Summary

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.

Introduction

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.[1,3] Moreover, despite reduction in distant brain control, overall survival (OS) was similar with SRS to the surgical bed compared to WBRT.[3] Hence, administering SRS to the surgical cavity could be an effective strategy to reduce local recurrence and to delay or to avoid 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.

Methods

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.

Results

Table 1 Baseline patient characteristics

Table 2 Tumor characteristics

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. 1). Median survival was 17 months (95% CI, 11-25). Univariate analysis revealed the following factors to be statistically significant predictors of improved survival: female gender (p=0.0214; HR:0.444), breast cancer primary (p=0.0325; HR:0.341), ECOG 0 performance status (p=0.0085; HR:0.322), being without active extracranial metastasis at the time of brain SRS (p=0.0003; HR:0.277), and metachronous brain metastases (p=0.0056; HR:0.357) (Table 3). Of them, 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) factors remained as statistically significant predictors of survival on multivariate analysis (Table 3).

Fig. 1. Overall survival rate.

Table 3 Univarite and multivariate analysis of factors associated with overall survival

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).

Discussion

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%.[3,6,7] Cumulative incidence rate of DF was 37% at 1-year in our study and it was supported by the result of phase 3 NCCTG N107C/CEC3 trial in which DF rate was 35.3% at 1-year.[3] Cumulative incidence rate of LF was 15% at 1 year in our patient cohort. The diagnosis of LF was determined by MRI and was not confirmed by pathological evaluation. This could be a limitation of our study. However, although LF occurred in 12 (23%) of 53 patients, isolated LF was observed in only 4 (7.5%), relatively small percentage of, patients. Salvage WBRT was applied to approximately one-fourth of our patient cohort due to LF, LMD, or DF, and those patients underwent salvage WBRT with a median time interval of 1 year after SRS. These results demonstrated that cavity SRS seems to be an optimal treatment approach for operated brain metastases, despite the increased risk of higher LMD incidence and the reduction of distant brain control over WBRT.

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.[8] Median OS was 12.3 months for patients who underwent post-operative SRS in phase 3 NCCTG N107C/CEC3 trial.[3] Number of fraction varied from one to five in our study, and 1-year OS rate and median survival were 54% and 17 months, respectively. We found 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) to be predictive of improved OS on multivariate analysis. Therefore, these factors could pave a way for physicians to make the appropriate therapeutic decision.

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.

Conclusion

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.

References

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