ORIGINAL ARTICLE

Intracranial Germ Cell Tumors: Efficacy of Neoadjuvant ￼￼￼
Chemo-radiotherapy without Surgical Biopsy
Satoshi Takahashi, Kazunari Yoshida and Takeshi Kawase

Department of Neurosurgery, School of Medicine, Keio University, Tokyo, Japan(Received for publication on May 21, 2010)(Revised for publication on December 1, 2010)(Accepted for publication on January 20, 2011)

In this report, we review 41 patients with intracranial germ cell tumors (GCTs) treated at the Department of Neurosurgery, Keio University School of Medicine, in the 25-year period between January
1982 and July 2006. The main aim of the present study was to compare the effectiveness of our current
intracranial GCT management protocol, comprising neoadjuvant chemo-radiotherapy without surgicalbiopsy of tumors as far as possible, to that of historical controls. In all patients, charts were reviewed
and tumor and patient characteristics, including age, sex, type of tumor marker secreted, treatment
protocol, and clinical outcomes, were compared. The relationship between these variables was analyzed
by means of the Cox proportional hazards model. Thus far, four patients treated by approaches otherthan the current protocol have died of their tumor. The overall 5-, 10-, and 15-year survival rates of
all the patients calculated by the Kaplan-Meier method were 91.9%, 88.6%, and 88.6%, respectively.
According to the results of the Cox proportional hazards model, patients with secreting GCTs show
statistically poorer prognoses than those with non-secreting GCTs (P = 0.0073), and although not statistically significant, patients treated with our current protocol tend to show better prognoses than historical controls (P = 0.0543). All five patients with secreting GCT treated using our current protocol are
still alive after an average follow-up period exceeding 7 years, and only one of these has shown tumor
recurrence. With our current treatment protocol comprising neoadjuvant chemo-radiotherapy without
surgical biopsy, prognoses of patients with GCTs have improved compared to historical controls at our
institution. (Keio J Med 60 (2) : 56–64, June 2011)

Keywords: chemotherapy, intracranial germ cell tumors, neoadjuvant therapy, radiotherapy￼￼￼Introduction

Human chorionic gonadotropin (hCG) and alpha-fetoprotein (AFP) are considered to be powerful markers ofsome types of GCTs. If patients have elevated serum and/or cerebrospinal fluid (CSF) titers of these tumor markers, their tumors are considered to be secreting GCTs; inpatients whose sera and CSF do not contain these tumor
markers, the tumors are considered to be non-secreting
GCTs. Except for teratomas, all non-germinomatous
malignant GCTs are secreting GCTs.3 Previous reports
showed the efficacy of neoadjuvant therapy, comprising a
combination of chemotherapy and radiotherapy followedby complete excision of residual tumors in the treatmentof patients with secreting GCTs.10,11
In 1997, senior author K.Y. initiated a new treatment

Intracranial germ cell tumors (GCTs) are not rare in
Asian countries. In Japan, they account for 1.8–3.0% of
all primary brain tumors and make up about 15% of allbrain tumors in children.1,2 Intracranial GCTs include
several different clinical entities such as germinomas,
teratomas, yolk sac tumors, choriocarcinomas, and mixed
germ cell tumors.3,4 Among these, pure germinomas canbe cured by induction chemotherapy followed by reduced
volume radiation therapy,5 and mature teratomas can be
cured by total tumor removal.6 In contrast, the prognosisof patients with secreting, non-germinomatous, malignant GCTs remains poor.3,7–9

Reprint requests to: Kazunari Yoshida, MD, PhD, Department of Neurosurgery, School of Medicine, Keio University, 35 Shinanomachi, Shinjukuku, Tokyo 160-8582, Japan, E-mail: kazrmky@z3.keio.jp
Copyright © 2011 by The Keio Journal of Medicine.
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Keio J Med 2011; 60 (2): 56–64

57

Table 1 Data on 41 patients with intracranial germ cell tumors treated at Keio University Hospital between 1982 and 2006

Total cases
Male/female
Age at initial presentation
Range mean (SD)
Tumor location
Suprasellar region
Pineal region
Pineal and suprasellar regions
Basal ganglia
Histological diagnosis
Germinoma
Malignant teratoma
Germinoma with syncytiotrophoblastic giant cells
Mixed germ cell tumor
Diagnosis without surgical biopsy
Positivity for tumor markers
AFP
AFP and hCG
hCG
Follow-up periods
Range mean (SD)
Number of deaths during follow-up

All cases
41
29/12
6–42 years
18.46 (7.61)

Current protocol
14
9/5
8–42 years
17.79 (8.39)

Others27
20/7
6–32 years
18.81 (7.32)

16
14
10
1

6
4
4
0

10
10
6
1

14
1
1
2*
23

2
0
0
0
12

12
1
1
2
11

3
4
8
0–229 months
104.1 (64.2)
4

1
2
2
14–135 months
83.7 (41.1)
02
2
60–229 months
114.7 (71.9)4*Mixed choriocarcinoma and embryonal carcinoma, mixed germinoma and embryonal carcinoma.

protocol for intracranial GCTs at Keio University Schoolof Medicine. According to this protocol, neoadjuvant
chemo-radiotherapy is conducted without surgical biopsyof tumors as far as possible in order to prevent the frequently reported surgical dissemination of tumors.12
In the present study, we reviewed the treatment of intracranial GCTs at Keio University over a 25-year period.
Moreover, we evaluated the efficacy of our current protocol of managing the tumors with respect to historicalcontrols in our institution, especially in terms of secreting GCTs, which are regarded as a more malignant formof intracranial GCT.
Methods
Patient population
During the 25-year period from January 1982 to July
2006, we treated 41 patients with intracranial GCTs at the
Department of Neurosurgery, Keio University School of
Medicine (Table 1). There were 29 male patients and 12
female patients. The mean age of the patients at the timeof initial presentation was 18.46 years (range, 6–42 years).
Complete medical, neurological, and radiological examinations were performed in the pre- and post-treatment
periods. The mean follow-up period after the initial visit

to the outpatient clinic was 104.1 months (range, 0–229
months). Before treatment, all patients underwent (1) T1weighted magnetic resonance imaging (MRI) (with andwithout intravenous gadolinium infusion), T2-weighted
MRI, and fluid-attenuated inversion recovery (FLAIR)
MRI, and (2) computed tomography (CT) studies. If thetumor was attached to the surrounding arteries and deepveins, cerebral angiography was also performed. In all
patients, the serum and/or cerebrospinal fluid (CSF) titersof hCG and AFP were evaluated. An AFP concentrationof ≥ 10 ng/ml and an hCG (or hCG-β) concentration of≥ 20 mIU/ml (milli-international units per millimeter)
was defined as elevated in the present study.
Tumor location
The anatomical extent of the tumor is summarized in(Table 1). Sixteen (39.0%) tumors extended to the suprasellar region, 14 (34.1%) tumors were located in the pineal
region, 10 (24.4%) were double tumors located both in
the suprasellar region and pineal region, and 1 tumor was
located in the basal ganglia.
Treatment protocol
Before 1997, when senior author K.Y. initiated the cur-

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58

rent GCT management protocol, there was no established
GCT management protocol in our institution. At thattime, patients with GCTs were treated following individual ad hoc protocols consisting of surgery, chemotherapy,
radiotherapy, or a combination of these.
The current treatment protocol for intracranial GCTs
at Keio University is summarized in Figure 1. The
main characteristic of our current protocol is that the tumors are diagnosed without surgical biopsy as far as possible in order to prevent surgical dissemination of tumor
cells. First, presumed mature teratomas predicted by CT
and MRI findings with negative tumor markers are subjected to surgery (no patient in the present study fell into
this category). Other patients are basically treated without surgical biopsy as far as possible. For cases in which
CT and MRI findings are not compatible with those of
GCTs, we do not hesitate to conduct surgical biopsy of tumors (of the 14 patients treated by the current protocol, 2patients were subjected to this procedure). Other patientswith radiologically presumed GCTs are divided into twogroups according to tumor marker secretion: the tumor
marker not elevated – presumed pure germinoma group(AFP < 20 ng/ml and hCG < 10 mIU/ml, seven patientswere categorized in this subgroup in the current study)
and the secreting GCT group (AFP ≥ 20 ng/ml and/or
hCG ≥ 10 mIU/ml, five patients were categorized in thissubgroup in the current study). The treatment protocols
for each clinical entity are as follows.
Presumed mature teratoma
Based on CT and MRI findings and in the absence elevated tumor markers, the tumor is presumed to be a mature teratoma. Patients undergo surgical removal of thetumor. In cases where the histological diagnosis is not inagreement with a presumed mature teratoma (e.g., it isfound to be a pure germinoma), the patient is treated on
the basis of the histological diagnosis.
Tumor marker not elevated, presumed pure germinoma
In the present study, seven patients were categorized
in this subgroup. Patients with presumed pure germinomas undergo three courses of the chemotherapy regimen
CBDCA-VP16-G (day 1: carboplatin, 450 mg/m 2; days
1–3: etoposide, 150 mg/m2; and days 5–11: granulocytecolony stimulating factor (G-CSF), Neutrogin, 2 µg/kg)
followed by 24-Gy irradiation. In patients with localized
tumors, whole-ventricle irradiation is performed. In patients with disseminated tumors, whole-brain and spine
irradiation is performed additionally.

Secreting GCT
In the present study, five patients were categorized inthis subgroup. Patients with secreting GCTs undergo fivecourses of the chemotherapy regimen ICE-G (day 1: carboplatin, 450 mg/m2; days 2–4: etoposide, 150 mg/m 2
in combination with ifosfamide, 2 g/m2; and days 6–12:
G-CSF, Neutorgin, 2 µg/kg) followed by irradiation. For
localized tumors, 24-Gy whole-ventricle irradiation was
performed, and for disseminated tumors, 24-Gy wholebrain and spine irradiation in combination with 26-Gy
local irradiation was performed.
Tumor marker not elevated GCTs diagnosed after
surgical biopsy
When CT and MRI findings are not compatible withthose of GCTs, we do not hesitate to conduct surgical biopsy. In this group of patients, when histological diagnosis of a GCT is made, we conduct intraoperative intrathecal administration of 10 mg methotrexate (MTX)
to prevent surgical dissemination of the tumor. Thesepatients undergo an adjunctive chemotherapy regimen
comprising three courses of CBDCA-VP16-G with intrathecal administration of MTX, followed by 24-Gy wholebrain irradiation.
Recurrent GCTs
Patients with recurrent GCTs undergo five courses of
the chemotherapy regimen ICE-G. If possible, they undergo additional irradiation. In the present study, one patient with recurrent tumor was treated by this regimen. If
residual tumors are identified on follow-up MRI scans,patients undergo surgical removal of the residual tumor.
Follow-up and statistical analysis
The patients were followed up with MRI or CT imaging at approximately 6-month intervals, and the overall
survival rates were calculated using the Kaplan-Meiermethod. The overall survival period was defined as theperiod from the initial presentation of the patient to our
outpatient clinic (Keio University) to the last follow-up
visit. To determine the factors that affect prognoses ofpatients, tumor and patient characteristics, including
age, sex, type of tumor marker secreted, treatment protocol, and clinical outcomes, were compared. The relationship between these variables was analyzed using theCox proportional hazards model. To compare the overall
survival rates between the subgroups (i.e., secreting vs.
non-secreting and treatment with the current protocol vs.
treatment with other protocols), we conducted univariate
analysis of possible factors by using standard log-rank

Fig. 1

Current intracranial germ cell tumor treatment protocol at Keio University (instigated in 1997).

Keio J Med 2011; 60 (2): 56–64
59

Takahashi S, et al: Germ Cell Tumors

60

Fig. 2 Overall survival of 41 patients with intracranial germ cell tumors (Kaplan-Meier survival curve).

methods. Differences between the groups were considered to be significant at P ≤ 0.05.
Results
Tumor markers
Serum and/or CSF titers of the tumor markers hCG and
AFP were evaluated in all 41 patients. AFP alone was elevated in 3 patients, hCG alone was elevated in 8 patients,
and both AFP and hCG were elevated in 4 patients. In
the remaining 26 patients, serum and/or CSF titers of thetumor markers were not elevated.
Histological diagnosis of tumors
Histological diagnoses were established in 18 of 41 patients at the time before initial treatment (43.9%, Table1); the diagnoses comprised 14 germinomas, 1 germinoma with syncytiotrophoblastic giant cells, 1 malignant
teratoma, and 2 mixed GCTs (choriocarcinoma and embryonal carcinoma, and germinoma and embryonal carcinoma). The remaining 23 patients were treated without
histological diagnoses.
Treatment protocol
Since senior author K.Y. established the new protocol in
1997, 11 patients have been treated according to the protocol. Before 1997, 3 patients were coincidentally treatedwith the same regimen, and we included these 3 casesin the current treatment protocol subgroup in the present
study. Therefore, 14 patients were allocated to the current protocol treated subgroup. The remaining 27 patientswere treated by other protocols consisting of surgery, radiotherapy, chemotherapy, or a combination of these.
Follow-up review
A review of the most recent follow-up visits (mean follow-up period, 104.1 months since the initial presentation
to our outpatient clinic; range, 0–229 months) revealed
that 37 of the 41 patients were still alive. Four patientstreated by approaches other than by the current protocol
died of the disease during the follow-up period. The Kaplan-Meier survival curve of all 41 patients is shown in
Figure 2. The overall 5-, 10-, and 15-year survival rates
were 91.9%, 88.6%, and 88.6%, respectively.
Factors that affect prognosis
To determine the factors that affect the prognoses ofpatients, tumor and patient characteristics, including age,sex, type of tumor marker secreted, treatment protocol,and clinical outcomes, were compared. The Cox proportional hazards model showed that among the factors evaluated, only tumor marker secretion was a statistically relevant factor that affected prognosis (P = 0.0073, Table 2).
Patients treated by the current protocol tended to show
longer overall survival rates than patients treated by otherprotocols, but the difference was not statistically significant (P = 0.0543). The Kaplan-Meier survival curves ofpatients classified by the above two factors are shown in
Figures 3 and 4, and a summary of the p values calculated using the Cox proportional hazards model is given
in Table 2.
The Kaplan-Meier survival curve of the 15 patientswith secreting GCTs subgrouped by the treatment pro-

Keio J Med 2011; 60 (2): 56–64

61

Fig. 3 Comparison of overall survival rates (Kaplan-Meier survival curve) between secreting GCTs (15 cases) and non-secreting
GCTs (26 cases).

Fig. 4 Comparison of overall survival rates (Kaplan-Meier survival curve) according to treatment protocol (patients treated by thecurrent protocol, 14; patients treated by approaches other than the current protocol, 27).

Table 2 Results of Cox proportional hazards model
FactorAge
SexMarker secretion (Yes/No)
Treated by current protocol (Yes/No)

P value

0.39400.86220.0073**0.0543**P ≤ 0.01

tocol is shown in Figure 5. The characteristics of thefive patients with secreting GCTs treated by the current
treatment protocol are summarized in Table 3; only oneof them showed tumor recurrence, 10 years after initialpresentation. The patient underwent additional chemoradiotherapy for treatment of the recurrent tumor according to our current management protocol, and the tumor
was controlled at 135 months from the initial presentation. The mean follow-up period of the five patients withsecreting GCTs treated by the current protocol from theinitial presentation is 88.2 months (range, 31–135), and all
the patients are alive.
￼￼Discussion

Intracranial GCTs are malignant brain tumors thatoriginate mainly in the suprasellar region, pineal region,

Takahashi S, et al: Germ Cell Tumors

62

Fig. 5 Comparison of overall survival rates (Kaplan-Meier survival curve) of 15 patients with secreting GCTs according to the treatment protocol (patients treated by the current protocol, 5; patients treated by approaches other than the current protocol, 10).
Table 3 Summary of five patients with secreting GCTs treated by the current treatment protocol
Age
Sex(year-old)
1
16
M
2
13
M
3
12
F
4
10
F
5
15
M
M: male, F: female, NA: not available
Case

AFP
(ng/ml)
560
4
54
1
8210

HCG
(mIU/ml)
86
36
27
<1
1

or basal ganglia of older children and young adults.3
GCTs encompass a number of histological subtypes, including germinomas, teratomas, embryonal carcinomas,
yolk sac tumors, choriocarcinomas, and mixed GCTs.3,4
Irradiation has been associated with a higher survival
rate in patients with germinomas, but this treatment is
controversial because of late side effects such as cognitive retardation and/or neuroendocrine deficiencies.3,5 In
contrast, few patients with non-germinomatous tumors(mainly secreting GCTs) survive for more than 3 years
despite surgical resection in combination with radiotherapy.3 After the success of cisplatin chemotherapy in thetreatment of gonadal GCTs, intracranial GCTs were thenext target of chemotherapy: the survival rates of patientswith intracranial GCTs improved, but the long-term outcome of patients with intracranial GCTs, especially secreting GCTs, remains dismal.13,14
On the basis of these reports, Keio University (seniorauthor K.Y.) started a new treatment protocol for the management of GCTs in 1997. Some of the features of the newtreatment protocol are as follows.
1. According to the radiological findings and characteristicsof the tumor markers, intracranial GCTs are divided into
four subgroups: tumor markers not-elevated, presumed pure

AFP CSF(ng/ml)
22
<2
NA
<1
NA

HCG CSF(mIU/ml)
24
140
NA
562
NA

Follow-up
period
135
98
115
62
31

Recurrence
Yes
No
No
No
No

germinomas; secreting GCTs; presumed mature teratomas;
and possible GCTs that need surgical biopsy for diagnosis.
2. As far possible, tumor biopsy is not used to confirm thehistological diagnosis.
3. Neoadjuvant therapy comprising chemotherapy and radiotherapy is performed.
4. The dose of irradiation is suppressed to the minimum possible level.
5. If residual tumor is detected after neoadjuvant therapy, theresidual tumor should be resected.

Thus far, we have treated 14 patients with intracranial
GCTs with this protocol (11 since 1997).
The overall 5-, 10-, and 15-year survival rates of all
41 patients in the current study were 91.9%, 88.6%, and88.6%, respectively. This result is similar to the reported
10-year survival rate in pure germinoma patients treated with craniospinal radiation therapy alone (around90%).5,15–18
To determine the factors that affect the prognoses ofpatients, tumor and patient characteristics, including age,sex, type of tumor marker secreted, treatment protocol,and clinical outcomes, were compared by the Cox proportional hazards model. Of the four variables evaluated,
only tumor marker secretion was shown to be a statisti-

Keio J Med 2011; 60 (2): 56–64

cally significant factor that affected prognosis. Patientswith non-secreting GCTs tended to live longer than thosewith secreting GCTs, as reported previously.3 Patientstreated with the current protocol tended to live longer
than those treated by other protocols; however, the difference was not statistically significant (P = 0.0543). In
the current series, only four patients died of the tumor;
this is probably one of the reasons why the current results
were not statistically significant. We believe that a longerterm study with a larger sample size is required to prove
the possible efficacy of our current protocol statistically.
We should mention that the current protocol is a uniform
protocol, as described above; however, other protocols
consist of ad-hoc approaches. Consequently, the difference between the survival periods in patients treated withthe current protocol and in patients treated with ad-hoc
protocols indicates the benefit of a uniform therapy alongwith the current protocol over ad-hoc protocols including
outdated approaches.
The efficacy of our current protocol compared to historical controls at our institution is especially evident withregard to the overall survival rates of patients with secreting GCTs. Even thought the results were not statisticallysignificant by a log-rank test (P = 0.1338), patients inthis subgroup treated with the current protocol tended tolive longer than those treated with other protocols. In thepresent study, the overall 5-year survival rate of patientswith secreting GCTs treated by the current protocol was
100%. According to previous reports, the median lengthof survival in this subgroup is less than 2 years, and fewer
than 30% live as long as 5 years after initial diagnosis.7–9
Robertson, et al.19 reported a better 4-year overall survival rate: it was 74% in secreting GCT patients treated withmultimodality therapy. In the present series, we followed
up five patients with secreting GCTs treated with our current management protocol for an average of more than
7 years (88.2 months) since initial presentation, and all
the patients are still alive. Although only five of our patients were in this subgroup, we believe that the outcomeof this new management protocol is at least comparable tothat of previous reports, and that it can ensure longer survival of patients with intracranial secreting GCTs. As forpatients with tumor marker not-elevated presumed puregerminomas or histologically confirmed germinomas, nodeath was observed during the study periods irrespectiveof treatment protocols. So our suggested new current protocol seems especially effective in patients with secreting
GCTs, which is thought to be more malignant in nature.
As for neoadjuvant chemotherapy for secreting GCTs,
in 1994, Herrmann, et al. reported the cases of three secreting intracranial GCT patients who underwent neoadjuvant chemotherapy and reported the effect of preoperative chemotherapy in terms of reduction of tumor volume
and normalization of tumor markers.12 In 1999 and 2003,
Ushio, Kochi, and colleagues reported that they administered neoadjuvant chemo-radiotherapy to 11 patients with63

secreting GCTs. They performed surgical biopsy of thetumor before treatment in five cases in which histological diagnosis without the tumor marker was controversial. It is noteworthy that they administered neoadjuvant
chemo-radiotherapy without surgical biopsy of the tumor
in six cases. They concluded that neoadjuvant therapy,
consisting of combined chemo-radiotherapy, followed bycomplete excision of residual tumors is highly effective inpatients with intracranial secreting GCTs.10,11
Before administration of chemo-radiotherapy, tumor
biopsy is usually performed at other hospital to obtaina histological diagnosis of presumed intracranial GCTs
that arise in the suprasellar region, pineal region, and/or
basal ganglia.12 However, most intracranial GCTs havemixed histological characteristics, and treatment is successful only when the most malignant component of thetumor is targeted. Therefore, a biopsy specimen obtainedby surgical biopsy is not always representative of thecomplex histological characteristics of tumors and may
sometimes have limited value in terms of diagnosis.20,21
Furthermore, it is known that surgery, even a stereotactic
biopsy of GCTs, can cause dissemination of tumor cells
into the CSF and lead to metastases along the ventricular wall or within the subarachnoid space.12 According
to our new protocol, instead of classifying GCTs on thebasis of histological diagnosis of the surgical biopsy
specimen, we attempt to classify intracranial GCTs according to the characteristics of the tumor markers andradiological findings into four subgroups: (1) presumed
pure germinoma, (2) secreting GCT, (3) teratoma, and (4)possible GCTs that need surgical biopsy for diagnosis.
We administer neoadjuvant chemo-radiotherapy without
surgical biopsy to patients in subgroups (1) and (2). Surgical dissemination of GCTs has been reported previously;
we therefore think that the use of neoadjuvant chemo-radiotherapy without surgical biopsy, especially in the caseof patients who show marked elevation in the levels oftumor markers, is justified.22,23 In addition, one case of
extraneural metastasis of intracranial GCT24 and one of
GCT arising from multiple sites of the body25 have also
been reported. Multimodal therapy allows long-term survival of patients with intracranial GCTs. We believe that
neoadjuvant therapy without surgical biopsy of tumors
could have an effect on preventing tumor relapse.
Our current treatment protocol, i.e., neoadjuvant
chemo-radiotherapy without surgical biopsy as far as possible followed by residual tumor resection, has been routinely conducted since 1997. Follow-up results revealed
that with this current protocol, patients with intracranial
GCTs tend to live longer compared to historical controls
at our institution. A noteworthy result was that all fivepatients with secreting GCTs treated with this protocol
survived, with an average follow-up period of more than
7 years. With our current treatment protocol comprisingneoadjuvant chemo-radiotherapy without surgical biopsy,
prognoses of patients with GCTs have improved com-

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64

pared to historical controls at our institution.
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