Brain metastases are the most common form of
brain tumor. Approximately 25% of patients with cancer develop
intracranial metastases. The incidence appears to have increased
during the past decade, perhaps because of increasing survival in
patients with better systemic treatment. Improved survival of
patients with intracranial metastatic disease may lead to a greater
incidence of neurocognitive deficits for long-term survivors.
Treatment options for patients with brain
metastases include medical management, surgical resection,
whole-brain irradiation (WBI), and stereotactic radiosurgery (SRS).
After resection of a brain
metastasis, adjuvant radiotherapy in the form of WBI decreased the
rate of local recurrence from 46% to 10% and elsewhere in the brain
from 37% to 14%. Should immediate WBI be deferred, the option
is retained to manage distant intracranial relapses with such
repeated local modalities as SRS and surgery or with salvage WBI.
To minimize the potential late effects of
WBI investigators explored the use of SRS alone, deferring the use
of WBI for salvage treatment if needed. Both retrospective analyses
and prospective trials reported no apparent survival benefit in
patients with brain metastases when WBI was combined with SRS as
opposed to using SRS alone.
Given the lack of a survival benefit for
using immediate WBI after resection or radiosurgery and the
potential late effects of WBI,
we generally deferred WBI in
patients locally treated with limited number of brain metastases.
However, recognizing the high local failure rate of surgical removal
alone, we used adjuvant SRS to the resection cavity. The purpose of
this retrospective review was to analyze the outcome in this patient
population.
Radiosurgical
technique
The
CyberKnife Robotic Radiosurgical System (Accuray) was used to
deliver radiosurgical treatments. In this frameless method, patients
were immobilized supine on the CyberKnife treatment table with an
Aquaplast mask (WFR/Aquaplast Corp., Wyckoff, NJ). A high-resolution
thin-slice (1.25-mm) computed tomogram was obtained by using a GE
Light Speed 8i or 16i Scanner (Milwaukee, WI) after administration
of 125 ml of Omnipaque intravenous contrast (iohexol, 350 mg I/ml;
Nycomed, Inc., Princeton, NJ). In selected patients, when resection
cavity borders or other intact metastases could not be well
visualized on computed tomographic (CT) imaging, a postcontrast
stereotactic magnetic resonance imaging (MRI) scan also was obtained
and fused to the stereotactic CT scan to improve target
identification. The acquired scans were transferred by network to
the CyberKnife treatment planning workstation.
The neurosurgeon, radiation oncologist, and
radiation physicist performed tumor delineation, dose selection, and
planning. Given the limitations of a retrospective analysis with
multiple treating physicians, final target definition and dose
selection were variable.
Target volume was delineated as the edge of the resection cavity,
including any residual tumor in cases of subtotal resection.
In these cases, the surrounding intact brain parenchyma received a
fall-off dose outside the prescription isodose line.
As we gained additional
experience, in a minority of cases (n
= 10), the resection cavity volume was expanded with a 2-mm margin
to define the final target volume. Prescribed dose was
physician dependent, but based roughly on guidelines from Radiation
Therapy Oncology Group 90-05, with multisession treatments primarily
used for treatment volumes larger than 3-cm diameter targets.
Local and distant
control
Overall, local failure was observed in 10 of
69 cavities. Of note, all
failures were adjacent to the resection cavity and none occurred
along the unirradiated surgical corridor leading to the resection
cavity. Crude overall local tumor control rate was 86%.
Kaplan-Meier local control rates at 6 and 12 months were 88% and
79%, respectively. Of 10 patients who experienced local failure,
median time to progression was 5.7 months (range, 3.2–14.2 months).
Two patients experienced local failure at an intact metastasis
treated using primary SRS.
Using univariate analysis, conformality index and modified
conformality index (by quartile) were the only significant
predictors of local failure. Increases in absolute values of both
conformality and modified conformality indices, which correspond to
less conformal plans, resulted in improved local control. The rate
of local control in the least conformal quartile was 100%,
significantly different than the 64% rate of control observed with
the 75% most conformal plans (p < 0.05). Although smaller
tumor volume generally was associated with larger conformality
indices, target volume was not associated with local control (p
= 0.29).
Through analysis of the conformality index (prescription isodose
volume/target isodose volume [PIV/TIV]), one can roughly estimate
the additional volume of brain irradiated compared with the outlined
target volume. If one assumes that the TIV and PIV correspond to
idealized spheres (volume = 4/3 π radius3),
the additional margin provided by the PIV covering the TIV can be
calculated. Patients with a 2.4-mm margin of brain tissue included
in the prescribed volume (the least conformal quartile) had 100%
local control compared with 1.7-mm (78% local control), 1.5-mm (52%
local control), and 0.8-mm (43% local control) margins in the
remaining quartiles
The
addition of a planned 2-mm margin on the resection cavity (n
= 10) yielded local control of 100% compared with 70% (n
= 59) for those treated without the planned addition of a margin.
However, this difference was not significant (p =
0.15). No other factors, including tumor volume, dose,
single-session equivalent dose, number of sessions, fusion of MRI
for planning, histologic characteristics, extent of tumor resection,
and number of metastases, proved significant on univariate analysis.
Distant failure occurred in 32 of 65
patients (49%). Kaplan-Meier 6- and 12-month distant control rates
were 70% and 47%, respectively. Median time to distant failure was
10.2 months.
Discussion
In patients with limited brain metastases, WBI is associated
with an acute detriment in quality-of-life measures potential
delayed neurocognitive deficits, and lack of overall survival
benefit. Consequently, an alternative to conventional
cranial irradiation for patients who have undergone surgical
resection of brain metastases remains desirable. Based on this
rationale, with patients in whom surgical resection is preferred
to obtain histologic confirmation or alleviate mass effect, we
generally deferred immediate WBI for those with a limited number
of brain metastases and a favorable KPS. In place of WBI, we
used SRS as the primary treatment for unresected metastases or
as adjuvant therapy to the postoperative resection cavity. To
the best of our knowledge, this retrospective analysis is the
first published report describing the use of postoperative
radiosurgery to the surgical resection bed of brain metastases,
thereby reserving WBI.
To justify the use of SRS alone to the resection cavity, local
control rates should be similar to those reported for
postoperative WBI. In this regard, Patchell
reported outcomes in 95 patients with a gross totally resected
isolated metastasis who were randomly assigned to either no
additional therapy or postoperative WBI. The WBI decreased the
rate of local failure at the original tumor site from 46% to
10%. Of note, no difference in overall survival or functionally
independent survival was seen with the addition of WBI; observed
median survival was approximately 11 months. Moreover, an
additional study by Patchell , in which patients with single
metastases were randomly assigned to either WBI or surgery and
WBI, reported a 20% rate of local failure in the postoperative
WBI arm.
A similar retrospective series of
postoperative radiosurgical boost to the resection cavity,
reported in only abstract form, analyzed 61 patients treated to
a median marginal dose of 16 Gy to a median target volume of 8.7
cm3. Local failure occurred in
30% of patients, with 1-year probability of 39%. Median survival
time was 14.9 months.
Results of a Phase II trial
investigating the use of GliaSite RTS (Cytyc Surgical Products
II, Mountain View, CA) intracavitary low-dose rate brachytherapy
for treatment of the postsurgical cavity for single metastases,
deferring immediate WBI, recently were reported. Sixty-two
patients underwent brachytherapy balloon catheter system
placement at the time of surgical resection. During a median
dwell time of 114 hours, 60 Gy was delivered at a 1-cm depth.
Assessed by using MRI, the crude local control rate was 83%,
with a predicted 1-year rate of 79%.
The local control rate in our series was
86% overall, with actuarial rates of 88% and 79% at 6 and 12
months, respectively.
The 14% rate of local failure we observed when using SRS to
treat the resection cavity compares favorably with the 46%
recurrence rate described after surgical resection alone and 10%
to 20% in patients who underwent surgical resection and
subsequent WBI. Moreover, the local relapse rate we
observed is similar to that reported for resected brain
metastases treated with GliaSite brachytherapy (17%)
When the present series was analyzed by
means of univariate analysis, conformality indices were the only
factors associated with local failure; a higher conformality
index (i.e., a less conformal isodose volume) was
associated with a decreased likelihood of local relapse.
Although smaller target volumes tend to be associated with
higher conformality indices, in the present series, no
significant correlation could be discerned between the size of
the resection cavity treated and rate of local control. Two
possible explanations for this phenomenon are: (1) the
difficulties encountered in accurately delineating the margins
of a recent resection cavity on MRI and CT scans, or (2)
in some cases, the possibility of an infiltrating
radiographically invisible tumor margin. The end result is that
an overly conformal margin in such cases appears to be
counterproductive. In
lieu of using less conformal plans, we recommend the addition of
a margin that encompasses the cavity. Given the approximately 2
mm suggested through calculation of the idealized spherical
margin of the PIV on the TIV based on conformality index, as
well as a trend toward improved local control seen with the
planned addition of a 2-mm margin, we suggest and now
routinely add a 2-mm margin with this technique.
Similar recommendations
for the addition of a 1-mm margin for SRS treatment of intact
metastases were made. Although inclusion of a margin may
improve local control rates, it is notable that failure rates of
17% were seen with brachytherapy, even when the median balloon
surface dose was 314 Gy, a dose expected to be adequate for
treating malignant disease.
The actuarial distant intracranial
failure rate in this series was 53% at 1 year, similar to other
series: 50% for brachytherapy alone, 43–63% for SRS alone , and
50% for surgery alone (estimated from survival curve). A concern
with the omission of immediate WBI in the treatment of patients
with brain metastases is that a greater distant brain failure
rate may lead to more deaths from neurologic progression of
disease; Patchell reported that the addition of WBI
decreased the rate of death from neurologic causes from 44% to
14%. However, a recent randomized trial involving patients with
unresected brain metastases showed no differences in neurologic
function when combined WBI and SRS treatment was compared with
SRS alone. At 1 year, neurologic death rates were 19% and 23%,
respectively; these are similar to the 25% seen in our series.
Meanwhile, other series reported lower neurologic death rates,
with 13% (1-year actuarial) for SRS alone and 11% (crude) for
brachytherapy. Given the limitations inherent to retrospective
studies, it was not possible with the current series to formally
measure the impact of tumor recurrence on quality of life.
As with any approach in which WBI is
omitted, frequent surveillance imaging is required to detect
distant occurrence of new metastases at a time when they are
small and amenable to treatment. Studies reported that of 21% of
patients with breast cancer who required repeated SRS, 12% and
50% experienced failure within 2 and 6 months, respectively.
Therefore, in patients for whom such surveillance imaging is not
possible, postoperative WBI is recommended.
Historically, the use of WBI after
surgical resection of a brain metastasis was considered the
standard of care. Although interpretation of available data
regarding the omission of WBI is controversial,
we routinely defer the
use of immediate postsurgical WBI in patients with limited
number of metastases and favorable KPS to minimize the acute
toxicities and potential long-term neurocognitive dysfunction in
these patients. In our series, SRS treatment of the
postoperative resection cavity yields local control rates
similar to previous reports investigating postoperative WBI.
Less conformal treatment plans appear to produce greater rates
of local control. As a surrogate, we recommend the addition of a
2-mm margin around the resection cavity when using the current
technique.
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