Accelerator-Based Stereotactic Radiosurgery for Brainstem Metastases

Abstract

Stereotactic radiosurgery represents a noninvasive alternative treatment for intracranial metastases.
To investigate the treatment outcome of linear accelerator-based stereotactic radiosurgery (linac-SRS) for brainstem metastases.
We retrospectively reviewed our database of patients who were diagnosed with brainstem metastases and underwent linac-SRS between 1997 and 2008 at the University of California, Los Angeles.
A total of 45 patients with 48 brainstem metastases were treated. The median target volume was 0.40 mL (range, 0.02-5.70 mL), and median prescription dose was 14 Gy (range, 10-17 Gy) at 90% isodose curve. The median survival time was 11.6 months. Longer survival time was associated with higher Karnofsky performance status. The local control rate was 92% at 6 months and 88% at 1 year. Univariate analysis demonstrated a significant relationship between local control and tumor volume (≤0.4 mL vs >0.4 mL, P = .023) and SRS mode (conventional circular arc vs dynamic conformal arc, P = .044). There was a trend toward improved local control and prescription dose >14 Gy (P = .059). Two patients had brainstem complications following treatment, and the complication rate was 4.7% at 2 years. Serious morbidity occurred with 17 Gy.
Linac-SRS using a median dose of 14 Gy provided excellent local control in patients with brainstem metastases less than 0.4 mL with relatively low serious morbidity. The results of the study support the use of linac-SRS for patients with brainstem metastases. We advocate 14 to 16 Gy, given the high local control rate and low complication rate with this dose.

Full text

Accelerator-Based Stereotactic Radiosurgery for
Brainstem Metastases
BACKGROUND: Stereotactic radiosurgery represents a noninvasive alternative treat-
ment for intracranial metastases.
OBJECTIVE: To investigate the treatment outcome of linear accelerator-based stereo-
tactic radiosurgery (linac-SRS) for brainstem metastases.
METHODS: We retrospectively reviewed our database of patients who were diagnosed
with brainstem metastases and underwent linac-SRS between 1997 and 2008 at the
University of California, Los Angeles.
RESULTS: A total of 45 patients with 48 brainstem metastases were treated. The median
target volume was 0.40 mL (range, 0.02-5.70 mL), and median prescription dose was 14
Gy (range, 10-17 Gy) at 90% isodose curve. The median survival time was 11.6 months.
Longer survival time was associated with higher Karnofsky performance status. The local
control rate was 92% at 6 months and 88% at 1 year. Univariate analysis demonstrated
a significant relationship between local control and tumor volume (#0.4 mL vs .0.4 mL,
P= .023) and SRS mode (conventional circular arc vs dynamic conformal arc, P=.044).
There was a trend toward improved local control and prescription dose .14 Gy (P=.059).
Two patients had brainstem complications following treatment, and the complication rate
was 4.7% at 2 years. Serious morbidity occurred with 17 Gy.
CONCLUSION: Linac-SRS using a median dose of 14 Gy provided excellent local control
in patients with brainstem metastases less than 0.4 mL with relatively low serious
morbidity. The results of the study support the use of linac-SRS for patients with
brainstem metastases. We advocate 14 to 16 Gy, given the high local control rate and
low complication rate with this dose.
KEY WORDS: Brainstem metastases, Radiosurgery, Stereotactic radiosurgery
Neurosurgery 70:953–958, 2012 DOI: 10.1227/NEU.0b013e31823c40fe www.neurosurgery-online.com
Brainstem involvement occurs with an esti-
mated frequency of 3% to 7% in patients
with central nervous system metastases
from systemic malignancies.
1-3
Whole brain
radiation therapy (WBRT) with or without
neurosurgical intervention represents standard
therapy for patients with brain metastases.
However, brainstem metastases are not consid-
ered resectable. The use of WBRT has been the
mainstay of treatment and extends survival to
3 to 5 months.
4,5
WBRT results in inevitable alopecia and late
brain toxicities, which range in severity from mild
deficits in cognitive dysfunction to overt dementia
in up to 11%.
6-8
Stereotactic radiosurgery (SRS)
delivers a single large fraction of radiation to
a well-defined small intracranial target with very
steep peripheral dose falloff. SRS represents
a noninvasive alternative treatment for intracra-
nial metastases that is not associated with alopecia
or neurocognitive impairment.
9,10
Several authors have documented local con-
trol rates of 77% to 100% following gamma
knife radiosurgery (GKS) for brainstem
metastases.
1-3,11-14
We report the first study
of linear accelerator-based SRS (linac-SRS) for
brainstem metastases.
Chun-Shu Lin, MD*‡
Michael T. Selch, MD‡
Steve P. Lee, MD‡
Jeffrey K. Wu, MD‡
Furen Xiao, MD§
David S. Hong, MD‡
Chien-Hua Chen, MDk
Aamir Hussain, MD‡
Percy P. Lee, MD‡
Antonio A. De Salles, MD,
PhD§
*Department of Radiation Oncology,
Tri-Service General Hospital, National
Defense Medical Center, Taipei, Taiwan;
‡Department of Radiation Oncology,
David Geffen School of Medicine,
University of California, Los Angeles,
California; §Department of Neurosur-
gery, David Geffen School of Medicine,
University of California, Los Angeles,
California; kDepartment of Neurosur-
gery, Taichung Veterans General Hos-
pital, Taichung, Taiwan
Correspondence:
Chun-Shu Lin, MD,
Department of Radiation Oncology,
Tri-Service General Hospital,
No.325, Sec. 2, Chenggong Rd,
Neihu Dist., Taipei City 114, Taiwan.
E-mail: chunshulin@gmail.com
Received, April 26, 2011.
Accepted, September 21, 2011.
Published Online, October 12, 2011.
Copyright ª2011 by the
Congress of Neurological Surgeons
ABBREVIATIONS: CCA, conventional circular arc;
CR, complete response; DCA, dynamic conformal
arc; GKS, gamma knife radiosurgery; KPS, Karnof-
sky performance status; linac, linear accelerator;
NR, no change; PR, partial response; RPA, recursive
partitioning analysis; SRS, stereotactic radiosur-
gery; WBRT, whole brain radiation therapy
RESEARCH—HUMAN—CLINICAL STUDIES
TOPIC RESEARCH—HUMAN—CLINICAL STUDIES
NEUROSURGERY VOLUME 70 | NUMBER 4 | APRIL 2012 | 953
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METHODS
We retrospectively reviewed our database of patients who were
diagnosed with brainstem metastases and treated with linac- SRS between
1997 and 2008 at the University of California, Los Angeles. Patients with
both newly diagnosed and recurrent brainstem metastases were included.
SRS was offered as a treatment option either as an initial treatment, a boost
in conjunction with WBRT, or in the salvage setting after failed WBRT.
Recursive partitioning analysis (RPA) was recorded for all patients.
15
Patient characteristics, neurological symptoms, Karnofsky performance
status (KPS), and tumor volume were all encoded before SRS and at each
return visit. This study was approved by the University of California, Los
Angeles institutional review board.
A dedicated linac-SRS (Novalis, BrainLAB GmbH, Heimstetten,
Germany) was installed in 1997.
16
This system consists of a 6-MeV
electron linac coupled to a miniature multileaf collimator that is
mounted permanently to the linac. It can operate in several modes,
and conventional circular arc (CCA) SRS and dynamic conformal arc
(DCA) SRS were used in this series. DCA-SRS technique uses multiple
arcs rotating about a single isocenter. With the use of the a miniature
multileaf collimator to define its shape, the beam conforms to the target
volume with every 10 degrees of arc. The dose output with arc mode is
between 0.3 cGy/degree and 20 cGy/degree. The rotational accuracy of
the couch and gantry is less than 0.40 mm.
On the SRS day, local anesthesia was administrated and a Brown-
Roberts-Wells stereotactic head frame was applied. Computed tomography
(CT) and gadolinium-enhanced magnetic resonance imaging (MRI) were
performed for treatment planning. The gross tumor volume was defined by
gadolinium-enhanced T1-weighted MRI sequence. The margins were 1 to
2 mm for creation of the planning target volume. Treatment planning was
performed by using BrainScan version 4.0 treatment-planning software
(BrainLAB GmbH, Heimstetten, Germany). The prescription dose was set
at the 90% isodose curve for all patients.
Patients were followed with gadolinium-enhanced MRI every 3 months
when possible and regular clinical examinations. Lesions were measured on
the MRI scan in the anterior-posterior, transverse, and vertical dimensions,
and the product of these 3 dimensions was used to estimate the tumor
volume.Tumor response of thebrainstem lesions after SRS wasevaluated by
the use of serial MRIscans. Complete disappearance of the brainstem lesion
was defined as a complete response (CR), 50% decrease of tumor volume as
a partialresponse (PR), and ,50% decrease, no change, or ,25% increase
in tumor volume as no response (NR). We also defined a treatment failure
as 25% increase in tumor volume of the brainstem lesion.
3,12
Local control
was defined as stabilization or improvement of the treated lesion (CR, PR,
or NR). Symptomatic brainstem necrosis and hemorrhage were designated
as treatment-related complications.
All statistical analysis was performed using SPSS 16.0 software. Survival
time and local control were computed from the date of SRS by the use of
the Kaplan-Meier method. Prognostic factors were evaluated by using the
log-rank test. The significance of various factors was further analyzed with
the use of the Cox regression model. An a-error of .05 was chosen for
statistical significance.
RESULTS
A total of 45 patients with 48 brainstem metastases were
included in this study (1 patient presented with 2 lesions, and
another patient had 3 lesions) (Table 1). There were 16 men and
29 women ranging in age from 21 to 84 years (mean, 59.9 years).
The median KPS was 80 (range, 20-100). Four patients (9%)
were RPA class 1, 29 (64%) were RPA class 2, and 12 (27%) were
RPA class 3 at the time of SRS. Twenty-nine patients (64%) had
neurological symptoms at the time of diagnosis of brainstem
metastasis. The primary malignancy was breast cancer in 15
patients (33%), non–small-cell lung cancer in 13 patients (29%),
renal cell carcinoma in 5 patients (11%), melanoma in 3 patients
(7%), and other malignancies in 9 patients (20%). Eleven
patients (24%) had a single brain metastasis, and the remaining
34 patients (76%) had multiple brain metastases. The median
metastases number for the 34 patients with .1 lesion was 6
(range, 1-15). SRS was used as the first local treatment in 24
patients (53%), as a planned boost in conjunction with WBRT in
4 (9%), and in the salvage setting after failed WBRT in 17
(38%). The median dose of WBRT was 37.5 Gy. Thirty-five
lesions (73%) were located in the pons, 7 (15%) in the midbrain,
and 6 (12%) in the medulla oblongata.
Twenty-five patients with 26 lesions (54%) were treated with
CCA-SRS, and 20 patients with 22 lesions (46%) were treated
with DCA-SRS. The mean and median target volume was 0.9 mL
TABLE 1. Summary of Patient and Treatment Variables
a
Characteristic Value
Patients, n 45
Brainstem metastases, n 48
Sex, n
Male 16
Female 29
Mean age, y (range) 59.9 (21-84)
Median KPS score (range) 80 (20-100)
RPA
Class 1 4
Class 2 29
Class 3 12
Histological type
Breast cancer 15
Non–small-cell lung cancer 13
Renal cell cancer 5
Melanoma 3
Other 9
Prior radiotherapy, n 21
Location of brainstem metastases, n
Midbrain 7
Pons 35
Medulla oblongata 6
SRS mode
CCA mode 26
DCA mode 20
Median tumor volume, mL (range) 0.40 (0.02-5.70)
Median marginal dose in Gy (range) 14 (10-17)
a
KPS, Karnofsky performance status; RPA, recursive partitioning analysis; CCA,
conventional circular arc; DCA, dynamic conformal arc; SRS, stereotactic
radiosurgery.
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and 0.40 mL, respectively (range, 0.02-5.70 mL). The median
prescription dose was 14 Gy (range, 10-17 Gy) at the 90% isodose
curve. The mean arc number for each lesion was 6 (range, 4-18).
To date, 7 patients have been lost to follow-up, 36 patients are
known to have died, and 2 patients are still alive. The median survival
time was 11.6months (Figure 1) and follow-up time was 26.0 and
41.2 months for the 2 surviving patients. Univariate analyses
demonstrated that only higher KPS was significantly associated
with longer survival time. The median survival duration was 10.7
months for patients with KPS ,80 compared with 14.2 months
for those with KPS $80 (P= .002). Survival time was not
associated with sex (P= .603), age (P= .589), RPA classes
(P= .098), extracranial disease control (P= .781), primary tumor
location (P= .292), local brainstem tumor control (P= .186), single
or multiple brain metastases (P= .956), previous brain irradiation
(P= .993), or the sequence of SRS and WBRT (P=.722).
Three patients with 4 metastases died less than 3 months after
SRS and did not have follow-up imaging. Follow-up imaging was
available for 44 lesions in 42 patients, performed an average of
7.6 months (range, 1-37.1 months) after SRS. Among these 42
patients, 10 underwent a single follow-up MRI 2 to 3 months after
treatment. Nine lesions had CR, 18 PR, 13 NR, and 4 treatment
failure. Accordingly, 40 of the 44 available lesions remained
controlled, yielding a crude local control rate of 91%. The local
control probability was 92% at 6 months and 88% at 1 year, with
a median local control rate not reached (Figure 2). Univariate
analysis demonstrated a significant relationship between local
control and tumor volume (#0.4 mL vs .0.4 mL, P= .023)
(Figure 3), and SRS mode (CCA vs DCA, P= .044). There was
a trend toward improved local control and prescription dose .14
Gy (P= .059) (Figure 4). On multivariate analysis, no variables
were found significant.
Treatment-related complications occurred in 2 patients, and
the complication rate was 4.7% at 2 years (Figure 5). One
patient developed radiation necrosis of the brainstem lesion
6 months after SRS. The diagnosis was determined by
clinical presentation and radiographic appearance. The
patient had worsening of a preexisting trigeminal nerve deficit
following SRS of a 1.2 cm (1.76 mL) lesion with 17 Gy
prescribed at the 90% isodose. This was the highest dose
utilized in this study. Another patient had new-onset facial
palsy 1 month following SRS of a 0.7 cm (0.18 mL) lesion
FIGURE 1. Kaplan-Meier curve showing patient survival after radiosurgery.
The median survival time was 11.6 months.
FIGURE 2. Kaplan-Meier curve showing the local control rate after radio-
surgery. The local control probability was 92% at 6 months and 88% at 1 year,
with a median local control rate not reached.
FIGURE 3. Kaplan-Meier curves showing the relationship between local control
and tumor volume. Regarding local control, smaller brainstem tumor benefited
from radiosurgery treatment (#0.4 mL vs .0.4 mL, P= .023).
ACCELERATOR-BASED SRS FOR BRAINSTEM METASTASES
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with 12 Gy prescribed at the 90% isodose. The lesion was in
the facial nerve nucleus.
DISCUSSION
SRS has emerged as a viable treatment option for patients with
brain metastases. The results of this retrospective review demon-
strate that the outcome following linac-SRS for metastases
affecting the brainstem is equivalent to that following GKS.
After a median follow-up of 11.6 months, the crude local
control rate in our series was 91%, a result equal to GKS series
(Table 2). Shuto et al
12
treated 25 patients with 31 brainstem
tumors with GKS. The mean prescription dose to the tumor
margin was 13.0 Gy, and the local control rate was 77.4%. Kased
et al
3
reviewed 42 patients with 44 brainstem metastases that had
GKS. The median dose was 16.0 Gy and the crude local control
rate was 85%. Yen et al
13
reported 53 patients with 53 metastatic
brainstem lesions that underwent GKS. The mean prescription
dose was 17.6 Gy, and the local control rate was 87%. Fuentes
and colleagues
1
treated 28 patients, and 28 brainstem lesions
were irradiated with GKS. The mean marginal dose was 19.6 Gy,
and the crude local control rate was 92%. Huang et al
11
reported
the outcomes after GKS in 26 patients with 27 brainstem
metastases. The median dose to the tumor margin was 16 Gy,
and the local control rate in brainstem tumors was 95%.
Lorenzoni et al
14
reported 25 patients with 27 brainstem
metastases treated with GKS. The mean marginal dose was
20 Gy, and the local control rate was 95%. Hussain et al
2
retrospectively analyzed the outcome of brainstem metastases
treated by GKS. Twenty-two patients with 25 brainstem lesions
were treated. The median marginal dose was 16 Gy, and the local
control was 100%.
In our series, only tumor size was predictive of local control rate.
Kim et al
17
analyzed 53 patients with 121 metastatic brain lesions
treated by GKS. The 1-year actuarial local control rate was 48%.
Smaller volume and nonrenal cell carcinoma were associated with
better local control. Sheehan et al
18
reviewed 273 patients with
non–small-cell lung cancer who had undergone GKS to treat 627
brain metastases. Factors affecting local tumor control included
tumor volume and treatment dose.
However, there is a bias for comparison between our study and
GKS series. Table 2 showed that the median volume in the
majority of GKS series was at or above 1 mL, whereas the volume
in our study was 0.4 mL. Shaw et al
19
analyzed Radiation
Therapy Oncology Group protocol 90-05 and compared GKS
with linac-SRS. He claimed that local control was superior for
GKS compared with linac. The differences may be volume
related, and this was not mentioned in his report. Our linac-SRS
results are not in agreement for lesions in the brainstem. Shaw
et al stated that, although GKS treatments tended to be more
conformal than those on the linac-SRS, this is unlikely to
account for the difference in local control. Our series also implies
there is no disadvantage to homogeneity compared with GKS
inhomogeneity.
Prescribed dose had no impact on local control in our study.
This may be due to the small patient population, few local
relapses, or narrow range of applied doses in our experience. In
GKS series, several authors reported dose-response data for brain
metastases.
3,12,18,20
Shuto et al
12
reported a significant corre-
lation between the marginal dose delivered and the effect on
neuroimaging. Kased et al
3
stated that a dose of less than 16 Gy
was associated with a significantly higher risk of tumor
progression. He recommended a median dose of 16 Gy
provided excellent local control with relatively low morbidity
FIGURE 4. Kaplan-Meier curves showing the relationship between local control
and prescription dose. There was a trend toward improved local control and
prescribed dose .14 Gy (P= .059).
FIGURE 5. Kaplan-Meier curve showing the complication rate after radio-
surgery. The complication rate was 4.7% at 2 years.
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in patients with brainstem metastases less than 1 mL or
nonmelanoma, nonrenal cell histology. In Sheehan’sseries,
627 brain metastases were reviewed, and higher treatment
isodose correlated in a significant fashion with local tumor
control.
18
Shiau et al
20
studied 261 brain lesions treated in 119
patients, and longer local control was significantly associated
with higher prescribed dose.
In our experience, serious morbidity occurred with 17 Gy.
Hussain et al
2
reported pontine injury after 18 Gy. Other GKS
investigators, however, reported safe delivery with 17.6 to 20 Gy
to brainstem lesions. We advocate 14 to 16 Gy given the high
local control rate and low complication rate with this dose.
CONCLUSION
Linac-SRS with the use of a median dose of 14 Gy provided
excellent local control with relatively low serious morbidity in
patients with brainstem metastases less than 0.4 mL. The results of
the study support the use of linac-SRS for patients with brainstem
metastases. SRS alone can be considered for solitary brainstem
metastasis. The rarity of complications precludes analysis of
predictive factors, particularly the possible influence of prior
WBRT, treatment isodose, prescribed dose, and tumor size. In our
experience, serious morbidity occurred with 17 Gy. We advocate
14 to 16 Gy given the high local control rate and low complication
rate with this dose.
Disclosure
The authors have no personal financial or institutional interest in any of the
drugs, materials, or devices described in this article.
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TABLE 2. Summary of Published Reports of Stereotactic Radiosurgery for Brainstem Metastases
a
Authors Year
Treatment
Modality
Mean
Age, y
Patients/
Lesions,
n
Median
Target
Volume, mL
Median
Dose,
Gy
Local
Control,
%
Median
Survival,
mo
Symptomatic
SRS-Related
Toxicity, %
Factors Predictive
of Improved Local
Control
Huang et al
11
1999 GKS 56 26/27 1.1 16 95 9 0 -
Shuto et al
12
2003 GKS 57.1 25/31 2.1 (mean) 13 (mean) 77 4.9 8 Radiation dose
Fuentes et al
1
2006 GKS 57.7 28/28 2.1 (mean) 19.6 (mean) 92 12 0 -
Yen et al
13
2006 GKS 57.3 53/53 2.8 (mean) 17.6 (mean) 87 11 0 -
Hussain et al
2
2007 GKS 60 (median) 22/25 0.9 16 100 8.5 5 -
Kased et al
3
2007 GKS 55 (median) 42/44 0.26 16 85 9 10 Nonmelanoma or radiation dose
Lorenzoni et al
14
2008 GKS 54 25/27 0.6 (mean) 20 (mean) 95 11.1 0 -
Present study 2011 Linac- SRS 59.9 45/48 0.4 (mean, 0.9) 14 91 11.6 4 Smaller tumor volume
a
GKS, gamma knife radiosurgery; SRS, stereotactic radiosurgery; Linac, linear accelerator.
ACCELERATOR-BASED SRS FOR BRAINSTEM METASTASES
NEUROSURGERY VOLUME 70 | NUMBER 4 | APRIL 2012 | 957
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11. Huang CF, Kondziolka D, Flickinger JC, Lunsford LD. Stereotactic radiosurgery
for brainstem metastases. J Neurosurg. 1999;91(4):563-568.
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20. Shiau CY, Sneed PK, Shu HK, et al. Radiosurgery for brain metastases:
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COMMENT
Stereotactic radiosurgery (SRS) for patients with metastatic brain
disease is one of the most well-studied procedures performed by
neurosurgeons. In addition to the vast amount of information available
from retrospective studies on this topic, a number of randomized clinical
trials (RCTs) have been conducted which show that SRS improves local
tumor control when given in addition to whole brain radiation therapy
(WBRT),
1
provides survival benefit for patients with a single tumor
when given in addition to WBRT,
2
and had similar survival periods
when SRS was used alone compared with SRS and WBRT for patients
with 1 to 4 brain metastases.
3
Of note, the omission of WBRT is
associated with a higher rate of new tumor formation when SRS is
performed alone. However, because patients are typically eligible for
further treatments to treat tumor progression noted on follow-up
imaging after SRS, no survival benefit has been demonstrated by the
addition of WBRT to SRS alone. Based on these RCTs, there has been
a general movement toward using SRS alone for patients with newly
diagnosed brain metastases to eliminate the potential neurotoxicity that
has been associated with WBRT.
4
Because surgical resection and SRS have been proven to provide
survival benefit in comparison with WBRT alone, it has also
become apparent that patient selection for these procedures has the
greatest impact on overall survival time. The primary factors
impacting survival in most series are tumor histology, performance
status, and the extent of a patient’s systemic disease. Other factors
that may play a role in patient outcomes are age, number of
tumors, and tumor location. Gamma Knife SRS has been
demonstrated in multiple series to be safe and effective for
patients with brainstem metastases.
5
However, there are few
specific data of the usefulness of LINAC-based SRS for patients
with brainstem tumors. Moreover, patients with brainstem
metastases are excluded from participation in the ongoing
NCCTG N0574, a RCT in which a number of the participating
centers perform LINAC-based SRS. In the current study, the
authors report on 45 patients having LINAC-based SRS for
brainstem metastases. With the use of a median tumor margin
dose of 14 Gy, local tumor control (88% at 1 year) and
complications (4.7%) were similar to reports from Gamma Knife
centers. Median overall survival was 11.6 months, with longer
survival periods noted in patients with higher Karnofsky
performance status. The results show that LINAC-based SRS
can be safely performed for patients with brainstem metastases at
dedicated centers with experienced physicians and physicists.
Stereotactic radiosurgery should be considered the preferred
treatment for patients with brainstem metastases if they remain
active and have limited systemic disease.
Bruce E. Pollock
Rochester, Minnesota
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LIN ET AL
958 | VOLUME 70 | NUMBER 4 | APRIL 2012 www.neurosurgery-online.com
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