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J Neurosurg 102:10–16, 2005
Long-term outcomes in patients with vestibular schwannomas
treated using gamma knife surgery: 10-year follow up
TOSHINORI HASEGAWA, M.D., YOSHIHISA KIDA, M.D., TATSUYA KOBAYASHI, M.D.,
MASAYUKI YOSHIMOTO, M.D., YOSHIMASA MORI, M.D., AND JUN YOSHIDA, M.D.
Department of Neurosurgery, Gamma Knife Center, Komaki City Hospital, Komaki; and Department of
Neurosurgery, Nagoya University, Nagoya, Japan
Object. Gamma knife surgery (GKS) has been a safe and effective treatment for vestibular schwannomas in both the
short and long term, although less is known about long-term outcomes in the past 10 years. The aim of this study was to
clarify long-term outcomes in patients with vestibular schwannomas treated using GKS based on techniques in place in the
early 1990s.
Methods. Eighty patients harboring a vestibular schwannoma (excluding neurofibromatosis Type 2) were treated using
GKS between May 1991 and December 1993. Among these, 73 patients were assessed; seven were lost to follow up. The
median duration of follow up was 135 months. The mean patient age at the time of GKS was 56 years old. The mean tumor
volume was 6.3 cm3, and the mean maximal and marginal radiation doses applied to the tumor were 28.4 and 14.6 Gy, respectively. Follow-up magnetic resonance images were obtained in 71 patients. Forty-eight patients demonstrated partial
tumor remission, 14 had tumors that remained stable, and nine demonstrated tumor enlargement or radiation-induced edema requiring resection. Patients with larger tumors did not fare as well as those with smaller lesions. The actuarial 10-year
progression-free survival rate was 87% overall, and 93% in patients with tumor volumes less than 10 cm3. No patient experienced malignant transformation.
Conclusions. Gamma knife surgery remained an effective treatment for vestibular schwannomas for longer than 10
years. Although treatment failures usually occurred within 3 years after GKS, it is necessary to continue follow up in patients to reveal delayed tumor recurrence.
KEY WORDS • vestibular schwannoma • acoustic neuroma • gamma knife surgery •
outcome
ECAUSE vestibular schwannomas are benign lesions,
the goals in their treatment consist of achieving longterm tumor control and maintaining cranial nerve
function. To date, numerous investigators have reported that
GKS is a safe and effective treatment in patients harboring
vestibular schwannomas.2–5,10,11,13,14,16,19–24,30 Short-term outcome data have demonstrated that GKS is an acceptable
alternative to resection for vestibular schwannomas. In contrast, there are few data on long-term outcomes longer than
10 years after GKS.14 Because vestibular schwannomas are
not removed during GKS, we must determine whether this
therapeutic method can prevent tumor growth over the long
term. A treated tumor can progress even if it has temporarily regressed, although the chance for this is very rare.
Additionally, delayed malignant transformation following
GKS has been reported in rare cases.7,29 Thus, we evaluated
long-term outcomes and factors affecting therapeutic failure
in patients who had been treated longer than 10 years ago.
We endeavored to identify a need for further treatment after GKS and the risk of delayed malignant transformation.
B
Abbreviations used in this paper: GKS = gamma knife surgery;
MR = magnetic resonance; PFS = progression-free survival.
10
We also attempted to assess an end point for follow up after GKS.
Clinical Material and Methods
Patient and Tumor Characteristics
Between May 1991 and December 1993, 80 patients harboring a vestibular schwannoma (excluding neurofibromatosis Type 2) were treated using GKS at Komaki City Hospital in Japan. Of these, 73 patients were assessed; seven
were lost to follow up. The patients’ characteristics are featured in Table 1. Twenty-five patients were men and 48
were women, with a mean age of 52 years (range 18–79
years) at the time of GKS. Nineteen patients (26%) had undergone prior surgery, and 54 (74%) underwent GKS as the
initial treatment. Tumor type was classified as follows: type
A, intracanalicular or cerebellopontine angle tumors without compression of the brainstem; and type B, tumors with
compression of the brainstem. Hearing and facial symptoms
were assessed on the basis of the Gardner–Robertson classification6 and the House–Brackmann grading system,9 respectively. Preradiosurgical hearing status and facial funcJ. Neurosurg. / Volume 102 / January, 2005
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Gamma knife surgery for vestibular schwannomas
TABLE 1
Summary of characteristics in 73 patients
harboring vestibular schwannomas
TABLE 2
Gardner–Robertson grades both pre- and post-GKS
No. of Patients (%)
Variable
sex
male
female
age (yrs)
range
mean
side of tumor
lt
rt
no. of prior ops
0
1
2
3
tumor type
A
B
tumor volume (cm3)
range
mean
max dose (Gy)
range
mean
tumor margin dose (Gy)
range
mean
no. of isocenters
range
mean
isodose (%)
range
mean
Value (%)
Facial Nerve Function Grade
I
II
III
IV
V
total
25 (34)
48 (66)
18–79
52
Pre-GKS
3 (4)
16 (22)
29 (40)
6 (8)
19 (26)
73 (100)
Post-GKS
3 (4)
4 (6)
24 (35)
13 (19)
25 (36)
69 (100)
37 (51)
36 (49)
54 (74)
16 (22)
2 (3)
1 (1)
39 (53)
34 (47)
0.2–36.7
6.3
16.3–36.0
28.4
10.0–18.0
14.6
1–12
4.8
40–80
52
tion are shown in Tables 2 and 3, respectively. At the time
of GKS, 19 patients (26%) had useful hearing (Gardner–
Robertson Class I or II) and 59 (78%) had normal facial
function.
Radiosurgical Procedures
Gamma knife surgery was performed with the aid of the
Leksell stereotactic frame (model G; Elekta Instruments,
Atlanta, GA). The frame was applied after mild sedation
and local anesthesia had been administered, and thereafter all patients underwent MR imaging studies. Axial and
coronal T1-weighted images with contrast enhancement
were used in dose planning, as was a dose-planning system
(KULA system; Elekta Instruments). The maximal and tumor margin doses varied from 16 to 36 Gy (mean maximal
dose 28.4 Gy) and from 10 to 18 Gy (mean tumor margin
dose 14.6 Gy), respectively. The isodose line for the tumor
margin varied from 40 to 80% (mean isodose line 52%).
Tumor volume varied from 0.2 to 36.7 cm3 (mean volume
6.3 cm3). Radiosurgical doses to the tumor margin were
higher than those presently in use (12–13 Gy).
Follow-Up Analysis
Clinical follow-up data were obtained from either the patient or his or her referring doctor if they lived a great distance from our institution. When necessary, patients were
J. Neurosurg. / Volume 102 / January, 2005
contacted by telephone to update their outcome statuses for
the purposes of this study. Hearing was evaluated using serial audiometry. Neuroimaging studies were requested at
3-month intervals for the 1st year after GKS, at 6-month intervals for the next 2 years, and annually thereafter. Tumor
enlargement or regression was defined as a change of 6 2
mm in one direction, which was measured using calipers.
Statistical Analysis
Progression-free survival was calculated using the product limit method of Kaplan and Meier. When figuring PFS,
treatment failure was defined as tumor progression or radiation-induced peritumoral edema requiring resection. To
analyze factors correlated with PFS we assessed the following: patient age (, 65 years compared with $ 65 years), patient sex (male compared with female), tumor type (type
A compared with type B), maximal radiation dose (, 28
Gy compared with $ 28 Gy), tumor margin dose (, 15
Gy compared with $ 15 Gy), number of isocenters (, 5
compared with $ 5), prior treatment (no compared with
yes), and tumor volume (, 10 cm3 compared with $ 10
cm3). Factors affecting PFS were assessed using the logrank test and the Cox proportional hazards model. A final
multivariate analysis was performed using a stepwise backward elimination.
Results
In this study, the median follow-up period was 135
months. In December 2003, 68 patients were alive and five
were dead. One patient died of complications related to radiation-induced edema 19 months after GKS.
Tumor Control
In 71 of 73 patients, follow-up MR images had been ob-
TABLE 3
House–Brackmann grade in 73 patients pre-GKS
Hearing
Function Grade
I
II
III
IV
V
VI
Description
normal
mild dysfunction
moderate dysfunction
moderately severe dysfuntion
severe dysfunction
total paralysis
No. of
Patients (%)
57 (78)
9 (12)
1 (1)
6 (8)
0 (0)
0 (0)
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TABLE 4
Factors affecting PFS in 71 patients with vestibular
schwannomas treated with GKS*
p Value
Factor
FIG. 1. Graph demonstrating a Kaplan–Meier curve of PFS in 73
patients with vestibular schwannomas treated using GKS.
tained. At the last follow up, 48 patients (68%) had partial
tumor remission, 14 (20%) had tumors that remained stable, and nine (13%) experienced treatment failure—tumor
enlargement (7%) in five patients and radiation-induced
edema (6%) requiring surgical resection in three patients
and causing death in one patient. In the nine patients with
treatment failure, the time to therapeutic failure following
GKS varied from 3 to 27 months. Actuarial 10-year PFS
was 87% (Fig. 1). In the univariate analysis, tumor volume
(p = 0.0013), number of isocenters (p = 0.028), tumor type
(p = 0.035), and prior treatment (p = 0.037) affected PFS
significantly. In the multivariate analysis, only tumor volume (p = 0.0054; Fig. 2) remained significant (Table 4).
Of 31 patients who had undergone follow up at our institution, additional tumor shrinkage occurred in 26 (84%),
according to the last MR image obtained immediately after
GKS compared with that obtained 5 years after GKS (Fig.
3). Although several patients showed slight tumor expansion at 5 years after GKS, the tumor size had decreased 10
years after GKS with no additional treatment (Fig. 4). No
patient with tumor control at the 5-year follow up experienced tumor recurrence thereafter.
Salvage Treatment
Of 73 patients, 11 (15%) underwent additional treatment
No. of
Patients
10-Year
PFS (%)
25
46
92
85
58
13
88
83
52
19
92
74
38
33
95
78
57
14
93
64
36
35
80
94
45
26
82
96
25
46
76
93
sex
male
female
age (yrs)
,65
$65
prior treatment
no
yes
tumor type
A
B
tumor volume (cm3)
,10
$10
max dose (Gy)
,28
$28
tumor margin dose (Gy)
,15
$15
no. of isocenters
,5
$5
Univariate
Analysis
Multivariate
Analysis
0.4410
NT
0.6860
NT
0.0369†
0.2042
0.0354†
0.3322
0.0013†
0.0054†
0.0795
0.1293
0.0954
0.3065
0.0278†
0.5496
* NT = not tested.
† Significant difference at p , 0.05.
following GKS. Seven patients underwent craniotomy—
three despite an unchanged tumor volume or only a slight
tumor expansion 19, 28, and 56 months after GKS. Four
patients underwent a second GKS session 24, 27, 32, and
38 months after the first procedure. Among these four,
three patients demonstrated tumor shrinkage and one patient underwent a third GKS procedure 114 months and a
craniotomy 124 months after the first GKS. Nine patients
(12%) had hydrocephalus requiring placement of a ventriculoperitoneal shunt (mean tumor volume 12.7 cm3, range
1.5–41.2 cm3).
Hearing Preservation
Both pre- and postradiosurgical hearing function based
on the Gardner–Robertson classification are featured in Table 2. Audiometric evaluations were conducted in 69 patients. In four patients, a hearing test was not performed or
could not be assessed due to early tumor resection. Nineteen
patients (28%) had useful hearing before treatment. After
GKS, hearing function was unchanged in 47 patients (68%)
and had deteriorated in 22 (32%); no patient had improved
hearing after GKS. Of the 19 patients with useful hearing
before GKS, useful hearing was preserved in seven (37%).
Other Complications
FIG. 2. Graph of Kaplan–Meier curves showing actuarial PFS in
a comparison between patients with tumor volumes greater than or
equal to 10 cm3 and those with tumor volumes less than 10 cm3.
12
Eight patients (11%) suffered persistent (five patients) or
transient (three patients) facial palsy 6 to 15 months after
GKS. Six patients (8%) developed facial numbness 6 to 13
months after GKS. This numbness was transient in two paJ. Neurosurg. / Volume 102 / January, 2005
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Gamma knife surgery for vestibular schwannomas
FIG. 3. Axial contrast-enhanced MR images revealing a right vestibular schwannoma at the time of GKS (A), tumor regression 5 years post-GKS (B), and additional tumor regression 10 years post-GKS (C).
tients. One patient (1%) had facial spasm. Malignant transformation occurred in no one.
Discussion
Tumor Control
In this study, the tumor control rate (partial remission or
stable) was 87% 10 years after GKS. Compared with the
results in other reports, this rate seems a little low for vestibular schwannomas treated using GKS. Note, however, that
these lesions occurred in patients who were treated in the
early days of GKS. Until 1996 we used the KULA system.
Now we use GammaPlan software (Elekta Instruments) so
that axial images can be reformatted into coronal and sagittal ones, thus helping to make more conformal plans. In
five of nine patients whose tumor did not respond to treatment, the lesion volume was greater than 15 cm3. Two
patients harbored a vestibular schwannoma larger than 30
cm3, which caused compression of the brainstem together
with marked deviation of the fourth ventricle at the time of
GKS. Consequently, they demonstrated neurological deterioration due to severe radiation-induced edema and underwent craniotomy 3 and 11 months after GKS. Another
FIG. 4. Axial contrast-enhanced MR images demonstrating a left vestibular schwannoma at the time of GKS (A), slight
tumor expansion 5 years post-GKS (B), and tumor regression 10 years post-GKS without further treatment (C).
J. Neurosurg. / Volume 102 / January, 2005
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FIG. 5. Axial (A) and coronal (B) contrast-enhanced MR images exhibiting a vestibular schwannoma larger than 20 cm3
at the time of GKS. Axial contrast-enhanced image (C) displaying central necrosis of the tumor, and axial T2-weighted image (D) revealing severe radiation-induced edema 17 months after GKS.
patient whose tumor volume was greater than 20 cm3 developed radiation-induced edema and died 19 months after
GKS (Fig. 5). Analysis of these results indicates that tumors
larger than 20 cm3 were not suitable for GKS and that resection instead should have been performed.18,28,32 Actuarial 10year PFS in patients whose tumor volume was less than 10
cm3 was 93%. Considering tumor diameter on MR images as an indication for GKS, treatment failure occurred in
four of 50 patients with a mean tumor diameter of less than
2.5 cm, in none of 13 patients with a lesion diameter 2.5 to
3 cm, and in five of eight patients with a tumor diameter
greater than 3 cm. In patients with a mean tumor diameter
of more than 3 cm, the actuarial 10-year PFS was only 38%
compared with 93% in patients with a lesion diameter less
than 3 cm (p , 0.0001).
It is crucial to select patients who are suitable candidates
for GKS. At present, we assert that GKS is appropriate in
treating vestibular schwannomas less than 3 cm in mean di14
ameter or less than 15 cm3 in volume. Larger tumors causing symptomatic compression of the brainstem should be
surgically removed first, and then residual or recurrent tumor can be managed with GKS. Four patients underwent a
second GKS session 24, 27, 32, and 38 months after the first
procedure. Tumor remission occurred in three of these patients. One patient underwent a third GKS 114 months after
the first procedure and a tumor resection at 125 months. In
instances of initial treatment failure, the second GKS appeared to be as effective as the first procedure, although one
should take care to avoid radiation injury. Fortunately, none
of the patients in our study showed any new neurological
deterioration after the second procedure.
In the early era of radiosurgery, three patients underwent
craniotomy following GKS despite an unchanged or slight
increase in tumor volume. It is not uncommon for a tumor
temporarily to expand slightly with central necrosis before
tumor shrinkage.13,14 Such a change usually occurs within 3
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years after GKS, but should not be considered to indicate
treatment failure. At 3 years after GKS, the patients’ referring doctors decided to perform a resection because they did
not understand the biological process that would likely lead
to later tumor regression.
In this study, all treatment failures demonstrated on MR
images occurred within 3 years after GKS and salvage treatments were performed within 5 years. Compared with MR
images obtained 5 years after GKS, those obtained 10 years
after demonstrated further tumor shrinkage in most cases
(84%). Among patients with good tumor control by 5 years
post-GKS, none demonstrated tumor recurrence after that.
This result indicates that GKS remains effective more than
5 years after the procedure and that this time may be considered an end point of follow up. Noren20 and colleagues21
found that all vestibular schwannomas considered to be under control 5 years after GKS remained so after 20 years.
Similarly, Kondziolka, et al.,13 reported long-term outcomes
in 162 patients with 5 to 10 years of follow up. These investigators also determined that no treatment failure occurred
in any patient after 3 years following GKS. Recently, Kondziolka, et al.,14 reported long-term results of more than 10
years for benign intracranial tumors in 285 patients, demonstrating that GKS provided high tumor control rates and
low morbidity rates over the long term. They also showed
that the 10-year actuarial tumor control rate for vestibular
schwannomas was 97%. These reports were consistent with
our findings.
Some researchers have been concerned about long-term
outcomes in patients with benign tumors after treatment
with GKS, because there has been no evidence that radiosurgery can prevent tumor growth over the long term. This
concern has particularly been raised regarding younger patients. Although tumors can recur more than 10 years after
GKS, they can also recur following resection.1,17,27
Among patients who had undergone GKS in this study,
hydrocephalus occurred in nine. The mean tumor volume in
these patients was 12.7 cm3, and the tumor compressed the
brainstem in six patients. Hydrocephalus is more likely to
occur in patients with larger tumor volumes (p = 0.26, Fisher exact test), although the number of patients was too small
to prove this trend conclusively.
Functional Results
Recently there has been a trend of patients having useful
hearing when the vestibular schwannoma is diagnosed. In
these cases, treatment options include microsurgery, radiosurgery, fractionated radiotherapy, or observation.12,15,18,28,32,33
The choice of treatment remains controversial. According to an analysis of conservative management, the majority of vestibular schwannomas grow slowly but eventually
require intervention. As a result, one third of patients lose
useful hearing and more than 70% lose their eligibility for
tumor removal with hearing preservation.33 Although microsurgery can often be used to remove the tumor completely, this procedure frequently resulted in hearing loss or
facial palsy despite recent improvements in microsurgical
techniques.12,26,31 Moreover, severe morbidity or death was
not completely eliminated.27 Therefore, stereotactic radiosurgery has been established as a therapeutic alternative.
According to data in recent publications, hearing is preserved at a rate of approximately 40 to 70% following reJ. Neurosurg. / Volume 102 / January, 2005
duced-dose radiosurgery.3,11,24,26 The variance in these rates
depends heavily on patient selection. Iwai, et al.,11 reported
that hearing was preserved in 56% of patients with preradiosurgically useful hearing who had been treated with
a low dose of 8 to 12 Gy to the tumor margin. Nine percent of patients had improved hearing. Flickinger, et al.,3 reported that hearing was preserved in 74% of patients with
useful hearing before surgery who received a mean dose of
13 Gy to the tumor margin. In this study of higher radiation
doses, the hearing preservation rate in patients with previously useful hearing was 37% and no patient had improved
hearing function. Persistent or transient facial palsy developed in 11% of patients. These results seem to be worse
compared with those in other recent reports. This is not surprising, however, given that we used higher tumor margin
doses of 14 to 17 Gy for small lesions in the early days of
GKS, which emphasizes our learning curve in this setting.
Of 19 patients who had useful hearing before GKS, hearing
was preserved in seven and worsened in 12. Eleven of 12
patients with worsened hearing received a tumor margin
dose of more than 14 Gy. On the other hand, six of seven patients with preserved hearing received a tumor margin
dose of 13 Gy or less. A tumor margin dose of 13 Gy or less
led to a significantly better rate of hearing preservation (p =
0.0017, Fisher exact test). Niranjan, et al.,19 reported useful hearing in 10 of 10 patients who had received a tumor
margin dose of 14 Gy or less but in only one of five patients who had received more than 14 Gy. At present, we
use a reduced tumor margin dose of 11 to 13 Gy regardless
of hearing function. In addition, we use multiple isocenters
to make a more conformal dose plan with thin-sliced MR
images. With these refinements, we are able dramatically
to reduce complications such as hearing deterioration, facial numbness, facial palsy, or radiation-induced edema.
Currently, our rate of facial palsy is close to zero. With the
introduction of the new gamma knife (model C) with its automatic positioning, which makes it easier to make a more
conformal plan with an increased number of isocenters, further reductions in complication rates are expected.8,25 Nonetheless, it will be necessary to follow up patients treated
using a reduced radiation dose to make sure of the efficacy
at 10 years.
Conclusions
Gamma knife surgery remained effective for more than
10 years in the majority of patients harboring a vestibular
schwannoma, indicating that radiosurgery can be an acceptable alternative to resection in selected patients. No patient
had developed delayed malignant transformation during the
time of this study. No patient with good tumor control after 5 years following GKS developed tumor recurrence or
underwent further treatment. These results may indicate
that an acceptable end point for follow up of a vestibular
schwannoma treated using GKS is 5 years. Regardless, we
will continue to follow up our patients as we learn more
about even longer-term outcomes.
Acknowledgment
We are grateful to Douglas Kondziolka, M.D., M.Sc., F.R.C.S.
(C), for his helpful comments.
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Manuscript received February 25, 2004.
Accepted in final form July 6, 2004.
Address reprint requests to: Toshinori Hasegawa, M.D., Department of Neurosurgery, Komaki City Hospital, Gamma Knife Center,
1–20 Jobushi, Komaki, Aichi Prefecture 485–8520, Japan. email:
h-toshi@komakihp.gr.jp.
J. Neurosurg. / Volume 102 / January, 2005