intensive chemotherapy followed by reduced-dose radiotherapy for biopsy-proven cns germinoma with...
TRANSCRIPT
CLINICAL STUDY
Intensive chemotherapy followed by reduced-dose radiotherapyfor biopsy-proven CNS germinoma with elevated beta-humanchorionic gonadotropin
Do Hoon Lim • Keon Hee Yoo • Na Hee Lee • Soo Hyun Lee • Ki Woong Sung •
Hong Hoe Koo • Ji Hye Kim • Yeon-Lim Suh • Yoo Sook Joung •
Hyung Jin Shin
Received: 18 August 2013 / Accepted: 20 January 2014
� Springer Science+Business Media New York 2014
Abstract In this study, 10 patients with biopsy-proven
germinoma with a beta-human chorionic gonadotropin (b-
HCG) level [50 mIU/ml received intensive chemotherapy
followed by reduced-dose radiotherapy (RT) to reduce late
effects from RT. CSF b-HCG levels were[200 mIU/ml in
five patients. After endoscopic or stereotactic biopsy, four
cycles of induction chemotherapy were administered prior
to RT. A CEB regimen (carboplatin ? etoposide ? bleo-
mycin) and a CyEB regimen (cyclophosphamide ? eto-
poside ? bleomycin) were alternated. No residual tumor
remained after induction chemotherapy in six patients, only
cystic lesions were present at the primary tumor site in
three, and a small solid residual tumor was observed in the
remaining patient; however, all these patients had normal
b-HCG levels. If complete response was achieved before
initiation of RT, 19.5 Gy craniospinal RT
(CSRT) ? 10.8 Gy local RT was administered to the
tumor bed. If residual lesion was suspected, the dose of RT
was selected according to the presence/absence of tumor
dissemination at diagnosis (19.5 Gy CSRT ? 19.8 Gy
local RT for localized tumors and 24.0 Gy
CSRT ? 16.2 Gy local RT for disseminated tumors). Eight
patients, including four patients with a b-HCG level
[200 mIU/ml, received 19.5 Gy CSRT. All patients
remain disease free at a median follow-up of 58 (range
35–94) months from diagnosis. Our data suggest that
pathologically pure germinoma with a significantly ele-
vated b-HCG level might be cured with reduced-dose RT if
intensive chemotherapy is provided.
Keywords Central nervous system germ cell tumor �Germinoma � Chemotherapy � Radiotherapy � Human
chorionic gonadotropin
Introduction
Central nervous system (CNS) germ cell tumors (GCTs)
are traditionally divided into germinomas andDo Hoon Lim and Keon Hee Yoo have contributed equally to this
work.
D. H. Lim
Department of Radiation Oncology, Samsung Medical Center,
Sungkyunkwan University School of Medicine, Seoul, Republic
of Korea
K. H. Yoo � N. H. Lee � S. H. Lee � K. W. Sung (&) �H. H. Koo
Department of Pediatrics, Samsung Medical Center,
Sungkyunkwan University School of Medicine, 50 Irwon-Dong,
Gangnam-Gu, Seoul 135-710, Republic of Korea
e-mail: [email protected]
J. H. Kim
Department of Radiology, Samsung Medical Center,
Sungkyunkwan University School of Medicine, Seoul, Republic
of Korea
Y.-L. Suh
Department of Pathology, Samsung Medical Center,
Sungkyunkwan University School of Medicine, Seoul, Republic
of Korea
Y. S. Joung
Department of Psychiatry, Samsung Medical Center,
Sungkyunkwan University School of Medicine, Seoul, Republic
of Korea
H. J. Shin
Department of Neurosurgery, Samsung Medical Center,
Sungkyunkwan University School of Medicine, Seoul, Republic
of Korea
123
J Neurooncol
DOI 10.1007/s11060-014-1381-x
nongerminomatous GCTs (NGGCTs). Germinomas are
more common than NGGCTs and account for two-thirds of
CNS GCTs. Radiotherapy (RT) encompassing the entire
neuroaxis was once the standard treatment for germinomas,
with cure rates in excess of 90 % [1]. In recent years
however, induction chemotherapy has been utilized to
reduce both RT volume and dose, and many reports indi-
cate that such strategies yield cure rates similar to those
achieved with RT alone [2–5].
It is well recognized that pure germinomas can include
syncytiotrophoblastic cells that produce and excrete beta-
human chorionic gonadotropin (b-HCG) [6, 7]. However,
the prognostic significance of elevated b-HCG level in
CNS germinoma remains controversial. Long-term relapse-
or progression-free survival rates for germinoma patients
with elevated b-HCG level have been reported to range
from 44 to 100 % [2, 3, 8–13]. Earlier studies suggested
that the presence of b-HCG producing and secreting cells,
and elevation of b-HCG in serum and/or cerebrospinal fluid
(CSF), were associated with a higher relapse rate in
patients with otherwise pure germinomas [2, 8, 9]. How-
ever, more recent studies suggested that elevation of serum
or CSF b-HCG levels had no adverse impact upon out-
comes in pathologically pure germinomas [3, 10–13]. Fu-
jimaki and Matsutani [13] reported that there was no
difference in relapse-free survival and overall survival
between germinomas without b-HCG secretion and ger-
minomas with b-HCG secretion at serum or CSF levels of
up to 200 mIU/ml. However, many European and USA
multi-center trials have considered patients with a b-HCG
level greater than 50 mIU/ml in either serum or CSF to be
at high risk for relapse, even in the face of a pathologically
pure germinoma, and such patients have been treated with
NGGCT protocols, including intensive chemotherapy and
full dose craniospinal RT (CSRT) [4, 14]. However, RT,
particularly CSRT, is associated with long-term sequelae,
including deficits within the domains of intelligence,
attention, memory, and psychomotor processing speed [15,
16]. In the present study, patients with biopsy-proven
germinoma with an elevated b-HCG level ([50 mIU/ml)
received intensive chemotherapy followed by reduced-dose
RT. We developed the treatment strategy of intensive
chemotherapy followed by reduced dose RT to maintain
high cure rates while minimizing the late effects of RT.
Patients and methods
Patients
Patients newly diagnosed with CNS germinoma with serum
or CSF b-HCG levels [50 mIU/ml between October 2005
and September 2010 were considered eligible for inclusion
in this study. At diagnosis, all patients underwent endo-
scopic or stereotactic biopsy with or without endoscopic
third ventriculostomy (ETV). A pediatric neuropathologist
confirmed pure germinoma in all cases. Alpha-fetoprotein
(a-FP) and b-HCG levels in serum and CSF were deter-
mined at diagnosis. Disease extent at diagnosis was
assessed using brain and spinal magnetic resonance imag-
ing (MRI) and CSF cytology. Samsung Medical Center
Institutional Review Board approved this study and all
parents and guardians provided written informed consent.
Induction treatment prior to RT
Four cycles of induction chemotherapy were administered
prior to RT. A CEB regimen (carboplatin 450 mg/m2/day
on days 0 and 1; etoposide 150 mg/m2/day on days 0, 1,
and 2; bleomycin 15 mg/m2/day on day 2) and a CyEB
regimen (cyclophosphamide 2,000 mg/m2/day on days 0
and 1; etoposide 150 mg/m2/day on days 0, 1, and 2; ble-
omycin 15 mg/m2/day on day 2) were alternated (Fig. 1).
Each induction chemotherapy cycle was scheduled to be
28 days apart, but some delays were permitted to allow the
absolute neutrophil count (ANC) and platelet count to
recover to 1,000 and 100,000/ll, respectively.
Radiotherapy
RT was administered using a 4- or 6-MV linear accelerator
at a daily dose of 1.8 Gy for the primary site and 1.5 Gy for
the craniospinal axis. Basically, the primary target volume
was the craniospinal axis with a reduced radiation dose.
After CSRT, boost irradiation was delivered to the primary
tumor site of the brain and the clinical target volume was
determined with a 1.0 cm margin from the tumor bed or
residual tumor. The dose of RT was determined according
to both the response to induction chemotherapy and the
tumor status at diagnosis (Fig. 1). If complete response
(CR) was achieved before initiation of RT, 19.5 Gy of
CSRT combined with an additional 10.8 Gy of local RT to
the tumor bed was given. If any residual remaining lesion
was suspected in the primary tumor site before initiation of
RT, the dose of RT was decided according to the tumor
status at diagnosis. In brief, 24.0 Gy of CSRT combined
with an additional 16.2 Gy of local RT to the residual
tumor was given if leptomeningeal seeding was present at
diagnosis. Otherwise, 19.5 Gy of CSRT combined with an
additional 19.8 Gy of local RT to the residual tumor was
given.
Assessment of response and toxicity criteria
Responses were evaluated by assessing neuroimaging
findings and by measuring b-HCG in the serum and/or
J Neurooncol
123
CSF. Evaluation was repeated every two cycles of che-
motherapy and during the first 4 weeks after completion
of RT, every 3 months for the first year after completion
of RT, every 4 months for the second year, every
6 months for the third year, and then every 12 months
thereafter. Toxicity was graded according to the National
Cancer Institute Common Terminology Criteria, version
4.0.
Evaluation of late adverse effects
Late adverse effects were evaluated at least annually after
completion of RT. Diagnosis of growth hormone defi-
ciency was based on a decline in growth rate, and con-
firmed by biochemical testing. Hypothyroidism was
diagnosed by elevation of thyrotropin. Adrenal insuffi-
ciency was diagnosed based on the failure to increase
cortisol levels after corticotropin-releasing hormone
administration. Cognitive function was evaluated using the
Korean-Wechsler Adult Intelligence Scale-IV (K-WAIS-
IV). Cardiac, renal, hepatic, auditory, ophthalmologic, and
immune functions were also evaluated.
Results
Patient characteristics
Ten consecutive patients were enrolled during the study
period. Patient characteristics are listed in Table 1. The
median age at diagnosis was 15.1 (range 11.4–20.8) years.
The common symptoms at presentation were headache (5),
polydipsia/polyuria (5), decreased visual acuity (4), and
vomiting (3). The tumor was located at the suprasellar area in
four patients, at the pineal area in three, at both the supra-
sellar and the pineal area in one, and at the basal ganglia in
two. Leptomeningeal seeding was present at diagnosis in six
patients. CSF b-HCG levels were [200 mIU/ml in five
patients, four of whom had levels[500 mIU/ml.
Induction treatment
All patients experienced neutropenic fever during induction
chemotherapy. One patient (Patient No. 7) could not complete
induction chemotherapy due to temporary acute renal failure
after the second chemotherapy cycle. Induction chemotherapy
was successfully administered in the remaining cases without
significant organ toxicity. No residual tumor remained after
induction chemotherapy in six patients, only cystic lesions
were present at the primary tumor site in three (Fig. 2), and a
small solid residual tumor was observed in the remaining
patient; however, all patients had normal b-HCG levels. No
patient underwent second-look surgery.
Radiotherapy
Five of the six patients who were in CR before initiation of
RT received 19.5 Gy of CSRT combined with an additional
10.8 Gy of local RT to the tumor bed (total 30.3 Gy). The
remaining patient who was in CR (Patient No. 7) received
Fig. 1 Treatment scheme. At diagnosis, all patients underwent
endoscopic or stereotactic biopsy with or without ETV. Four cycles
of induction chemotherapy were administered prior to RT. A CEB
regimen and a CyEB regimen were used alternated at 4-week
intervals. If CR was achieved before initiation of RT, 19.5 Gy
craniospinal RT (CSRT) ? 10.8 Gy local RT was administered to the
tumor bed. If residual lesion was suspected, the RT dose was decided
according to the presence/absence of tumor dissemination at diagno-
sis (19.5 Gy CSRT ? 19.8 Gy local RT for localized tumors and
24.0 Gy CSRT ? 16.2 Gy local RT for disseminated tumors)
J Neurooncol
123
24.0 Gy of CSRT combined with an additional 16.2 Gy of
local RT because the patient could not complete induction
chemotherapy. Three of the four patients who had remaining
cystic or solid lesions prior to RT received 19.5 Gy of CSRT
combined with an additional 19.8 Gy of local RT to the
residual lesion (total 39.3 Gy), and the remaining patient
received 24.0 Gy of CSRT combined with an additional
16.2 Gy of local RT to the residual lesion (total 40.2 Gy).
Survival
All patients remain disease free at a median follow-up of
58 (range 35–94) months from diagnosis.
Late adverse effects
Neuroendocrine dysfunction was a frequent late effect
(hypothyroidism in six patients, glucocorticoid deficiency in
six, diabetes insipidus in six, sex hormone deficiency in
three, and growth hormone deficiency in three). While all
five patients with suprasellar or bifocal tumors had neuro-
endocrine dysfunction, no patient with a pineal tumor
experienced neuroendocrine dysfunction. Median height at
diagnosis was -0.2 (range -3.5 to 0.8) standard deviations
from the mean for patient age and the median height at a
median of 60 (range 32–92) months after diagnosis was
-0.3 (range -5.0 to 0.3) standard deviations from the mean.
Median values for full-scale intelligence quotient, verbal
comprehension index, perceptual reasoning index, working
memory index, and processing speed index evaluated at a
median of 50 (range 37–77) months after diagnosis was 91
(range 61–106), 92 (range 81–114), 84 (range 59–120), 96
(range 75–115) and 89 (range 52–104), respectively.
Discussion
There is consensus that serum or CSF b-HCG levels of up
to 50 mIU/ml are not associated with adverse outcomes in
pathologically pure germinomas [4]. However, the arbi-
trary cut-off point of 50 mIU/ml of b-HCG to distinguish
between low-risk and high-risk germinomas does not have
a sound biological or clinical basis. For example, Fujimaki
and Matsutani [13] found no difference in outcomes
between germinomas without b-HCG secretion and ger-
minomas with b-HCG secretion at serum or CSF levels of
up to 200 mIU/ml. However, many multi-center trials have
considered patients with a level of b-HCG greater than
50 mIU/ml in either serum or CSF to be at high risk for
relapse, and such patients have been treated according to
NGGCT protocols, including intensive chemotherapy and
full dose CSRT. Chemotherapy utilizing combinations of
cisplatin or carboplatin, etoposide, and either ifosfamide orTa
ble
1P
atie
nt
char
acte
rist
ics
No
.S
ex/a
ge
(yea
r)at
Dx
Pri
mar
ysi
teC
linic
alpre
senta
tion
atD
x
M stag
eB
iop
sym
eth
od
a-F
Pat
Dx
Ser
um
/CS
F(n
g/m
l)
b-H
CG
atD
xS
eru
m/C
SF
(mIU
/ml)
Tu
mo
rst
atu
sat
RT
b-H
CG
atR
TS
eru
m/C
SF
(mIU
/ml)
CS
RT
/L
RT
(Gy
)F
inal
ou
tco
me
1F
/12
.1S
H,
V0
En
dosc
op
ic1
.0/1
.02
16
.2/9
32
.0N
ore
sid
ual
lesi
on
NE
/1.4
19
.5/1
0.8
94
m?
,D
sfr
ee
2M
/16
.3B
GW
1S
tere
ota
ctic
1.9
/1.0
98
.4/9
6.8
No
resi
du
alle
sio
nN
E/2
.51
9.5
/10.8
84
m?
,D
sfr
ee
3F
/11
.4S
DI
2E
nd
osc
op
ic2
.0/1
.06
7.3
/48
2.7
No
resi
du
alle
sio
nN
E/1
.91
9.5
/10.8
81
m?
,D
sfr
ee
4M
/12
.4B
GH
,V
,V
A,
W,
DP
,D
I3
En
dosc
op
ic1
.0/1
.05
7.1
/81
7.1
Cyst
icre
sid
ual
lesi
on
NE
/0.6
24
.0/1
6.2
72
m?
,D
sfr
ee
5F
/13
.8S
VA
,D
I0
En
dosc
op
ic1
.0/1
.01
52
8.6
/12
819
Cyst
icre
sid
ual
lesi
on
NE
/2.1
19
.5/1
9.8
59
m?
,D
sfr
ee
6M
/16
.4P
H0
En
dosc
op
ic2
.0/2
.02
7.0
/17
7.2
So
lid
resi
dual
lesi
on
NE
/1.0
19
.5/1
9.8
57
m?
,D
sfr
ee
7M
/18
.3S
?P
H,
V,
DI
3E
nd
osc
op
ic1
.0/1
.02
.4/7
3.6
No
resi
du
alle
sio
n1
.5/1
.82
4.0
/16.2
a5
1m
?,
Ds
free
8M
/20
.8S
VA
,D
I2
En
dosc
op
ic1
.0/1
.02
72
.5/4
31
6.6
No
resi
du
alle
sio
n2
.0/2
.41
9.5
/10.8
40
m?
,D
sfr
ee
9M
/13
.3P
H1
En
dosc
op
ic1
.0/2
.04
8.5
/64
.0N
ore
sid
ual
lesi
on
1.0
/1.0
19
.5/1
0.8
39
m?
,D
sfr
ee
10
M/2
0.5
PH
,D
P0
En
dosc
op
ic1
.0/1
.02
2.7
/91
.9C
yst
icre
sid
ual
lesi
on
1.0
/1.0
19
.5/1
9.8
35
m?
,D
sfr
ee
Mst
age:
0n
ole
pto
men
ing
eal
seed
ing
,1
po
siti
ve
CS
Fcy
tolo
gy
,2
seed
ing
atce
rebru
m,
3se
edin
gat
spin
alco
rd
Dx
dia
gn
osi
s,S
sup
rase
llar
reg
ion
,B
Gb
asal
gan
gli
a,P
pin
eal
regio
n,
Hh
ead
ach
e,V
vo
mit
ing
,W
mo
tor
wea
kn
ess,
DI
dia
bet
esin
sip
idu
s,V
Ad
ecre
ased
vis
ual
acu
ity
,D
Pd
iplo
pia
,a-
FP
a-f
eto
pro
tein
,b
-H
CG
b-h
um
anch
ori
on
icg
on
ado
tro
pin
,C
SF
cere
bro
spin
alfl
uid
,N
En
ot
eval
uat
ed,
CS
RT
cran
iosp
inal
RT
,L
RT
loca
lR
Tto
tum
or
bed
,D
sd
isea
sea
CR
was
achie
ved
bef
ore
init
iati
on
of
RT
;h
ow
ever
,2
4.0
Gy
of
CS
RT
?1
6.2
Gy
of
LR
Tw
ere
giv
enb
ecau
seth
ep
atie
nt
cou
ldn
ot
com
ple
tein
du
ctio
nch
emo
ther
apy
du
eto
tem
po
rary
acu
tere
nal
fail
ure
afte
rth
ese
con
dch
emo
ther
apy
cycl
e
J Neurooncol
123
cyclophosphamide, followed by 30–36 Gy of CSRT and an
additional 18–24 Gy of boost RT to the primary site have
been commonly used to treat NGGCTs in North American
and European trials over the last few decades. In the
Children’s Oncology Group ACNS0122 trial, NGGCT
patients received six cycles of chemotherapy (carboplatin/
etoposide alternating with ifosfamide/etoposide) followed
by 36 Gy of CSRT and an additional 18 Gy of boost RT to
the primary site. In the SIOP CNS GCT-96 trial, NGGCT
patients received four cycles of chemotherapy (cisplatin,
ifosfamide, and etoposide) followed by 30 Gy of CSRT
and an additional 24 Gy of boost RT to the primary site. In
the present study, bleomycin was administered with both
carboplatin/etoposide and cyclophosphamide/etoposide
cycles to intensify chemotherapy while reducing the RT
doses (19.5–24.0 Gy of CSRT and 10.8–19.8 Gy of boost
RT to the primary site) to minimize late effects from RT,
particularly CSRT. As a result, all patients remain relapse
free, and eight of them, including four of five patients with
a b-HCG level greater than 200 mIU/ml, received 19.5 Gy
of CSRT. Our data suggest that pathologically pure ger-
minomas with a significantly elevated b-HCG level can be
cured with reduced-dose RT if effective chemotherapy is
provided.
We used short-term intensive induction chemotherapy to
reduce the RT dose. Our induction chemotherapy regimen
was generally acceptable, although all patients experienced
neutropenic fever and one patient could not complete the
induction chemotherapy due to temporary acute renal
failure. Response to induction chemotherapy was good.
There was no tumor progression during induction
chemotherapy. Six patients had no residual tumor, three
patients had only cystic lesions at the primary tumor site,
and the remaining patient had a small solid residual tumor
after induction chemotherapy, which disappeared after RT.
However, all of these patients had normal b-HCG levels
after induction chemotherapy and no patient underwent
second-look surgery. These findings suggest that our
induction chemotherapy regimen is both feasible and
effective.
In the present study, the RT dose was tailored according
to the response to induction chemotherapy and the tumor
status (presence or absence of leptomeningeal seeding) at
diagnosis. However, a few questions remain. We treated
patients with a higher dose of RT if a residual lesion was
suspected prior to RT, including cystic lesions at the pri-
mary tumor site with or without mild enhancement. The
first question is whether a lower dose of RT could be used
in such cases without jeopardizing relapse-free survival.
Cystic residual lesions with a normal b-HCG level after
induction chemotherapy could potentially be treated with
the same dose as that used for CR patients. A second
question is whether the volume of RT can be further
reduced in germinoma patients with significantly elevated
b-HCG levels. RT doses and volume in the present study
were 19.5–24.0 Gy to the neuroaxis and an additional
10.8–19.8 Gy to the primary site (total focal doses
30.3–40.2 Gy). Recently, investigators suggested that a
localized pure germinoma could be treated with a reduced-
dose and volume of RT if effective chemotherapy was
provided [11, 17–19]. They showed that whole ventricle
irradiation (or whole brain irradiation for basal ganglia
Fig. 2 A representative case (Patient No. 4). Tumor was located in
the left basal ganglia (a). b-HCG levels normalized after two cycles
of chemotherapy (CT). Only a cystic lesion with mild marginal
enhancement remained after two and four cycles of induction
chemotherapy (b, c), and persisted even after RT (d)
J Neurooncol
123
tumors) did not result in greater recurrence than CSRT for
localized pure germinoma, and that CSRT could be
reserved for patients with leptomeningeal seeding at diag-
nosis. O’Neil et al. [18] reported that neurocognitive,
social, and emotional functioning could be preserved by
reducing the dose and volume of RT in pediatric and
adolescent patients with CNS germinomas. These findings
suggest that whole ventricle irradiation might have been an
adequate substitute for CSRT in the four patients with
localized tumors in the present study.
All patients in the present study underwent endoscopic
or stereotactic biopsy. However, exact pathological diag-
noses might be error-prone, as they are highly dependent
on the sampling method, particularly for biopsies that
comprise only a small piece of a given tumor. Therefore,
some patients in the present study, particularly patients
with an extremely high b-HCG level, might have had a
hidden component of choriocarcinoma that was not inclu-
ded in the biopsied sample. However, all patients remained
relapse free regardless of b-HCG level. These findings
suggest that our treatment strategy (intensive chemother-
apy followed by reduced-dose RT) might also be effective
in the treatment of CNS NGGCTs.
Our treatment strategy aimed to minimize late effects by
reducing the dose of RT, which we achieved by supple-
menting RT with intensive chemotherapy. Neuroendocrine
dysfunction was a frequent late effect and was observed in
six patients; however, five of these patients had suprasellar
tumors and therefore already had neuroendocrine dys-
function at diagnosis. In contrast, none of the patients with
pineal tumors demonstrated neuroendocrine dysfunction.
Vertical growth was also not significantly disturbed by our
treatment strategy. In addition, most patients demonstrated
acceptable cognitive function. Taken together, our findings
suggest that our treatment strategy may decrease late
adverse effects from RT, particularly CSRT. However,
dose-intense chemotherapy can also result in significant
late adverse effects. Therefore, a longer follow-up duration
is needed to assess whether our strategy will ultimately
reduce overall late adverse effects.
In summary, although the number of patients in the present
study was low, our data suggest that pathologically pure
germinomas with a significantly elevated b-HCG level can be
successfully treated with reduced-dose RT if intensive che-
motherapy is provided. However, a longer follow-up study is
needed to evaluate whether the benefits of RT dose-reduction
outweigh the long-term risks of intensive chemotherapy.
Furthermore, a prospective study with a larger cohort of
patients is needed to confirm our findings.
Acknowledgments This study was supported by a Grant from the
National R&D Program for Cancer Control, Ministry of Health and
Welfare, Republic of Korea (No. 0520300).
Conflict of interest We declare that there are no competing finan-
cial interests in relation to this work.
References
1. Aoyama H, Shirato H, Kakuto Y, Inakoshi H, Nishio M, Yoshida
H, Hareyama M, Yanagisawa T, Watarai J, Miyasaka K (1998)
Pathologically-proven intracranial germinoma treated with radi-
ation therapy. Radiother Oncol 47:201–205
2. Aoyama H, Shirato H, Ikeda J, Fujieda K, Miyasaka K, Sa-
wamura Y (2002) Induction chemotherapy followed by low-dose
involved-field radiotherapy for intracranial germ cell tumors.
J Clin Oncol 20:857–865
3. Matsutani M, Japanese Pediatric Brain Tumor Study Group
(2001) Combined chemotherapy and radiation therapy for CNS
germ cell tumors: the Japanese experience. J Neurooncol
54:311–316
4. Finlay J, da Silva NS, Lavey R, Bouffet E, Kellie SJ, Shaw E,
Saran F, Matsutani M (2008) The management of patients with
primary central nervous system (CNS) germinoma: current con-
troversies requiring resolution. Pediatr Blood Cancer 51:313–316
5. Calaminus G, Kortmann R, Worch J, Nicholson JC, Alapetite C,
Garre ML, Patte C, Ricardi U, Saran F, Frappaz D (2013) SIOP
CNS GCT 96: final report of outcome of a prospective, multi-
national nonrandomized trial for children and adults with intra-
cranial germinoma, comparing craniospinal irradiation alone with
chemotherapy followed by focal primary site irradiation for
patients with localized disease. Neuro Oncol 15:788–796
6. Ho DM, Liu HC (1992) Primary intracranial germ cell tumor.
Pathologic study of 51 patients. Cancer 70:1577–1584
7. Washiyama K, Sekiguchi K, Tanaka R, Yamazaki K, Kumanishi
T, Oyake Y (1987) Immunohistochemical study on AFP, HCG
and PLAP in primary intracranial germ cell tumors. Prog Exp
Tumor Res 30:296–306
8. Sawamura Y, Ikeda J, Shirato H, Tada M, Abe H (1998) Germ
cell tumours of the central nervous system: treatment consider-
ation based on 111 cases and their long-term clinical outcomes.
Eur J Cancer 34:104–110
9. Utsuki S, Kawano N, Oka H, Tanaka T, Suwa T, Fujii K (1999)
Cerebral germinoma with syncytiotrophoblastic giant cells: fea-
sibility of predicting prognosis using the serum hCG level. Acta
Neurochir (Wien) 141:975–977
10. Ogino H, Shibamoto Y, Takanaka T, Suzuki K, Ishihara S,
Yamada T, Sugie C, Nomoto Y, Mimura M (2005) CNS germi-
noma with elevated serum human chorionic gonadotropin level:
clinical characteristics and treatment outcome. Int J Radiat Oncol
Biol Phys 62:803–808
11. Kanamori M, Kumabe T, Saito R, Yamashita Y, Sonoda Y, Ariga
H, Takai Y, Tominaga T (2009) Optimal treatment strategy for
intracranial germ cell tumors: a single institution analysis.
J Neurosurg Pediatr 4:506–514
12. Kim A, Ji L, Balmaceda C, Diez B, Kellie SJ, Dunkel IJ, Gardner
SL, Sposto R, Finlay JL (2008) The prognostic value of tumor
markers in newly diagnosed patients with primary central nervous
system germ cell tumors. Pediatr Blood Cancer 51:768–773
13. Fujimaki T, Matsutani M, The Japanese Pediatric Brain Tumor
Study Group (2005) HCG-producing germinoma: analysis of
Japanese Pediatric Brain Tumor Study Group results [abstract].
Neuro-oncology 7:518
14. Kretschmar C, Kleinberg L, Greenberg M, Burger P, Holmes E,
Wharam M (2007) Pre-radiation chemotherapy with response-
based radiation therapy in children with central nervous system
germ cell tumors: a report from the Children’s Oncology Group.
Pediatr Blood Cancer 48:285–291
J Neurooncol
123
15. Sands SA, Kellie SJ, Davidow AL, Diez B, Villablanca J, Weiner
HL, Pietanza MC, Balmaceda C, Finlay JL (2001) Long-term
quality of life and neuropsychologic functioning for patients with
CNS germ-cell tumors: from the First International CNS Germ-
Cell Tumor Study. Neuro Oncology 3:174–183
16. Mabbott DJ, Monsalves E, Spiegler BJ, Bartels U, Janzen L,
Guger S, Laperriere N, Andrews N, Bouffet E (2011) Longitu-
dinal evaluation of neurocognitive function after treatment for
central nervous system germ cell tumors in childhood. Cancer
117:5402–5411
17. Khatua S, Dhall G, O’Neil S, Jubran R, Villablanca JG,
Marachelian A, Nastia A, Lavey R, Olch AJ, Gonzalez I, Gilles F,
Nelson M, Panigrahy A, McComb G, Krieger M, Fan J, Sposto R,
Finlay JL (2010) Treatment of primary CNS germinomatous
germ cell tumors with chemotherapy prior to reduced dose whole
ventricular and local boost irradiation. Pediatr Blood Cancer
55:42–46
18. O’Neil S, Ji L, Buranahirun C, Azoff J, Dhall G, Khatua S, Patel
S, Panigrahy A, Borchert M, Sposto R, Finlay J (2011) Neuro-
cognitive outcomes in pediatric and adolescent patients with
central nervous system germinoma treated with a strategy of
chemotherapy followed by reduced-dose and volume irradiation.
Pediatr Blood Cancer 57:669–673
19. Shikama N, Ogawa K, Tanaka S, Toita T, Nakamura K, Uno T,
Ohnishi H, Itami J, Tada T, Saeki N (2005) Lack of benefit of
spinal irradiation in the primary treatment of intracranial germi-
noma: a multiinstitutional, retrospective review of 180 patients.
Cancer 104:126–134
J Neurooncol
123