Postoperative Stereotactic Radiosurgery Without Whole-Brain Radiation Therapy for Brain Metastases: Potential Role of Preoperative Tumor Size

doi:10.1016/j.ijrobp.2012.05.027

International Journal of Radiation OncologyBiologyPhysics

Volume 85, Issue 3, 1 March 2013, Pages 650-655

Presented at the 52nd Annual Meeting of the American Society for Radiation Oncology (ASTRO), in San Diego, CA, October 21-November 4, 2010.

https://doi.org/10.1016/j.ijrobp.2012.05.027 Get rights and content

Purpose

Radiation therapy following resection of a brain metastasis increases the probability of disease control at the surgical site. We analyzed our experience with postoperative stereotactic radiosurgery (SRS) as an alternative to whole-brain radiotherapy (WBRT), with an emphasis on identifying factors that might predict intracranial disease control and overall survival (OS).

Methods and Materials

We retrospectively reviewed all patients through December 2008, who, after surgical resection, underwent SRS to the tumor bed, deferring WBRT. Multiple factors were analyzed for time to intracranial recurrence (ICR), whether local recurrence (LR) at the surgical bed or “distant” recurrence (DR) in the brain, for time to WBRT, and for OS.

Results

A total of 49 lesions in 47 patients were treated with postoperative SRS. With median follow-up of 9.3 months (range, 1.1-61.4 months), local control rates at the resection cavity were 85.5% at 1 year and 66.9% at 2 years. OS rates at 1 and 2 years were 52.5% and 31.7%, respectively. On univariate analysis (preoperative) tumors larger than 3.0 cm exhibited a significantly shorter time to LR. At a cutoff of 2.0 cm, larger tumors resulted in significantly shorter times not only for LR but also for DR, ICR, and salvage WBRT. While multivariate Cox regressions showed preoperative size to be significant for times to DR, ICR, and WBRT, in similar multivariate analysis for OS, only the graded prognostic assessment proved to be significant. However, the number of intracranial metastases at presentation was not significantly associated with OS nor with other outcome variables.

Conclusions

Larger tumor size was associated with shorter time to recurrence and with shorter time to salvage WBRT; however, larger tumors were not associated with decrements in OS, suggesting successful salvage. SRS to the tumor bed without WBRT is an effective treatment for resected brain metastases, achieving local control particularly for tumors up to 3.0 cm diameter.

Introduction

Metastatic disease to the brain is diagnosed in approximately 170,000 patients in the United States each year, making it the most common central nervous system (CNS) tumor in adults 1, 2. Historically, single intracranial metastases often were treated with surgical resection followed by whole-brain radiation therapy (WBRT) (3). However, recent work has suggested patients may experience neurocognitive impairment even within the first few months after WBRT; and, due to improved outcomes from therapies for systemic cancer, the proportion of patients who survive to develop long-term deficits may be increasing 4, 5. Also, the time, inconvenience, and travel demands of weeks of daily WBRT treatments are unappealing for many patients, and they may wish to defer WBRT to the point when it is most needed. In contrast, several recent reports investigating stereotactic radiosurgery (SRS) administered to the resection cavity without WBRT have produced rates of local control that compare favorably with those of initial WBRT, with 1-year local control rates ranging from 74%-100% 6, 7, 8, 9, 10, 11, 12, 13, 14.

Our study is a retrospective analysis of a cohort of patients who underwent surgical resection of intracranial metastases followed by linear accelerator (LINAC)-based SRS. We assessed various potential prognostic factors for disease control and survival, including the Graded Prognostic Assessment (GPA) score (15). The range of doses applied to a variety of target cavity sizes, the analysis of preoperative tumor size as well as target volume, and inclusion of the GPA index make this study unique in the literature exploring predictive factors for intracranial disease control and survival for patients undergoing postoperative SRS.

Section snippets

Methods and Materials

We retrospectively reviewed the records of all patients who underwent LINAC-based SRS to the surgical cavity after initial resection of brain metastases from February 2002 through December 2008, excluding patients who received WBRT prior to or immediately following operative resection. Institutional review board approval was obtained prior to data collection.

Whenever possible, SRS was performed within 4 weeks of surgical resection to minimize time for possible tumor regrowth while providing

Patient demographics

Included in the analysis were 49 lesions in 23 men and 24 women undergoing resection followed by SRS. The median age at SRS was 64 years (range, 24-85 years). The most common primary malignancy was non-small cell lung cancer (23) followed by melanoma (7) and breast cancer (5). Median preoperative tumor volume was 11.5 cm³. Thirty-seven lesions (76%) achieved GTR at surgery. The median KPS at the time of SRS was 80 (range, 50-100). Seven lesions at the time of SRS (14%) had GPA scores of up to

Discussion

Four randomized trials have examined the value of WBRT for the management of brain metastases treated either with surgery or SRS, yet none has shown a survival benefit with the addition of WBRT 4, 6, 17, 18. Furthermore, WBRT has been associated with some short- and long-term adverse effects, including declines in learning and memory functions (4).

Postoperative SRS as substitute for WBRT has been explored in several recent retrospective series, with 1-year actuarial local control rates varying

Conclusions

Overall, in this retrospective series, resection followed by SRS to the surgical cavity produced excellent local control rates. Preoperative tumor size but not target volume proved significantly associated with local control and with time to intracranial DR but not with OS. We conclude that postoperative SRS, initially deferring WBRT, is an effective treatment of brain metastases, especially in patients presenting with smaller tumors. Close radiological follow-up is recommended for the early

References (20)

E.L. Chang et al.
Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial
Lancet Oncol
(2009)
L. Do et al.
Resection followed by stereotactic radiosurgery to resection cavity for intracranial metastases
Int J Radiat Oncol Biol Phys
(2009)
S.G. Soltys et al.
Stereotactic radiosurgery of the postoperative resection cavity for brain metastases
Int J Radiat Oncol Biol Phys
(2008)
P.J. Kelly et al.
Stereotactic irradiation of the postoperative resection cavity for brain metastasis: a frameless linear accelerator-based case series and review of the technique
Int J Radiat Oncol Biol Phys
(2012)
P.W. Sperduto et al.
A new prognostic index and comparison to three other indices for patients with brain metastases: an analysis of 1,960 patients in the RTOG database
Int J Radiat Oncol Biol Phys
(2008)
D.W. Andrews et al.
Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial
Lancet
(2004)
S. Brem et al.
An era of rapid advancement: diagnosis and treatment of metastatic brain cancer
Neurosurgery
(2005)
J.G. Cairncross et al.
Radiation therapy for brain metastases
Ann Neurol
(1980)
A.K. Sills
Current treatment approaches to surgery for brain metastases
Neurosurgery
(2005)
S. Gori et al.
Central nervous system metastases in HER-2 positive metastatic breast cancer patients treated with trastuzumab: incidence, survival, and risk factors
Oncologist
(2007)

There are more references available in the full text version of this article.

Cited by (85)

Efficacy of hypofractionated Gamma Knife radiosurgery in treating surgical beds of metastatic brain tumors
2024, Journal of Clinical Neuroscience
Surgery alone for metastatic brain tumors (METs) often results in local recurrence due to microscopic residual tumor tissue. While stereotactic radiosurgery (SRS) is commonly used post-surgery, hypofractionation may be required for large surgical beds. This study evaluated the efficacy and safety of hypofractionated Gamma Knife radiosurgery (hf-GKRS) for the first time as a post-operative adjuvant therapy.
This retrospective study involved 24 patients (28 surgical beds) who underwent hf-GKRS within four weeks after surgery. The study primarily focused on local control (LC) rate and analyzed distant intracranial failure (DICF), intracranial progression-free survival (PFS), leptomeningeal disease (LMD), overall survival (OS), and radiation necrosis (RN).
During a median follow-up of 9 months, LC was achieved in 89.3 % of surgical beds. LC estimates at 6, 12, and 24 months were 96.4 %, 82.7 %, and 82.7 %, respectively. DICF was observed in 45.8 % of patients, and LMD was identified in two patients (8.3 %). At the end of the follow-up, 58.3 % of patients were alive, and the median OS was 20 months. RN occurred in only one surgical bed (3.6 %). No grade 5 toxicity was observed. The univariate analysis identified a longer interval to GKRS (HR 11.842, p = 0.042) and a larger treatment volume (HR 1.103, p = 0.037) as significant factors for local failure.
hf-GKRS shows potential as an effective and safe adjuvant treatment for surgical beds. It offers an alternative to SRS, SRT, or WBRT, particularly for larger volumes or tumors near critical structures. Further research is needed to confirm these results and optimize treatment approaches.
Preoperative Versus Postoperative Radiosurgery of Brain Metastases: A Meta-Analysis
2024, World Neurosurgery
While postoperative resection cavity radiosurgery (post-SRS) is an accepted treatment paradigm for brain metastasis (BM) patients who undergo surgical resection, there is emerging interest in preoperative radiosurgery (pre-SRS) followed by surgical resection as an alternative treatment paradigm. Here, we performed a meta-analysis of the available literature on this matter.
Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a search of all studies evaluating pre-SRS and post-SRS was completed. Local recurrence (LR), overall survival (OS), radiation necrosis (RN), and leptomeningeal disease (LMD) were evaluated from the available data. Moderator analysis and pooled effect sizes were performed using a proportional meta-analysis with R using the metafor package. Statistics are presented as mean [95% confidence interval].
We identified 6 pre-SRS and 33 post-SRS studies with comparable tumor volume (4.5–17.6 cm³). There were significant differences in the pooled estimates of LR and LMD, favoring pre-SRS over post-SRS. Pooled aggregate for LR was 11.0% [4.9–13.7] and 17.5% [15.1–19.9] for pre- and post-SRS studies (P = 0.014). Similarly, pooled estimates of LMD favored pre-SRS, 4.4% [2.6–6.2], relative to post-SRS, 12.3% [8.9–15.7] (P = 0.019). In contrast, no significant differences were found in terms of RN and OS. Pooled estimates for RN were 6.4% [3.1–9.6] and 8.9% [6.3–11.6] for pre- and post-SRS studies (P = 0.393), respectively. Pooled estimates for OS were 60.2% [55.8–64.6] and 60.5% [56.9–64.0] for pre- and post-SRS studies (P = 0.974).
This meta-analysis supports further exploration of pre-SRS as a strategy for the treatment of BM.
Sensitizing brain metastases to stereotactic radiosurgery using hyperbaric oxygen: A proof-of-principle study
2022, Radiotherapy and Oncology
Increased oxygen levels may enhance the radiosensitivity of brain metastases treated with stereotactic radiosurgery (SRS). This project administered hyperbaric oxygen (HBO) prior to SRS to assess feasibility, safety, and response.
38 patients were studied, 19 with 25 brain metastases treated with HBO prior to SRS, and 19 historical controls with 27 metastases, matched for histology, GPA, resection status, and lesion size. Outcomes included time from HBO to SRS, quality-of-life (QOL) measures, local control, distant (brain) metastases, radionecrosis, and overall survival.
The average time from HBO chamber to SRS beam-on was 8.3 ± 1.7 minutes. Solicited adverse events (AEs) were comparable between HBO and control patients; no grade III or IV serious AEs were observed. Radionecrosis-free survival (RNFS), radionecrosis-free survival before whole-brain radiation therapy (WBRT) (RNBWFS), local recurrence-free survival before WBRT (LRBWFS), distant recurrence-free survival before WBRT (DRBWFS), and overall survival (OS) were not significantly different for HBO patients and controls on Kaplan-Meier analysis, though at 1-year estimated survival rates trended in favor of SRS + HBO: RNFS – 83% vs 60%; RNBWFS – 78% vs 60%; LRBWFS – 95% vs 78%; DRBWFS – 61% vs 57%; and OS – 73% vs 56%. Multivariate Cox models indicated no significant association between HBO treatment and hazards of RN, local or distant recurrence, or mortality; however, these did show statistically significant associations (p < 0.05) for: local recurrence with higher volume, radionecrosis with tumor resection, overall survival with resection, and overall survival with higher GPA.
Addition of HBO to SRS for brain metastases is feasible without evident decrement in radiation necrosis and other clinical outcomes.
Risk Factors of Second Local Recurrence in Surgically Treated Recurrent Brain Metastases: An Exploratory Analysis
2022, World Neurosurgery
Citation Excerpt :
The choice of treatment modality for newly diagnosed BMs mainly relies on the BM size and symptoms at patient presentation.33,34 In the neurosurgical literature, larger BM size, defined as BMs >3 cm, has been shown to increase the first local recurrence odds in patients with newly diagnosed BMs receiving resection and adjuvant stereotactic radiosurgery.35,36 Therefore, the observed association of worse second local recurrence prognosis for patients receiving both resection and radiation for newly diagnosed BMs might be explained by initial BM size and thus shorter progression-free survival.
A first local recurrence is common after resection or radiotherapy for brain metastasis (BM). However, patients with BMs can develop multiple local recurrences over time. Published data on second local recurrences are scarce. This study aimed to report predictors associated with a second local recurrence in patients with BMs who underwent a craniotomy for a first locally recurrent BM.
Patients were identified from a database at Brigham and Women's Hospital in Boston. Hazard ratios and 95% confidence intervals for predictors of a second local recurrence were computed using a Cox proportional hazards model.
Of 170 identified surgically treated first locally recurrent lesions, 74 (43.5%) progressed to second locally recurrent lesions at a median of 7 months after craniotomy. Subtotal resection of the first local BM recurrence was significantly associated with shorter time to second local recurrence (hazard ratio = 2.09; 95% confidence interval, 1.27–3.45). Infratentorial location was associated with a worse second local recurrence prognosis (hazard ratio = 2.22; 95% confidence interval, 1.24–3.96).
A second local recurrence occurred after 43.5% of craniotomies for first recurrent lesions. Subtotal resection and infratentorial location were the strongest risk factors for worse second local recurrence prognosis following resection of first recurrent BM.
Timing of Adjuvant Fractionated Stereotactic Radiosurgery Affects Local Control of Resected Brain Metastases
2021, Practical Radiation Oncology
Citation Excerpt :
In contrast, in the Stanford experience and in our cohort, equivalent dose was not predictive of LR.15 Some studies have identified larger tumor or resection cavity size as predictive of LC, with 2.0 cm to 3.0 cm commonly cited as a threshold.10-12,28 In this study, as in the Stanford experience, increased target volume was not found to be predictive of LR.15
For resected brain metastases (BMs), stereotactic radiosurgery (SRS) is often offered to minimize local recurrence (LR). Although the aim is to deliver SRS within a few weeks of surgery, a variety of socioeconomic, medical, and procedural issues can cause delays. We evaluated the relationship between timing of postoperative SRS and LR.
We retrospectively identified a consecutive series of patients with BM managed with resection and SRS or fractionated SRS at our institution from 2012 to 2018. We assessed the correlation of time to SRS and other demographic, disease, and treatment variables with LR, local recurrence-free survival, distant recurrence, distant recurrence-free survival, and overall survival.
A total of 133 patients met inclusion criteria. The median age was 64.5 years. Approximately half of patients had a single BM, and median BM size was 2.9 cm. Gross total resection was achieved in 111 patients (83.5%), and more than 90% of patients received fractionated SRS. The median time to SRS was 37.0 days, and the LR rate was 16.4%. Time to SRS was predictive of LR. The median time from surgery to SRS was 34.0 days for patients without LR versus 61.0 days for those with LR (P < .01). The LR rate was 2.3% with SRS administered ≤4 weeks postoperatively, compared with 23.6% if SRS was administered >4 weeks postoperatively (P < .01). Local recurrence-free survival was also improved for patients who underwent SRS at ≤4 weeks (P = .02). Delayed SRS was also predictive of distant recurrence (P = .02) but not overall survival.
In this retrospective study, the strongest predictor of LR after postoperative SRS for BM was time to SRS, and a cutoff of 4 weeks was a reliable predictor of recurrence. These findings merit investigation in a prospective, randomized trial.
Hypofractionated adjuvant surgical cavity radiotherapy following resection of limited brain metastasis
2020, Journal of Clinical Neuroscience
Following surgical resection of oligometastatic disease to the brain there is a high rate of local relapse which is reduced by the addition of focal radiation therapy, often delivered as single fraction stereotactic radiosurgery (SRS) to the surgical cavity. This study audited the outcomes of an alternative approach using hypofractionated radiation therapy (HFRT) to the surgical resection cavity.
Seventy-nine patients who received surgical resection and focal radiation therapy to the surgical cavity using HFRT with intensity modulated radiation therapy with or without stereotactic radiotherapy were identified. Doses were delivered in five fractions every second day for 10 days. Follow-up involved MRI surveillance with three-monthly MRI scans post resection. The major endpoints were local control at the surgical cavity site, and presence of radiation necrosis at the treated site.
Seventy-nine patients were included for the analysis with a median follow-up of 10.8 months. Of the cohort, 56% experienced intracranial progression, with all patients progressing distant to the resection cavity, and 7% progressing locally in addition. The one-year local control rate was 89.8%. The median progression-free survival was 10.0 months and median overall survival was 14.3 months. There was one CTCAE grade 3 toxicity of symptomatic radiation necrosis with no grade 4–5 toxicities seen.
The rate of local relapse following HFRT to the surgical cavity is low with minimal risk of radiation necrosis. HFRT can be considered as an alternative to SRS for focal radiotherapy after brain metastasis resection.

View all citing articles on Scopus

: Conflict of interest: none.

View full text

Clinical InvestigationPostoperative Stereotactic Radiosurgery Without Whole-Brain Radiation Therapy for Brain Metastases: Potential Role of Preoperative Tumor Size

Purpose

Methods and Materials

Results

Conclusions

Introduction

Section snippets

Methods and Materials

Patient demographics

Discussion

Conclusions

Lancet Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Lancet

An era of rapid advancement: diagnosis and treatment of metastatic brain cancer

Neurosurgery

Radiation therapy for brain metastases

Ann Neurol

Current treatment approaches to surgery for brain metastases

Neurosurgery

Central nervous system metastases in HER-2 positive metastatic breast cancer patients treated with trastuzumab: incidence, survival, and risk factors

Oncologist

Clinical Investigation
Postoperative Stereotactic Radiosurgery Without Whole-Brain Radiation Therapy for Brain Metastases: Potential Role of Preoperative Tumor Size