Original Article

The Role of Postoperative Radiotherapy for

the Treatment of Gangliogliomas
Dirk Rades, MD1; Lena Zwick, MD1; Jan Leppert, MD2; Matteo M Bonsanto, MD2; Volker Tronnier, MD2;
Juergen Dunst, MD1; and Steven E. Schild, MD3

BACKGROUND: Because of their rarity, no prospective studies have been performed regarding gangliogliomas. The
optimal treatment regimen is unclear. In this study, the authors compared 4 therapies for local control (LC) and over-
all survival (OS) in patients with ganglioglioma. METHODS: In 402 patients with ganglioglioma, outcomes were com-
pared for patients who underwent gross total resection alone (GTR) (n ¼ 188), GTR plus radiotherapy (GTR þ RT)
(n ¼ 21), subtotal resection alone (STR) (n ¼ 113), and STR plus RT (STR þ RT (n ¼ 80). Age, sex, tumor site, and histo-
logic grade also were investigated. Subgroup analyses were performed for both low-grade and high-grade tumors.
RESULTS: The 10-year LC rates were 89% after GTR, 90% after GTR þ RT, 52% after STR, and 65% after STR þ RT (P <
.001); and the 10-year OS rates were 95%, 95%, 62%, and 74%, respectively (P < .001). After STR, irradiation signifi-
cantly improved LC (P ¼ .004) but not OS (P ¼ .22). After GTR, irradiation did not significantly improve LC (P ¼ .23)
or OS (P ¼ .29). On multivariate analyses, LC and OS were associated with therapy and pathologic grade, and OS
also was associated with tumor site. In low-grade tumors, STR þ RT resulted in better LC (P ¼ .016) but not better OS
(P ¼ .18); and, after GTR, LC (P ¼ .28) and OS (P ¼ 1.0) were not improved with postoperative radiotherapy. In high-
grade tumors, STR þ RT resulted in better LC (P ¼ .016) but not better OS (P ¼ .41); after GTR, LC (P ¼ .56) and OS
(P ¼ .61) were not improved with irradiation. CONCLUSIONS: According to this review, GTR should be performed
whenever safely possible and does not require postoperative irradiation. If only STR is achieved, then RT improves LC
of both low-grade and high-grade tumors and, thus, should be considered seriously. Cancer 2010;116:432–42. V C 2010

American Cancer Society.

KEYWORDS: ganglioglioma, resection, postoperative radiotherapy, overall survival, local control.

Gangliogliomas are rare neuroepithelial tumors that account for only 0.4% of central nervous system (CNS)
tumors and for 1.3% of brain tumors.1 The term ‘‘ganglioglioma’’ was introduced in 1926 for tumors composed of
dysplastic neurons and neoplastic glia cells.2,3 Gangliogliomas can be categorized further as either low-grade or high-
grade tumors. High-grade tumors have anaplastic features or necrosis of the glial components or an elevated MIB-1
labeling index
10%.4 These tumors are located most commonly within the brain, especially in the temporal lobe.5
The majority of patients are children or young adults who present with seizures. Tumor resection is considered the
treatment of choice, and the role of radiotherapy (RT) is controversial. It is not clear whether postoperative RT influ-
ences the outcome of patients with ganglioglioma. Furthermore, many physicians are hesitant to administer RT
because of the potential radiation-related morbidity in long-term survivors. This is of particular concern in these
patients, who often are aged <30 years.5 Because gangliogliomas are quite uncommon, no prospective studies have
been performed or can be expected in the near future. Most reports presented in the literature are case studies. To our
knowledge, the current literature-based, retrospective study is the largest series of ganglioglioma patients reported. It
was based on individual data from 402 patients and compared 4 different treatment regimens with respect to local
control (LC) and overall survival (OS). This study was performed to help define the role of postoperative RT for the
treatment of gangliogliomas.

Corresponding author: Dirk Rades, MD, PhD, Department of Radiation Oncology, University of Lubeck, Ratzeburger Allee 160, D-23538 Lubeck, Germany; Fax:
(011) 49-451-500-3324; rades.dirk@gmx.net
1
Department of Radiation Oncology, University of Lubeck, Lubeck, Germany; 2Department of Neurosurgery, University of Lubeck, Lubeck, Germany; 3Department
of Radiation Oncology, Mayo Clinic Scottsdale, Scottsdale, Arizona
DOI: 10.1002/cncr.24716, Received: February 26, 2009; Revised: April 13, 2009; Accepted: April 27, 2009, Published online November 11, 2009 in Wiley
InterScience (www.interscience.wiley.com)

432 Cancer January 15, 2010

 Radiotherapy for Gangliogliomas/Rades et al

Table 1. Patient Characteristics (Potential Prognostic Factors) Related to the

4 Treatment Groups

No. of Patients (%)

Characteristic GTR Alone, GTR1RT, STR Alone, STR1RT, P
N 5 188 N 5 21 N 5 113 N 5 80

Age, y .60
0-9, n 5 117 55 (29) 2 (10) 42 (37) 18 (23)
10-19, n 5 115 61 (32) 6 (29) 29 (26) 19 (24)
20-29, n 5 73 33 (18) 6 (29) 18 (16) 16 (20)
‡30, n 5 97 39 (21) 7 (33) 24 (19) 27 (34)

Sex .99
Female, n 5 180 85 (45) 9 (43) 51 (45) 35 (44)
Male, n 5 222 103 (55) 12 (57) 62 (55) 45 (56)

Tumor site .77

Temporal lobe 83 (44) 8 (38) 42 (37) 29 (36)
Frontal lobe 47 (25) 6 (29) 27 (24) 17 (21)
Other sites 58 (31) 7 (33) 44 (39) 34 (43)

Pathologic grade .31

Low grade, n 5 342 176 (94) 14 (67) 92 (81) 60 (75)
High grade, n 5 60 12 (6) 7 (33) 21 (19) 20 (25)

GTR indicates gross total resection; RT, radiotherapy; STR, subtotal resection.

MATERIALS AND METHODS
All reports of gangliogliomas published between 1978 and
2007 were reviewed for age, sex, tumor site, pathologic
grade, extent of resection, RT, LC, and survival. Criteria
for high-grade tumors were the presence of anaplastic his-
tologic features, such as necrosis and high mitotic activity,
or the presence of an MIB-1 labeling index
10%.3,4 A
high-grade lesion was diagnosed in 60 patients: in 16
patients, according to the MIB-1 labeling index alone; in
34 patients, because of the presence of anaplastic features
alone; and 10 patients fulfilled both criteria. Criteria for
inclusion in the current retrospective analysis were tumor
location within the brain, complete data regarding the
above-mentioned criteria, and a follow-up
12 months in
patients who were alive at the last follow-up.
Of 402 patients who met the criteria for inclusion
(396 patients from the literature plus 6 patients from our
institution), 188 patients underwent gross total resection
(GTR) alone, 21 patients underwent GTR followed by
RT, 113 patients underwent subtotal resection (STR)
alone, and 80 patients underwent STR followed by RT
(STR þ RT). The radiation dose (equivalent dose in 2-
gray [Gy] fractions [EQD2]) administered to the primary
tumor was stated in 52 patients and ranged from 30 Gy to
72 Gy (median dose, 54 Gy). The extent of resection was
determined by magnetic resonance imaging (MRI) and/or
computed tomography (CT) scans. MRI scans were
obtained in 259 patients (64%). Data on 396 patients
from the literature were obtained from 142 reports.1,5-145
Patients were followed until death or from 12 months to
408 months (median follow-up, 36 months) for those
who reportedly were alive at the last follow-up. The
patient characteristics related to the 4 treatment groups
are summarized in Table 1.
The 4 treatment regimens were compared with
respect to LC and OS. Local failure was confirmed histo-
logically or with MRI/CT scans. In addition, age, sex, tu-
mor site, and pathologic grade were investigated with
respect to LC and OS. Both LC and OS were calculated
from the end of treatment using the Kaplan-Meier
method.146 Differences between Kaplan-Meier curves
were determined with the Wilcoxon test. The Bonferroni
correction for multiple comparisons was used to adjust
the P values derived from the univariate analysis. Because
5 potential prognostic factors were investigated, P values
<.013 were considered significant and represented an a
level <.05. The prognostic factors that were identified as
significant in univariate analyses were included in multi-
variate analyses that were performed with the Cox propor-
tional-hazards model.
The following subgroup analyses were performed:
Patients who underwent GTR alone were compared with
those who underwent GTR þ RT, and patients who
underwent with STR alone were compared with those

Cancer January 15, 2010 433

Original Article

Table 2. Actuarial Local Control Rates Related to Potential Table 3. Actuarial Overall Survival Rates Related to Potential
Prognostic Factors: Univariate Analysis Prognostic Factors: Univariate Analysis

Local Control Rate, % Overall Survival

Rate, %
Variable At 5 Years At 10 Years P a

Variable At 5 Years At 10 Years Pa

Age, y .018
0-9, n 5 117 83 83 Age, y .06
10-19, n 5 115 87 77 0-9, n 5 117 91 87
20-29, n 5 73 82 72 10-19, n 5 115 94 88
‡30, n 5 97 62 59 20-29, n 5 73 90 77
‡30, n 5 97 78 70
Sex .021
Female, n 5 180 72 65 Sex .46
Male, n 5 222 85 80 Female, n 5 180 86 78
Male, n 5 222 90 84
Tumor site .029
Temporal lobe 85 80 Tumor site .012
Frontal lobe 81 73 Temporal lobe 94 86
Other sites 71 66 Frontal lobe 89 79
Other sites 82 76
Pathologic grade .001
Low grade, n 5 342 86 81 Pathologic grade <.001
High grade, n 5 60 31 21 Low grade, n 5 342 93 87
High grade, n 5 60 61 41
Treatment regimen <.001
GTR alone, n 5 188 93 89 Treatment regimen <.001
GTR1RT, n 5 21 90 90 GTR alone, n 5 188 99 95
STR alone, n 5 113 58 52 GTR1RT, n 5 21 95 95
STR1RT, n 5 80 72 65 STR alone, n 5 113 77 62
STR1RT, n 5 80 80 74
Entire cohort, N ¼ 402 79 73
Entire cohort, N ¼ 402 88 81
GTR indicates gross total resection; RT, radiotherapy; STR, subtotal
resection. GTR indicates gross total resection; RT, radiotherapy; STR, subtotal
a
According to the Bonferroni adjustment, P values <.013 were considered resection.
significant. a
According to the Bonferroni adjustment, P values <.013 were considered
significant.

who underwent STR þ RT. Additional subgroup analyses

comparing STR with STR þ RT and GTR with
GTR þ RT were performed separately for patients with
low-grade tumors and high-grade tumors.
RESULTS
Seventy-four of 402 patients (18%) developed a local re-
currence during follow-up. The 10-year LC rates were
89% after GTR, 90% after GTR þ RT, 52% after STR,
and 65% after STR þ RT (P < .001). On univariate anal-
ysis, LC was associated significantly with pathologic grade
and treatment regimen when the Bonferroni adjustment
was taken into account (Table 2). On multivariate analysis
of LC, pathologic grade (relative risk [RR]. 6.70; 95%
confidence interval [CI], 4.08-10.95; P < .001), and
treatment regimen (RR, 0,45; 95% CI, 0.33-0.59; P <
.001) maintained significance.
Forty-five patients (11%) died during follow-up.
The 10-year OS rates were 95% after GTR, 95% after
GTR þ RT, 62% after STR, and 74% after STR þ RT
(P < .001). On univariate analysis, OS was associated sig-
nificantly with tumor site, pathologic grade, and treat-
ment regimen (Table 3). On multivariate analysis of OS,
tumor site (RR, 1.64; 95% CI, 1.14-2.42; P ¼ .007),
pathologic grade (RR, 4.85; 95% CI, 2.59-9.01; P <
.001), and treatment regimen (RR, 0.36; 95% CI, 0.24-
0.53; P < .001) remained significant.
According to the subgroup analyses, STR þ RT
resulted in significantly better LC than STR alone (P ¼
.004) (Fig. 1, top left) but not in significantly better OS
(P ¼ .22) (Fig. 1, bottom left). In the patients who under-
went STR þ RT, the EQD2 (a/b ¼ 10 Gy for tumor cell
kill) was known for 40 patients who underwent
STR þ RT. A local recurrence was observed in 6 of 22
patients (27%) who received 54 Gy and in 7 of 18
patients (39%) who received >54 Gy. GTR and GTR-
RT resulted in similar LC (P ¼ .23) (Fig. 1, top right),
and OS (P ¼ .29) (Fig. 1, bottom right).
The additional subgroup analysis performed for the
342 patients with low-grade tumors suggested that
STR þ RT was significantly better than STR alone for LC
(P ¼ .016) (Fig. 2, top left) but not for OS (P ¼ .18)

434 Cancer January 15, 2010


Figure 1. These charts illustrate the impact of postoperative radiotherapy (RT) after subtotal resection (STR) or gross total resec-
tion (GTR) on (Top) local control and (Bottom) overall survival for the entire cohort.
(Fig. 2, bottom left). Of the 27 patients with low-grade
tumors who underwent STR þ RT who had a known
EQD2, 3 of 17 patients (18%) who received 54 Gy and
in 3 of 10 patients (30%) who received >54 Gy developed
a local failure. GTR þ RT resulted in similar LC (P ¼
.28) (Fig. 2, top right) and OS (P ¼ 1.0) (Fig. 2, bottom
right) compared with GTR alone for low-grade tumors.
The additional subgroup analysis performed for the
60 patients with high-grade tumors suggested that
STR þ RT was significantly superior to STR alone for LC
(P ¼ .016) (Fig. 3, top left) but not for OS (P ¼ .41) (Fig.
3, bottom left). Of the 13 patients who had high-grade
tumors within the STR þ RT group for whom the EQD2
was known, 3 of 5 patients (60%) who received 54 Gy
and 4 of 8 patients (50%) who received >54 Gy devel-
oped a local failure. GTR þ RT resulted in similar LC
(P ¼ .57) (Fig. 3, top right) and OS (P ¼ .61) (Fig. 3,
bottom right) compared with GTR alone for high-grade
tumors.
Cancer January 15, 2010
Radiotherapy for Gangliogliomas/Rades et al
DISCUSSION
The objective of this study was to help define the best
available treatment for gangliogliomas and to evaluate the
potential role of postoperative RT. Although this study is
the largest reported to date, the retrospective nature
should be kept in mind when interpreting the results. A
further limitation of this study is the lack of a central path-
ologic review. Many different pathologists have reviewed
the specimens with a wide variety of perspectives and ex-
perience. Also, the follow-up intervals after the comple-
tion of treatment may have varied. Thus, there is a certain
risk of a selection bias. However, prospective studies are
not available and cannot be expected in the near future,
because gangliogliomas are very rare. Therefore, despite
its limitations, a large retrospective analysis appears to be
the best approach available to determine the optimal treat-
ment for these tumors.
The current results suggest that GTR is significantly
better than STR with respect to both LC and OS. Thus,
435
Original Article
Figure 2. These charts illustrate the impact of postoperative radiotherapy (RT) after subtotal resection (STR) or gross total resec-
tion (GTR) on (Top) local control and (Bottom) overall survival from a subgroup analysis of patients who had low-grade tumors.
patients with ganglioglioma should undergo GTR when-
ever safely possible. However, not infrequently, only STR
of a ganglioglioma can be achieved. The role of RT is
poorly defined and controversial. According to the current
results, STR þ RT results in significantly better LC than
STR but does not significantly improve OS. However,
LC is an important endpoint, because recurrent ganglio-
gliomas may have a malignant course, including
craniospinal dissemination, or may cause neurologic
symptoms (such as seizures) or intracerebral hemor-
rhage.45,79,98,133,134,147-149 In addition, locally recurrent
tumors may require repeat craniotomies, which carry
additional risks. Furthermore, anaplastic astrocytoma or
even glioblastoma multiforme may develop at the time of
recurrence.135-139,150 Such malignancies were observed in
8 patients, including 3 patients after STR alone, 4 patients
after STR þ RT, and 1 patient after GTR þ RT. It
remains unclear whether such highly malignant brain
tumors occurred because of the malignant transformation
of gangliogliomas or should be considered second malig-
nancies induced by RT.
436
RT after GTR did not improve LC or OS. However,
the reported outcomes after the addition of RT may have
been biased negatively, because the GTR þ RT and
STR þ RT groups contained nonsignificantly higher pro-
portions of patients with high-grade tumors compared
with the GTR-alone and STR-alone groups. This finding
appears to reflect clinical practice. For patients with ana-
plastic tumors, physicians are more likely to recommend
postoperative RT than for patients with low-grade
tumors. Pathologic grade was the most important prog-
nostic factor in our multivariate analyses of LC and OS.
Because the imbalance of tumor grade between the resec-
tion alone and the resection plus RT groups in favor of
resection alone may have confounded the results of the
combined approach in relation to resection alone, separate
subgroup analyses were performed for the low-grade and
high-grade tumor groups. However, in both the low-
grade and high-grade subgroups, LC (but not OS) was
improved significantly with the addition of RT after STR,
as observed previously in the entire cohort. After GTR,
RT conferred no improvement in outcome for patients
Cancer January 15, 2010

Figure 3. These charts illustrate the impact of postoperative radiotherapy (RT) after subtotal resection (STR) or gross total resec-
tion (GTR) on (Top) local control and (Bottom) overall survival from a subgroup analysis of patients who had high-grade tumors.
with either low-grade or high-grade tumors. It appears
that a dose escalation beyond 54 Gy does not improve LC
compared with doses 54 Gy regardless of the pathologic
grade. However, given the small numbers of patients with
known radiation dose, a dose recommendation cannot be
made seriously from this review. The data regarding the
treatment volume of RT are limited and were available
only for 30 patients. Twenty patients received RT to the
tumor plus a safety margin, 9 patients received whole-
brain irradiation, and 1 patient received whole-brain irra-
diation plus a boost to the tumor site. Furthermore, local
recurrence has not been correlated with respect to isodose
lines. In the near future, radiosurgery and stereotactic con-
formal RT may be additional options for the treatment of
gangliogliomas. At the moment, only very few case reports
are available.151-154
Prognostic factors are important, because they can
help the physician to select appropriate treatment for the
individual patient. The prognostic significance of the
pathologic grade, which was the strongest predictor of
Cancer January 15, 2010
Radiotherapy for Gangliogliomas/Rades et al
outcomes in the current analysis, has been described
before. Rumana et al presented a retrospective study of 42
patients155 and observed 7 deaths in a group of 13 patients
(56%) with high-grade tumors and 3 deaths in a group of
29 patients (10%) with low-grade tumors (P ¼ .020).
Luyken et al presented the previously largest series of gan-
glioglioma patients (N ¼ 184).3 Because those authors
did not report individual patient data, none of their 184
patients were included in the current study. In the study
by Luyken et al, better LC was associated significantly
with favorable tumor site (temporal lobe; P < .001), lower
pathologic grade (P < .001), and complete tumor resec-
tion (P ¼ .028).
In conclusion, given the limitations of a retrospec-
tive review, the current data suggest that patients with
ganglioglioma should undergo GTR whenever safely pos-
sible, and GTR does not appear to require postoperative
RT. If only STR is achieved, then RT significantly
improves LC in both low-grade and high-grade tumors.
Therefore, RT should be considered seriously after STR.
437
Original Article
CONFLICT OF INTEREST DISCLOSURES
The authors made no disclosures.
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