Linear accelerator-based stereotactic radiosurgery for brainstem metastases: the Dana-Farber/Brigham and Women's Cancer Center experience.

Abstract

To review the safety and efficacy of linear accelerator-based stereotactic radiosurgery (SRS) for brainstem metastases. We reviewed all patients with brain metastases treated with SRS at DF/BWCC from 2001 to 2009 to identify patients who had SRS to a single brainstem metastasis. Overall survival and freedom-from-local failure rates were calculated from the date of SRS using the Kaplan-Meier method. Prognostic factors were evaluated using the log-rank test and Cox proportional hazards model. A total of 24 consecutive patients with brainstem metastases had SRS. At the time of SRS, 21/24 had metastatic lesions elsewhere within the brain. 23/24 had undergone prior WBRT. Primary diagnoses included eight NSCLC, eight breast cancer, three melanoma, three renal cell carcinoma and two others. Median dose was 13 Gy (range, 8-16). One patient had fractionated SRS 5 Gy ×5. Median target volume was 0.2 cc (range, 0.02-2.39). The median age was 57 years (range, 42-92). Follow-up information was available in 22/24 cases. At the time of analysis, 18/22 patients (82%) had died. The median overall survival time was 5.3 months (range, 0.8-21.1 months). The only prognostic factor that trended toward statistical significance for overall survival was the absence of synchronous brain metastasis at the time of SRS; 1-year overall survival was 31% with versus 67% without synchronous brain metastasis (log rank P = 0.11). Non-significant factors included primary tumor histology and status of extracranial disease (progressing vs. stable/absent). Local failure occurred in 4/22 cases (18%). Actuarial freedom from local failure for all cases was 78.6% at 1 year. RTOG grade 3 toxicities were recorded in two patients (ataxia, confusion). Linac-based SRS for small volume brainstem metastases using a median dose of 13 Gy is associated with acceptable local control and low morbidity.

Full text

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CLINICAL STUDY – PATIENT STUDY
Linear accelerator-based stereotactic radiosurgery for brainstem
metastases: the Dana-Farber/Brigham and Women’s Cancer
Center experience
Paul J. Kelly•Yijie Brittany Lin•Alvin Y. C. Yu•
Alexander E. Ropper•Paul L. Nguyen•
Karen J. Marcus•Fred L. Hacker•Stephanie E. Weiss
Received: 21 October 2010/Accepted: 20 December 2010
? Springer Science+Business Media, LLC. 2011
Abstract
accelerator-based stereotactic
brainstem metastases. We reviewed all patients with brain
metastases treated with SRS at DF/BWCC from 2001 to
2009 to identify patients who had SRS to a single brain-
stem metastasis. Overall survival and freedom-from-local
failure rates were calculated from the date of SRS using the
Kaplan–Meier method. Prognostic factors were evaluated
using the log-rank test and Cox proportional hazards
model. A total of 24 consecutive patients with brainstem
metastases had SRS. At the time of SRS, 21/24 had met-
astatic lesions elsewhere within the brain. 23/24 had
undergone prior WBRT. Primary diagnoses included eight
NSCLC, eight breast cancer, three melanoma, three renal
cell carcinoma and two others. Median dose was 13 Gy
(range, 8–16). One patient had fractionated SRS 5 Gy 95.
Median target volume was 0.2 cc (range, 0.02–2.39). The
median age was 57 years (range, 42–92). Follow-up
information was available in 22/24 cases. At the time of
analysis, 18/22 patients (82%) had died. The median
overall survival time was 5.3 months (range, 0.8–21.1
months). The only prognostic factor that trended toward
statistical significance for overall survival was the absence
To review the safety and efficacy of linear
radiosurgery (SRS) for
of synchronous brain metastasis at the time of SRS; 1-year
overall survival was 31% with versus 67% without syn-
chronous brain metastasis (log rank P = 0.11). Non-sig-
nificant factors included primary tumor histology and
status of extracranial disease (progressing vs. stable/
absent). Local failure occurred in 4/22 cases (18%).
Actuarial freedom from local failure for all cases was
78.6% at 1 year. RTOG grade 3 toxicities were recorded in
two patients (ataxia, confusion). Linac-based SRS for small
volume brainstem metastases using a median dose of
13 Gy is associated with acceptable local control and low
morbidity.
Keywords
Metastasis ? Linear accelerator
Stereotactic radiosurgery ? Brainstem ?
Introduction
Brain metastases represent the most common intracranial
tumor in clinical practice, with an estimated annual inci-
dence of 200,000 cases in the United States. Brainstem
metastases are relatively uncommon, however, comprising
approximately 5% of brain metastases [1, 2]. Stereotactic
radiosurgery is a potentially important treatment modality
for brainstem metastases. The management of brainstem
metastases presents a unique therapeutic challenge. Surgi-
cal resection is not feasible in most instances due to
potentially significant morbidity. In the brainstem, both
uncontrolled tumor growth and stereotactic radiosurgery
have the potential to cause significant neurologic deficits.
This potential for morbitiy coupled with a concern
regarding possible increased radiosensitivity of brainstem
tissue this has led to the exclusion of brainstem metastases
from various radiosurgery clinical trials [3–5]. Data on the
P. J. Kelly (&) ? P. L. Nguyen ? K. J. Marcus ?
F. L. Hacker ? S. E. Weiss
Department of Radiation Oncology, Dana-Farber/Brigham
and Women’s Cancer Center, 75 Francis Street (ASB1-L2),
Boston, MA 02115, USA
e-mail: pkelly@lroc.harvard.edu
Y. B. Lin ? A. Y. C. Yu
Harvard Medical School, Boston, MA, USA
A. E. Ropper
Department of Neurosurgery, Brigham & Women’s Hospital,
Boston, MA, USA
123
J Neurooncol
DOI 10.1007/s11060-010-0514-0

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safety and efficacy of stereotactic radiosurgery in the
management of brainstem metastases is lacking therefore,
and relies on retrospective reports from single institutions
[6–14]. Nine previous reports have been published. All but
one utilized the Elekta Gamma Knife radiosurgical deliv-
ery system. Here we report the Dana-Farber/Brigham and
Women’s experience with stereotactic radiosurgery in the
treatment of single brainstem metastases. This is the only
the second reported experience of linear accelerator-based
radiosurgery for brainstem metastases.
Materials and methods
This retrospective study was approved by the Dana-Farber/
Harvard Cancer Center institutional review board. All
cases of stereotactic radiosurgery performed at Brigham
and Women’s Hospital between January 1st 2001 and
December 30th 2009 were reviewed to identify patients
who received stereotactic radiosurgery for a single brain-
stem metastasis. In total, 24 consecutive patients were
identified. Brainstem stereotactic radiosurgery was offered
predominantly as a salvage therapy following previous
whole brain radiotherapy (N = 20). However, less fre-
quently it was used as a boost in conjunction with whole
brain radiotherapy (N = 3) or as the upfront treatment in
patients who refused whole brain radiotherapy (N = 1).
The majority of patients (16/24) had brainstem metastases
detected on surveillance neuroimaging prior to developing
symptoms. Only 4 patients presented with symptoms
attributable to brainstem metastases (ataxia, ptosis, cranial
nerve III and IV palsies). Four other patients presented with
symptomatic brain metastases located outside of the
brainstem and had an incidental finding of a brainstem
metastasis on MRI.
Stereotactic radiosurgery was performed using the No-
valisTMlinear accelerator-based radiosurgery platform.
Until April 2009 all patients were immobilized using a
BRW (Radionics) stereotactic head frame. After April
2009 conventional frame-based radiosurgery at our insti-
tution was replaced by frameless delivery using the ther-
mosplastic BrainLAB cranial mask immobilization. A
clinical comparison at our institution of patient setup and
intra-fraction motion using frame-based radiosurgery ver-
sus frameless image-guided radiosurgery for intracranial
lesions has previously been reported [15]. The target vol-
ume was contoured on fused contrast-enhanced computed
tomography and magnetic resonance images in all cases.
No margin was added to the contrast-enhancing lesion to
define the planning target volume (PTV). Planning was
performed using the BrainLAB BrainSCANTMstereotactic
treatment planning software. A stereoscopic kilovoltage
X-ray system combined with infrared (IR) position tracking
(Initially ExacTrac version 3.5 later version 5.0 by Brain-
LAB) was used for patient localization.
As a balance between efficacy and risk of clinically
significant side effects our institutional standard would be
to prescribe radiosurgery doses to non-brainstem targets
marginally lower than those employed in the Radiation
Therapy Oncology Group 95-08 randomized trial. Owing
to concern regarding the risk of a potential neurologic
deficit following radiosurgery to the brainstem, the pre-
scription dose for radiosurgery was reduced compared to
non-brainstem targets. This would constitute a 20–25%
reduction on dose employed for non-brainstem targets.
Generally plans were normalized to between the 70 and
80% isodoses, but were optimized in individual cases. The
institutional practice is to aim for 99% coverage of the
target by the prescription doses. Conformity index defined
as the ratio of the volume enclosed by the prescription
isodose/planning target volume was calculated in all cases.
Homogeneity index defined as the ratio of the Dmax/pre-
scribed dose was also calculated in all cases.
Patients underwent a first follow-up MRI at 4–8 weeks
following radiosurgery. Many patients had serially MRI
scans at 3–4 month intervals. Lack of follow-up imaging in
certain cases was due to rapid clinical deterioration or a
wish to undergo follow-up at local institutions.
Overall survival and freedom-from local failure were
calculated from the date of radiosurgery using the Kaplan–
Meier method. Freedom-from local failure was defined as
an absence of progression on follow-up MRI studies and
would include complete response, partial response and
stable disease as defined the Response Evaluation Criteria
in Solid Tumors (RECIST) criteria [16]. Patients were
censored at the time of last clinical follow-up for esti-
mating overall survival and at the time of last MRI for
estimating freedom-from local progression. Prognostic
factors for overall survival were evaluated using the log-
rank test and Cox proportional hazards model. (Table 1)
Results
A total of 24 patients (10 males, 14 females) underwent
stereotactic radiosurgery at Brigham and Women’s Hos-
pital for a single brainstem metastasis during the 9 year
period included in this study. With respect to performance
status, all but one of the patients was self caring (Karnofsky
performance scoreC70%) at the time of radiosurgery. The
most frequent primary tumor histologies were non-small
cell lung carcinoma (n = 8) and breast carcinoma (n = 8).
Other primary tumors included melanoma (n = 3), renal
cell carcinoma (n = 3) and others (n = 2). Brainstem
metastases were located in the midbrain (n = 10), the pons
(n = 13) and the medulla (n = 1).
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Notably stereotactic radiosurgery was offered as a sal-
vage treatment following previous whole brain radiother-
apy in the vast majority of cases (n = 20). The median
dose of previously delivered whole brain radiotherapy was
35 Gy (range 30–40). 21/24 cases (87%) had at least 1
synchronous brain metastasis at the time of brainstem
radiosurgery.
The median prescription dose was 13 Gy (range 8–16),
with a mode of 12 Gy. One patient underwent fractionated
stereotactic radiosurgery 5 Gy 9 5. The median planning
target volume was 0.2 cm3(range 0.02–2.39). At least 98%
of the target was covered by the prescription isodose in all
cases. Median normalization was 73% (range 52–90%).
The median conformity and homogeneity indices were 1.71
and 1.39, respectively.
Follow-up imaging was available in 22/24 cases. At the
time of analysis 18/22 patients had died. Of those patients
who died, 15/18 died of progressive systemic disease.
Three deaths were due to progressive CNS disease,
including 2 cases of leptomeningeal dissemination. No
death was attributable to progressive brainstem disease.
The median overall survival following brainstem radio-
surgery was 5.3 months (range 0.8–21.1 months). At the
time of analysis the four surviving patients had been fol-
lowed for 5, 8, 14 and 21 months. Actuarial 1-year overall
survival was 29%. The only prognostic factor that trended
toward statistical significance for overall survival was the
absence of synchronous brain metastasis as the time of
radiosurgery (1-year overall survival with vs. without
synchronous brain metastasis was 31 vs. 67%, log-rank
P = 0.11). Non-significant factors included primary tumor
histology (P = 0.69) and status of extracranial disease,
progressing versus stable/absent (P = 0.41). Local failure
occurred as the site of first failure in 4/22 evaluable cases.
Isolated distant failure occurred in 13/22 evaluable cases,
while simultaneous local and distant failure occurred in
3/22 cases. Actuarial Freedom-From Local Failure was
88.2% at 6 months and 78.6% at 1 year.
Of the patients who presented with symptoms attribut-
able to brainstem metastasis (N = 4), two had symptom-
atic improvement following SRS (ataxia, ptosis). Two
patients had persistent cranial nerve deficits following SRS.
However, in follow-up only one patient developed symp-
toms related to local failure (gaze palsy).
RTOG grade 3 toxicities were recorded in two patients
(one patient developed ataxia 10 days post-radiosurgery,
which resolved with corticosteroids and a further patient
developed acute confusion 48 h following radiosurgery).
Both patients progressed at distant sites within the brain on
the first follow-up MRI. No late radiation side effects were
recorded.
Discussion
Conventional teaching is that the brainstem is more
radiosensitive than other regions of the brain [17, 18].
Evidence in support of this is lacking, however. This
conclusion is likely based on an early publication by Boden
[19], who reported a high incidence of radionecrosis after
Table 1 Patient and treatment plan characteristics
Characteristic Value (%)
Patients 24
Gender
Male 10
Female 14
Age (years)
Median57
Range 42–92
Karnofsky performance score (%)
Median80
Age60–100
Follow-up (months)
Median6.6
Range0–21.1
Primary tumor
Non-small cell lung carcinoma8
Breast carcinoma8
Melanoma3
Renal cell carcinoma3
Others2
Location
Midbrain10 (42)
Pons 13 (54)
Medulla
Prior whole brain radiation therapy1
1 (4)
23 (96)
Synchronous brain metastasis at time of SRS21 (87)
Dose (Gy)
Median13
Range
Planning target volume (cm3)
8–16
Median 0.2
Range
Conformity index2
0.02–2.39
Median1.81
Range
Homogeneity index3
1.36–2.6
Median 1.39
Range 1.22–1.92
aMedian dose 35 Gy (range 30–40 Gy)
bRatio of the volume enclosed by the prescription isodose/planning
target volume
cRatio of the Dmax/prescribed dose
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fractionated radiotherapy for nasopharyngeal or middle ear
tumors. It is likely that radiation injury to the brainstem is
more likely to result in clinically apparent toxicity than is
radiation injury to other locations within the brain given the
close aggregation of fiber tracts and cranial nerve nuclei.
Furthermore salvage surgery for radionecrosis secondary to
stereotactic radiosurgery is not usually a feasible option.
Corticosteroids form the mainstay of therapy in the event
of radionecrosis, although more recently vascular endo-
thelial growth factor inhibitors, such as bevacizumab, have
shown promise in this regard [20, 21]. It is, therefore, the
functional consequence of a complication that is the pri-
mary concern in delivering radiosurgery to brainstem
targets.
Reports on brainstem stereotactic radiosurgery can be
divided into treatment of intrinsic lesions, such as metas-
tases or vascular malformations, or extrinsic lesions, such as
acoustic neuromas. To date, a total of nine reports of
brainstem radiosurgery for metastases have been published
[6–14]. All reports reflect retrospective experience at single
institutions. All but one used the Gamma Knife radiosur-
gery delivery system. This is the second reported series of
stereotactic radiosurgery to brainstem metastases using
linac-based radiosurgery. From a toxicity standpoint, pre-
vious reports quote a 0–11% of severe or life-threatening
complications following radiosurgery. These results, in line
with ours, are comparable to reported rates in the two
radiosurgery randomized trials, which both excluded
brainstem lesions [4, 5]. However, all brainstem series are
limited by retrospective design and the fact that the likeli-
hood of observing late radiation injury in this patient pop-
ulation is limited by poor life expectancy. The recent
QUANTEC review of radiation associated brainstem injury
addressed studies of single-fraction brainstem radiosurgery
for both intrinsic and extrinsic lesions [22]. Most conclu-
sions were drawn from the largest study which reported the
incidence of cranial neuropathy following radiosurgery for
149 patients with vestibular schwannoma. Robust recom-
mendations regarding ‘safe’ dose limits are unavailable.
Whether radiosurgery to specific locations within the
brainstem are more likely to precipitate injury is unknown.
In a series of brainstem radiosurgery for arteriovenous
malformations, Maruyama et al. [23] reported that the risk
of neurologic complications was significantly associated
with tectal midbrain location, possibly related to the loca-
tion of multiple cranial nerve nuclei in this area. In our
series both grade 3 toxicities were observed in patients with
midbrain lesions, however, neither lesion was located in the
tectum. Sharma et al. [24] reported an 18.4% incidence of
new imaging findings, defined as adverse radiation imaging
effects (ARIEs) after brainstem radiosurgery to median
prescription dose of 15 Gy. All patients had non-malignant
diagnoses, predominantly vascular anomalies. ARIEs
appeared to have a linear relationship with marginal dose
escalation from 12 to 25 Gy. Unsurprisingly, the develop-
ment of adverse radiation effects on MRI correlated with
the new neurologic deficits. In contrast, 3 out of a total of 38
patients in this cohort developed new neurologic symptoms
in the absence of imaging abnormality, which highlights the
limited sensitivity of standard MRI sequences in detecting
all clinically significant effects of radiosurgery.
Owing to a balance between toxicity concerns and
expected efficacy we utilized lower median dose (13 Gy)
than previous reports (median dose range 15–20 Gy). It
should be noted that our series included a higher proportion
of patients who had undergone previous whole brain
radiotherapy (96% vs. 13.6–92.3% in prior reports). Current
practice in many radiosurgery centers would be to withhold
WBRT in the upfront management of patients with limited
numbers of brain metastases, owing to a concern regarding
neurocognitive side effects and the lack of a survival benefit
to the addition of WBRT to SRS in two randomized trials
[5, 25]. No firm recommendations exist regarding pre-
scription dose for patients who have not had prior WBRT,
although from the limited retrospective data available,
doses in the range of 15–16 Gy for lesions of volumes less
than 1 cc appear to be associated with a low risk of symp-
tomatic radionecrosis. However, life expectancy is likely to
influence the incidence of radionecrosis, with longer term
survivors at higher risk of late radiation side effects. Free-
dom-from local failure was comparable to previous reports
(78.6% vs. 77–100%). With a median target volume of
0.2 cm3, our cohort had smaller target volumes than all
previous reports, which may explain why the rate of local
control was not reduced by using a lower median dose. The
small volume of tumors in our series is likely reflectedin the
fact that only four patients presented with symptoms
attributable to their brainstem metastasis. 2/4 cases
improved symptomatically following SRS. Significantly,
only 1/4 cases of local failure developed a new symptom
related to progressive brainstem disease (gaze palsy).
Our study is limited by a small sample size and retro-
spective design, however, no prospective study on this
subject has been published. We believe our study demon-
strates the safety and efficacy of linear accelerator-based
radiosurgery as a salvage therapy for small volume
brainstem metastases following previous whole brain
radiotherapy. However, a single-arm prospective multi-
institutional protocol would better address the true inci-
dence of radiation injury.
Conclusion
In patients with good performance status (KPS[70%),
linear accelerator-based stereotactic radiosurgery, using a
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median dose of 13 Gy, as a salvage therapy for small
volume single brainstem metastases following previous
whole brain radiation therapy is associated with acceptable
rates of local control and acute side effects. Absence of late
radiation side effects may be a function of poor survival in
this population.
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