Stereotatic radiosurgery of
468 brain metastases ≤2 cm: implications for SRS dose and whole brain
radiation therapy
Shehata. IJROBP 2004;59:87
For many decades, the standard treatment for brain
metastases has been whole brain radiotherapy (WBRT) with various
fractionated regimens as determined by the Radiation Therapy Oncology
Group (RTOG). In recent years, stereotactic radiosurgery (SRS) and surgery
have emerged as effective primary treatments for patients with brain
metastases, with improved survival compared with WBRT alone. In select
patients with single brain metastasis, the addition of postoperative WBRT
has been proved to prolong neurologic survival and prevent recurrence
compared with surgery alone. The effect of SRS alone compared with SRS
combined with WBRT has not been clearly defined; despite an improvement in
local tumor control with combined SRS and WBRT, some retrospective reports
failed to demonstrate a survival advantage.
Dose selection for the treatment of brain
metastases with SRS has historically been based on the inverse
relationship between the SRS dose and the treatment volume, correlating
with the incidence of brain necrosis. According to this principle,
smaller-sized brain metastases can better tolerate treatment with
increasing doses of SRS than can larger metastases. Currently, the RTOG
protocol 90-05 has been the only prospective study attempting to identify
the maximal tolerable dose of SRS for brain metastases ≤2 cm. We sought to
identify the optimal SRS dose and the associated impact of WBRT for brain
metastases ≤2 cm as determined by local tumor control rates and
complication rates.
The national standard stereostatic radiosurgery
(SRS) dose for brain metastases ≤2 cm is 24 Gy as established by the
Radiation Therapy Oncology Group study 90–05, in which planned whole brain
radiotherapy (WBRT) was not used. On the basis of our institutional
experience, the goal of this study was to determine the optimal SRS dose
and influence of WBRT on local tumor control among 468 ≤2-cm metastases.
Between October 1992 and May 2001, 468 newly diagnosed or recurrent ≤2-cm
brain metastases, among 160 patients, were treated with SRS (dose
range, 7–30 Gy; median, 20). A total of 240 metastases received
planned WBRT (range, 6.75–50.4 Gy; median, 40.5) vs. 228 metastases
that did not. The variables tested by multivariate analysis for their
potential effect on tumor control included histologic type, site of
metastasis, primary diagnosis, tumor volume, SRS dose, newly diagnosed vs.
recurrent metastasis, and planned WBRT vs. no planned WBRT.
Results
Follow-up ranged from 1 to 82 months (median 7).
On multivariate analysis, the addition of WBRT was the most significant
predictor of local tumor control. Overall, patients
who received WBRT
had superior local tumor control rates (97% vs. 87% in those who did not
receive WBRT; p = 0.0001).
Patients receiving WBRT and SRS
≥20 Gy achieved local control rates of 99% compared with 91% control rates
when treated with WBRT and SRS <20 Gy (p = 0.0029). Increasing
the SRS dose to >20 Gy resulted in no improvement in local tumor control
and a higher rate of Grade 3 and 4 neurotoxicity, approaching statistical
significance (5.9% vs. 1.9%, p = 0.078).
Discussion |
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For many malignancies, the standard of
practice is to aggressively treat local tumor recurrences with RT to
reduce the morbidity associated with the increased tumor burden. The
brain should be no exception, given its extreme sensitivity to mass
effect resulting from local tumor recurrence. Since the advent of SRS,
many have advocated that better-prognosis brain metastases patients
with an anticipated survival of ≥1 year should receive SRS alone
without the addition of planned WBRT. This practice was based on the
anticipation that adding WBRT would put these long-term survivors at
risk of demonstrating the late effects of neurocognitive decline with
no benefit to survival. RTOG study 95-08 demonstrated that SRS plus
WBRT significantly improved survival for brain metastases compared
with WBRT alone among the subset of patients with single brain
metastasis, recursive partitioning analysis Class I, age <50 years,
and non–small-cell lung cancer. Some studies have demonstrated that
the addition of WBRT to SRS compared with SRS alone does not provide
any significant benefit to quantitative survival. However, patients
with recurrent brain metastases present most commonly with a
symptomatic neurologic deficit. The consequences of tumor recurrence
may pose a greater threat to a patient's quality of survival and
clinical performance than the presumptive neurocognitive late effects
of WBRT. The management of brain metastases should emphasize the
improvement and preservation of neurologic function, with the maximal
therapy provided at the initial presentation of intracranial disease
to prevent brain recurrence. WBRT before SRS may provide a theoretical
advantage by decreasing the tumor volume to be treated with SRS and
subsequently reduce complication rates. In addition, maximal initial
therapy consisting of SRS and upfront WBRT was recently demonstrated
by Sneed to be associated with a lower rate of requirement for
salvage brain therapy (7%) compared with SRS alone (37%). The
increased need for salvage brain treatment and its potential impact on
quality of survival needs further evaluation.
Current data have shown a statistically
significant improvement in local control of brain metastases by the
addition of WBRT to SRS. The results of this study further emphasized
a statistically significant improvement in local control achieved by
the addition of WBRT to SRS. On multivariate analysis, we found the
addition of WBRT to be the most significant predictor of local tumor
control. Overall, patients who received WBRT had superior local tumor
control rates (97% vs. 87% for those who did not receive WBRT. At 1
year, patients who received SRS plus WBRT had a local control rate of
96% compared with 77% for SRS alone. The implications of improved
local control can be demonstrated in two recent studies that revealed
a statistically significant association between intracranial tumor
progression and neurocongnitive decline as measured by Folstein
Mini-Mental Status examination scores.
In addition to an improvement in local
control, Sneed found statistically significant improvement in
the interval of brain freedom from progression by the addition of WBRT
to SRS compared with SRS alone (15.9 months vs. 8.3 months,
p
= 0.008). Chidel demonstrated statistically significant
improvement in the intracranial disease-free survival rate at 2 years
with SRS plus WBRT compared with SRS alone (60% vs. 34%,
p =
0.027). Furthermore, the combination of upfront WBRT and SRS may be a
more cost-effective method of managing brain metastases than SRS
alone, given the significant cost associated with repeated SRS or
additional craniotomy for new metastases. Cost effectiveness, as
relates to this subject, is also in need of further evaluation.
Currently, limited data exist in the
literature on identifying the optimal SRS dose for the treatment of
brain metastases. Kjellberg described the inverse relationship
between the SRS dose and treatment volume with regard to SRS dose
selection on the basis of the incidence of radionecrosis. The SRS dose
has traditionally been influenced by location, physician preference,
total dose exposure (with or without WBRT), and the RTOG study 90-05
findings. The RTOG study 90-05 was a dose-escalation study attempting
to identify the maximal tolerable dose of a single fraction of SRS in
patients with recurrent, previously irradiated, brain metastases or
previously irradiated primary brain tumors. That study concluded that
24-Gy SRS was the maximal tolerable dose for tumors ≤2 cm on the basis
of an acute toxicity rate of <30% as the primary end point (RTOG Grade
3 or greater toxicity).
In this series, we attempted to identify the
optimal SRS dose with planned WBRT that provided the maximal level of
tumor control and the lowest level of complications (RTOG Grade 3 or
greater). According to these criteria, we found 20 Gy to be the
optimal SRS dose for brain metastases ≤2 cm. SRS doses ≥20 Gy resulted
in significantly improved local control compared with <20 Gy.
Additional stratification of the SRS dose demonstrated superior
local control rates with SRS doses of 20 Gy and >20 Gy compared with
<20 Gy. However, a higher level of complications was seen with SRS
doses >20 Gy compared with ≤20 Gy. A recent prospective trial of 79
patients by Majhail found SRS doses >20 Gy on multivariate
analysis to be significantly associated with a higher incidence of
early complications (p = 0.0083). On the basis of the results
presented by Majhail, as well as data from this series, we found 20 Gy
to be the optimal SRS dose. |
Conclusion
First,
optimal control of brain metastasis ≤2 cm
was seen with 20-Gy SRS combined with planned WBRT. Second, SRS doses >20
Gy resulted in no obvious improvement in local control and appeared to be
associated with a greater rate of complications. |