median overall survival was somewhat less than with
tamoxifen alone and the authors concluded the combina-
tion was not synergistic [68, 110].
Tamoxifen and celecoxib and etoposide and cyclophos-
phamide In a study that included 28 progressive glio-
blastomas patients, Kesari et al. created a regimen that
provided daily administration of low dose etoposide alter-
nating every 21 days with cyclophosphamide and daily
dose of both tamoxifen and celecoxib. The progression free
survival at 6 months was 9 % and the median progression
free survival was 11 weeks. Median overall survival from
initiation of treatment was 21 weeks. The histology of the
single partial response was not specified. The authors noted
that these patients were not candidates for conventional
protocols they derived no benefit from the regimen. The
unusual nature of the regimen did not lend itself to
meaningful comparison to historical controls and yielded
class III data [111].
In a study of 32 patients with progressive glioblastomas
or gliosarcomas, Puduvalli et al. administered tamoxifen
with intrapatient escalating doses of 100–400 mg/day along
with 125 mg/m2 irinotecan weekly for the first 4 weeks of
each 6-week cycle. The progression free survival at 6 weeks
was 25 % and the median progression free survival was
13 weeks. The median overall survival from treatment ini-
tiation was 36 weeks. There was one complete response and
one partial response. The authors called the combination
promising however, one can see that the disease control rates
are little better than those noted with tamoxifen combined
with BCNU or temozolomide [29, 30, 112].
EGFR inhibitor used in combination
Erlotinib and irinotecan In a prospective phase II study
that enrolled 43 assessable progressive glioblastomas
patients, de Groot et al. evaluated carboplatin intravenously
on day 1 of every 28-day cycle and daily erlotinib at
150 mg/day dose escalated to 200 mg/day, as tolerated.
The authors observed a progression free survival rate at
6 months of 14 % and a median progression free survival
of 9 weeks. The median overall survival was 30 weeks and
there was one partial response. The authors concluded there
was no benefit of this regimen in this patient population
[113].
Multiple agent combinations
Cetuximab and bevacizumab and irinotecan To assess
the management of first recurrence of glioblastoma with
multiple agents, Hasselbalch et al. utilized cetuximab,
bevacizumab, and irinotecan in a prospective phase II
analysis. The bevacizumab dosage was started at 5 mg/kg
initially and then escalated after safety analysis suggesting
a phase I component to the study. In the 32 evaluable
patients, the progression free survival rate at 6 months was
33 % and the median progression survival was 16 weeks;
median survival was 29 weeks. There were two complete
responses and nine partial responses for a total response
rate of 26 %. Although no statistical comparisons were
conducted, the authors reported that the addition of ce-
tuximab adds nothing to the combination of bevacizumab
and irinotecan alone and this provides class III data [114].
6-Thioguanine, capecitabine, celecoxib, and either tem-
ozolomide or lomustine Walbert et al. performed an
open-label study at a single center in adult patients with
recurrent high-grade glioma utilizing a multi-agent regi-
men designed to take advantage of the varying mechanisms
of action of each treatment. Patients were placed in two
cohorts depending on if they were temozolomide-naı̈ve, or
had previous temozolomide exposure, but not lomustine or
carmustine. All patients received 6-thioguanine, capecita-
bine, and celecoxib, and then received either temozolomide
or lomustine. Among the 43 glioblastoma patients,
6-month progression free survival was 14 %. Combining
the lomustine and temozolomide cohorts a response rate of
12 % (1 CR and 4 PR) was observed. Median overall
survival was 32 weeks. Hematological toxicity of grade 3
was observed in 24 % of all patients enrolled. The authors
conclude that this combination does not appear to be more
effective than other alkylating agent schedules for patients
with recurrent glioblastoma [115].
Summary of therapy based on specific molecules
or signaling pathways
There is a wide variety of targeted agents on various
molecular levels have been addressed in what, for the most
part, are well designed or written investigations. In fact,
two studies rise to class I information but the findings are
negative do not provide guidance as to use of targeted
therapy. The remainder of the studies are class III in nature
and do not provide repetitive findings form multiple
investigators to suggest a particular molecule, agent or
regimen warrants recommendation. Various studies were
stopped early because of futility or obvious toxicity [74,
116, 117]. Some studies of targeted agent combined with
other targeted agents or targeted agents combined with
cytotoxic agents suggest the potential for value but are
difficult to interpret when considering which component of
the combination is making the most meaningful combina-
tion. These factors result in the inability to make any firm
J Neurooncol (2014) 118:557–599 593
123
statements about these agents in recurrent or progressive
glioblastoma therapy beyond a recommendation that eli-
gible patients be enrolled in well-designed studies of these
therapies to further our understanding of their value.
A large number of publications are available in this field
but were excluded because of eligibility criteria used for
this guideline. Some studies provided detailed information,
but did not separate glioblastomas from other histologies
when evaluating survival effect or response [118–125].
Others included less than five glioblastomas in any one
treatment arm [126]. Some detailed studies separated
glioblastoma outcomes from other histologies but com-
bined different treatment with the targeted agent alone with
treatment using the targeted agent and other drugs making
assessment of the targeted agent alone impossible [54,
127–129].
Targeted therapies summary
Advances in genomics have significantly improved our
understanding of the molecular pathogenesis of glioblas-
toma, and allowed its classification into molecular subtype
[130–132]. This has translated into the development of
prognostic and predictive biomarkers, and the identification
of specific targets for potential treatments. The proliferation
of studies looking at therapies targeted to a specific signaling
pathway, metabolic pathway or other cellular transaction is
promising and indicates new concepts have left the labora-
tory and are being tested. When held up to rigorous stan-
dards of data assessment, one can see that their development
is relatively nascent. The antiangiogenic agents are perhaps
the most developed and studied and assessment of the use of
bevacizumab alone or in combination with a cytotoxic agent
in the setting of progressive glioblastoma but still provides
class III evidence. Thus only level III recommendations can
be made. The long list of other targeted therapies qualifying
for this guideline’s scientific foundation can be viewed
above. Reasons for resistance to targeted therapies are under
active study [133]. Responses of one sort or another have
been observed with some the agents but none rise above
class III evidence. Thus in those agents with a favorable
toxicity profiles further patient enrollment in clinical studies
designed to provide class II or better evidence is strongly
encouraged.
Key issues for future investigation
Investigators are testing various hypotheses based on the
molecular characterization of tumors as described above, and
more trials of novel targeted agents are currently underway.
Design of clinical trials There is growing concern that
the current methods of conducting clinical trials are
inefficient [134]. The number of agents and potential
combinations are increasing while resources are limited. In
addition, more and more phase II clinical trials are now
randomized, requiring larger patient sample size, and fur-
ther exhausting valuable resources [134, 135]. There is
growing interest in developing novel strategies to effi-
ciently conduct clinical trials that are able to readily
identify promising agents, and eliminate those that are
ineffective. Alternatives to traditional clinical trial designs
such as adaptive randomization based on Bayesian algo-
rithms potentially allows for evaluation of multiple agents
and combinations in fewer patients overall with more
patients randomized to the more efficacious agents [136].
Tumor genotyping Presently, the ability to comprehen-
sively genotype tumors is not readily available. However,
this is likely to become increasingly feasible as the cost of
sequencing declines. In the future an increasing number of
trials will include genetically enriched populations,
increasing the likelihood of success. Glioblastomas are a
heterogeneous group of tumors, and there is change in
genotype over time with treatment. Repeat biopsies at
recurrence may potentially allow identification of new
genetic alterations that will then dictate specific treatment.
Combination therapies of drugs targeting cell signaling
One of the reasons for the failure of prior trials has been the
use of agents directed against a single target. Potential
strategies to overcome issues such as redundancy of
molecular pathways, and co-activation and mosaic ampli-
fication of tyrosine kinases include the utilization of com-
bination therapies targeting complementary pathways (e.g.
phosphoinositide-3-kinase and mitogen-activated protein
kinase), targeting critical nodes in signaling networks, or
focusing on final common pathways such as cyclin-
dependent kinase 4 (CDK4), nuclear factor kappa b (NF-
jb), and Myc.
Angiogenesis and mechanisms of resistance Angiogene-
sis is a complex and critical process in glioblastoma, and
growing evidence points to a link between angiogenesis
and glioma stem cells [137]. The result of agents targeting
the vascular endothelial growth factor (VEGF) pathway
alone has produced only modest results. There is increasing
interest in trying to inhibit the putative mechanisms of
resistance to VEGF inhibitors using agents such as such as
integrin inhibitors (e.g. cilengitide), fibroblast growth fac-
tor receptor inhibitors (e.g. BIBF1120, E7080), and an-
giopoietin inhibitors (e.g. AMG-386), as well as drugs
targeting stromal derived factor 1a and its receptor
CXCR4, such as plerixafor [138–141].
594 J Neurooncol (2014) 118:557–599
123
Glioma stem cells Glioma stem cells are thought to be
more resistant to treatment that the tumor cells themselves.
There is increasing understanding of the pathways that are
active in the development and regulation of glioma stem
cells such as Olig2, sonic hedgehog, notch, and Wnt [142,
143]. While inhibition of the notch pathway by gamma
secretase inhibitors such as RO2949097 and MK0752, and
inhibition of the sonic hedgehog pathway by smoothened
inhibitors such as vismodegib have produced minimal
benefit, proposed studies targeting tumor stem cells with
the smoothened inhibitor LDE225, in combination with
targeting tumor cells with a PI3K inhibitor, such as
BKM120, hold more promise.
Immunotherapy One strategy to target glioblastoma is by
stimulating immune cells ex vivo and re-administering to
the patient, or using tumor-associated antigens to stimulate
the patient’s immune system; several trials of dendritic and
peptide vaccines (e.g. ICT-107, DCVax, rindopepimut) are
ongoing. Glioblastomas present a particular challenge for
immunotherapeutic strategies because of the production of
immunosuppressive factors such as transforming growth
factor-b, VEGF, prostaglandin E2, and interleukin-10
[144–146]. There has been tremendous progress in the field
of therapeutic immunotherapy and newer strategies of
immunostimulation are being considered with particular
interest in immunostimulatory agents such as CTLA4
antibodies such as ipilimumab, and anti-PD1 and PDL1
antibodies [147–149]. Clinical trials are being developed to
evaluate administration of T cells expressing chimeric
antigen receptors (CARs) targeting several glioblastoma
antigens including as EGFRvIII, human epidermal growth
factor receptor 2 (HER2), IL13Ra2, and CMV antigens
[150–153].
Metabolism Targeting tumor metabolism holds signifi-
cant potential. Strategies for targeting glioma cellular
metabolism, particularly, inhibitors of isocitrate dehydro-
genase (IDH) 1/2 mutations, are being developed [154,
155].
DNA damage
There is a potential for targeting the DNA damage response
to reverse therapeutic resistance to cytotoxic therapies.
Poly ADP-ribose polymerase (PARP) inhibitors are being
explored in this regard, particularly in PTEN deficient
glioblastoma [156, 157], as well as Wee-1 inhibitors.
Personalized medicine based on genotyping of individ-
ual tumors will likely transform future therapy for patients
with glioblastoma. The selection of agents will be
improved by use of more representative preclinical models,
improved imaging and molecular biomarkers, which will
help refine patient stratification, and novel trial designs will
accelerate the pace of drug development. These advances
will hopefully lead to much needed improvements in the
treatment for patients with glioblastomas.
Acknowledgments We would like to acknowledge the AANS/CNS
Joint Guidelines Committee for their review, comments and sugges-
tions, the contributions of Laura Mitchell, CNS Guidelines Manager
for organizational assistance, Maxine Brown for searching for and
retrieving literature and Amy Allison for reference library consulta-
tions. We would also like to acknowledge the following individual
JGC members for their contributions throughout the review process:
Sepideh Amin-Hanjani, MD, FAANS, FACS, FAHA, Martina Stip-
pler, MD, Alexander Khalessi, MD, Isabelle Germano, MD, Sean D.
Christie, MD, FRCS (C), Gregory J. Zipfel, MD, Zachary Litvack,
MD, MCR, Ann Marie Flannery, MD, Patricia B Raksin, MD, Joshua
M. Rosenow, MD, FACS, Steven Casha, MD, PhD, Julie G. Pilitsis,
MD, PhD, Gabriel Zada, MD, Adair Prall, Krystal Tomei, MD,
Gregory W Hawryluk, MD.
Conflict of interest Task Force Members report potential COIs
prior to beginning work on the guideline and at the time of publica-
tion. COI disclosures are reviewed by the Task Force Chair and taken
into consideration when determining writing assignments. Resolution
of potential COIs included Task Force members were assigned to
chapters that did not involve or in any way relate to the potential COIs
disclosed.
Funding These guidelines were funded exclusively by the CNS and
Tumor Section of the American Association of Neurological Sur-
geons and the Congress of Neurological Surgeons whom received no
funding from outside commercial sources to support the development
of this document unless otherwise stated in this section.
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