METHODS
Patients with brain metastases who underwent surgical resection and then had SRS to the surgical
cavity, between 2010 and 2021, at our department were identified. Local failure (LF), distant failure
(DF), leptomeningeal disease (LMD), overall survival (OS), and salvage whole brain radiotherapy
(WBRT) rates were calculated. Patient or treatment-related variables were evaluated for association
with LF, DF, LMD, and OS.
RESULTS
Fifty-three patients with total of 54 operated metastases were identified. The median follow-up period
was 13 months. Cumulative incidence rates of LF, LMD, and DF were 15%, 11%, and 37% at 1 year,
respectively. Salvage WBRT was employed in 13 (26%) patients. DF was less frequent in patients with
breast cancer primary compared to patients with other primaries (p=0.048, Hazard ratio [HR]:0.28)
on univariate analysis. One-year OS rate was 54%. Median survival was 17 months. Eastern cooperative
oncology group (ECOG) 0 performance status (p=0.0113; HR:0.328), being without active extracranial
metastasis at the time of brain SRS (p=0.0035; HR:0.321), and metachronous brain metastases
(p=0.0191; HR:0.399) were determined as statistically significant prognostic factors of survival
on multivariate analysis.
CONCLUSION
SRS to surgical cavity seems optimal treatment modality especially for the patients with one of the following
factors including ECOG 0 performance status, not having an active extracranial metastasis at the
time of SRS, and metachronous brain metastases.
Keywords: Brain metastases; stereotactic radiosurgery; surgical cavity
Stereotactic radiosurgery (SRS) to the surgical cavity
has been more widely applied in recent years with
the benefit of improved local control over surgery
alone and decreased neurocognitive decline compared
to WBRT.[
We, herein, reviewed and analyzed the data of our
patients who received single or multi-fraction SRS to
the surgical cavity following brain metastases surgery.
SRS and Follow-up Evaluation
All patients had a pre-operative brain MRI with contrast
and a pre-RT T1-weighted post-gadolinium MRI
that was acquired with a slice thickness of 1 mm. Patients
underwent immobilization with a five-point
thermoplastic mask and planning computed tomography
(CT) scan was obtained in the treatment position.
Pre-RT MRI was fused to planning CT scan for
quantifying the extent of resection and identifying target.
Clinical target volume (CTV) and organs at risk
were delineated. The planning target volume (PTV)
was defined as CTV plus a 1 mm margin. The number
of treatment fractions varied between one and five
based on PTV volume. The total radiation dose between
15 Gy and 30 Gy was prescribed. Dose planning
was performed with the Multiplan Software (Accuray
Inc., Sunyvale, CA, USA). CyberKnife treatment was
performed in an outpatient setting.
Follow-up after treatment consisted of clinical examination and brain MRI with contrast within 3 months of SRS and then at 3-month intervals, unless clinically indicated at an earlier time point.
Outcomes
All times to event were measured from the date of SRS.
Event was defined as follows: For local failure (LF), as
a new contrast-enhancing lesion, contiguous with or
within the surgical cavity, that was depicted by MRI
scan; for distant failure (DF), as occurrence of new brain
parenchymal metastases apart from the surgical site;
and for leptomeningeal disease (LMD), as occurrence
of LMD that was determined by MRI scan and clinical
signs. Patients without an event were censored at the last
contact date or at the time of salvage WBRT for failure
metrics. OS was calculated from the date of SRS to the
date of death or censoring at last clinical follow-up.
Variables evaluated for association with LF, DF, LMD, or OS included age (as a continuous variable evaluated only for OS), gender, the Eastern Cooperative Oncology Group (ECOG) performance status (0 vs. 1 to 2), the timing of brain metastases identification (metachronous versus precocious or synchronous), primary cancer (breast vs. others), active extracranial metastases, number of brain metastases (1 vs. 2 to 4), location of lesion (supratentorial vs. infratentorial), tumor maximal dimension before surgery (≤3 cm vs. >3 cm), dural contact, venous sinus contact, extent of surgery (total vs. subtotal excised), and number of SRS fractions (1 vs. 2 to 5).
Statistics
Rates of LF, DF, and LMD were calculated using cumulative
incidence methodology, accounting for death as
competing risk. OS rate was estimated using the Kaplan-
Meier method.
Variables associated with LF, DF, and LMD were analyzed using the Gray"s test for equality of cumulative incidence functions, with death considered a competing risk. Variables associated with OS were evaluated with Cox proportional hazards regression model on both univariate and multivariate analysis. Multivariate analysis was performed with the variables which were found statistically significant on the univariate analysis. Hazard ratios and 95% confidence intervals were calculated.
Statistical analysis was carried out with statistical software package 9.4 of the SAS system for Windows, 2002-2012 SAS Institute, Inc., Cary, NC. P<0.05 is considered statistically significant.
Survival and Failures
At the time of medical records" review, 36 (67.9%) of 53
patients had died, and 17 (32.1%) of 53 patients were alive.
The median follow-up period for all patients and alive
patients were 13 months (range 1-143) and 20 months
(range 5-143), respectively. Isolated LF, LMD and DF occurred
in four (7.5%), two (3.8%), and 17 (32.1%) of 53
patients, respectively. Five (9.4%) of 53 patients had both
LF and DF, two (3.8%) patients had both LF and LMD,
and one (1.9%) patient had LF, DF, and LMD. All of five
LMD events occurred within 1 year after SRS.
Cumulative incidence rates of LF, LMD, and DF were 15% (95% confidence interval [CI], 7-27), 11% (95% CI, 4-21), and 37% (95% CI, 23-50) at 1 year, respectively. There was not any factor that showed statistical significance for the association with LF or LMD. However, DF was low in patients with breast cancer primary compared to patients with other primaries (p=0.048, Hazard ratio [HR]:0.28) on univariate analysis.
One-year OS rate was 54% (Fig.
Salvage WBRT
Salvage WBRT was employed in 13 (26%) patients. Of
those patients, median time to salvage WBRT after SRS
was 12 months (range 2-21).
Cumulative incidence rate of LMD was 11% at 1 year in
our patient cohort, with death as a competing risk, respectively.
Our result seems relatively similar to those
reported in prior studies which were around 7% to
17%.[
Our analysis found that LF and LMD were not statistically
significantly influenced by any factor. This could
be due to the relatively small sample size of our patient
cohort. However, patients with breast cancer primary
had decreased DF (p=0.048, HR:0.28) on univariate
analysis. Improved systemic therapies applied in breast
cancer might lead to this outcome. Nonetheless, it is
difficult to draw such conclusion due to the presence of
small number of patients with breast cancer, 10 (18.9%)
patients, in our study.
Fractionation was not same between studies; some used
single fraction SRS, while others used multi-fraction
SRS. Multi-fraction SRS could be favorable for avoiding
potential enhanced clinical side effects resulted from
single fraction SRS applied for large metastases. There
also exist discrepancies in survival rates between studies.
These inconsistent results seem due to the retrospective
nature of the studies and existence of highly heterogeneous
histologies in the studies. One-year OS rates were
from 41.8% to 70% for post-operative SRS and from
58% to 81.9% for post-operative multi-fraction SRS in
retrospective studies.[
Limitations of the Study
We acknowledge that our study has several limitations.
Those include being retrospective, including fairly heterogeneous
patient population, and small sample size.
However, most of the studies on this subject have similar
limitations.
Peer-review: Externally peer-reviewed.
Conflict of Interest: All authors declared no conflict of interest.
Ethics Committee Approval: The study was approved by the Kartal Dr. Lütfi Kırdar City Hospital Clinical Research Ethics Committee (no: 2022/514/220/7, date: 22.02.2022). Financial Support: None declared.
Authorship contributions: Concept - U.Y., G.Y., E.A., N.I.; Design - U.Y., G.Y., E.A., N.I.; Supervision - U.Y., G.Y., E.A., N.I.; Funding - U.Y.; Materials - U.Y., G.Y., E.A., N.I.; Data collection and/or processing - U.Y.; Data analysis and/or interpretation - U.Y.; Literature search - U.Y.; Writing - U.Y.; Critical review - U.Y., G.Y., E.A., N.I.
