Rates Of Distant Brain Failure Research Articles

Stereotactic Radiosurgery for Brain Metastases in Patients With Small Cell Lung Cancer

Treatment of small cell lung cancer (SCLC) with brain metastatic disease has traditionally involved whole brain radiation therapy (WBRT). The role of stereotactic radiosurgery (SRS) is unclear. Our study was a retrospective review of an SRS database evaluating patients with SCLC who received SRS. A total of 70 patients and 337 treated brain metastases (BM) were analyzed. Forty-five patients had previous WBRT. The median number of treated BM was 4 (range, 1-29). Median survival was 4.9 months (range, 0.70-23.9). The number of treated BM was correlated with survival; patients with fewer BM had improved overall survival (P < .021). The number of treated BM was associated with different brain failure rates; 1-year central nervous system control rates were 39.2% for 1 to 2 BM, 27.6% for 3 to 5 BM, and 0% for >5 treated BM. Patients with previous WBRT had worse brain failure rates (P < .040). For patients without previous WBRT, the 1-year distant brain failure rate was 48%, and median time to distant failure was 15.3 months. SRS for SCLC in patients with <5 BM appears to offer acceptable control rates. Patients with >5 BM have high rates of subsequent brain failure and are not ideal candidates for SRS.

Stereotactic radiosurgery for brain metastases from small cell lung cancer without prior whole-brain radiotherapy: A meta-analysis

ObjectivesAssess upfront Stereotactic radiosurgery (SRS) effectiveness for small cell lung cancer (SCLC) brain metastases (BM). Where possible, a comparison with whole-brain radiotherapy (WBRT) was performed. MethodsFollowing PRISMA and MOOSE guidelines, eligible studies were identified on Medline, Embase, Cochrane Library, and proceedings of annual meetings between inception and July 01, 2020. ResultsNine observational studies with 1638 patients were included. The median overall survival (OS) was 8.3 months (95% CI 7.1–9.5 months, I2 = 0%). OS rate at 12 months was 39% (95% CI 31–44%, I2 = 0%). The relative risk between SRS and WBRT for the OS at 12 months was 1.33 (95% CI 1.13–1.51, P = 0.0001). The projected OS for 6, 12, 18- and 24-months comparing SRS with WBRT was 67% vs. 57%, 39% vs. 29%, 22% vs. 15% and 15% vs 9%, favoring SRS (P < 0.001). The LC rate at 12 months was 93% (95% CI 91–94%, I2 = 0%). The distant brain failure rate (DBFR) at 12 months was 41% (95% CI 33–48%, I2 = 52%, P = 0.08). The SRS or WBRT as salvage treatment after upfront SRS was 32% and 19%, respectively. The freedom from neurologic death at 12 months was 87% (95% CI 84–89%). ConclusionBased on the pooling of a large sample of retrospective studies our meta-analysis suggests that for high selected SCLC patients with limited BM upfront SRS produces favorable lesion control and survival outcomes. These findings support the design of randomized clinical trial to confirm the role of SRS in this clinical scenario.

Long Term Outcomes And Patterns Of Failure After Single Fraction Preoperative Radiosurgery For Brain Metastases

Postoperative (post-op) radiosurgery (SRS) after resection of brain metastases (BM) is associated with up to 30% risk of leptomeningeal disease (LMD). Approximately 60-70% of LMD is nodular pattern in this setting, which is thought to be associated with surgical tumor spillage. We have previously demonstrated that preoperative (pre-op) SRS is a feasible alternative to post-op SRS. Herein we report patterns of failure and long terms outcomes for patients (pts) treated with pre-op SRS. The records for pts with BM treated with pre-op SRS and planned surgical resection were reviewed. Pts with classically radiosensitive tumors, prior or planned adjuvant whole brain radiotherapy (WBRT), or no cranial imaging ≥ 1 month after surgery were excluded. Pre-op SRS dose was based on lesion size and was reduced approximately 10-20% from standard. No gross tumor volume (GTV) margin expansion was used. Surgery generally followed within 48 hours. Overall survival (OS) was estimated using the Kaplan-Meier method. Intracranial event rates were estimated using cumulative incidence with competing risk of death. Radiographic pattern of LMD was classified as classical “sugarcoating” (cLMD) vs. nodular (nLMD). The study cohort consisted of 141 pts with 150 lesions treated with single fraction pre-op SRS followed by planned surgery between 2005 – 2018. Most pts had a single BM (67%), underwent gross total resection (GTR, 96%), and had non-small cell lung cancer (41%). Median interval between pre-op SRS and surgery was 2 days, median SRS dose was 15 Gy, and median GTV volume was 8.4 cc (approximately equivalent to 2.5 cm diameter lesion). The 2-year cavity local recurrence (LR) rate was 23% overall and 20% in pts status post GTR. Five of 6 pts status post subtotal resection experienced LR. Multivariate analysis demonstrated GTR and renal cell histology as significantly associated with reduced risk of LR. SRS dose, lesion volume, and time between pre-op SRS and surgery were not significant. The 2-year LMD rate was 5%. Two of the 9 patients with LMD (22%) had nLMD while 78% had cLMD. The 2-year radiation necrosis (RN), symptomatic RN, and non-LMD distant brain failure rate was 7%, 4%, and 58%, respectively. Median OS was 19 months. Thirty-seven pts with 40 lesions had long term (≥2 years of cranial imaging) follow-up. In this subset, the 5-year cavity LR, symptomatic RN, and LMD rate was 25%, 8%, and 12%, respectively. Single fraction pre-op SRS is an effective treatment for surgically resected BM with low rates of cavity LR, RN, and LMD. LMD after pre-op SRS seems to be distinct from post-op SRS with a lower overall rate and lower proportion of nLMD pattern, which supports pre-op SRS sterilization of surgical tumor spillage. Outcomes in pts with long term imaging follow-up are consistent with the overall cohort. These data support further studies of pre-op SRS, including a randomized trial of pre-op vs. post-op SRS.

Impact of breast cancer subtype on clinical outcomes after Gamma Knife radiosurgery for brain metastases from breast cancer: a multi-institutional retrospective study (JLGK1702).

Brain metastasis (BM) is one of the most important issues in the management of breast cancer (BC), since BMs are associated with neurological deficits. However, the importance of BC subtypes remains unclear for BM treated with Gamma Knife radiosurgery (GKS). Thus, we conducted a multicenter retrospective study to compare clinical outcomes based on BC subtypes, with the aim of developing an optimal treatment strategy. We studied 439 patients with breast cancer and 1-10 BM from 16 GKS facilities in Japan. Overall survival (OS) was analyzed by the Kaplan-Meier method, and cumulative incidences of systemic death (SD), neurologic death (ND), and tumor progression were estimated by competing risk analysis. OS differed among subtypes. The median OS time (months) after GKS was 10.4 in triple-negative (TN), 13.7 in Luminal, 31.4 in HER2, and 35.8 in Luminal-HER2 subtype BC (p < 0.0001). On multivariate analysis, poor control of the primary disease (hazard ratio [HR] = 1.84, p < 0.0001), active extracranial disease (HR = 2.76, p < 0.0001), neurological symptoms (HR 1.44, p = 0.01), and HER2 negativity (HR = 2.66, p < 0.0001) were significantly associated with worse OS. HER2 positivity was an independent risk factor for local recurrence (p = 0.03) but associated with lower rates of ND (p = 0.03). TN histology was associated with higher rates of distant brain failure (p = 0.03). HER2 positivity is related to the longer OS after SRS; however, we should pay attention to preventing recurrence in Luminal-HER2 patients. Also, TN patients require meticulous follow-up observation to detect distant metastases and/or LMD.

External Validity of a Nomogram and Recursive Partitioning Analysis to Predict for Distant Brain Failure After Stereotactic Radiosurgery Alone for Brain Metastases: Multi-institutional Analysis

Patients (pts) with brain metastases (BM) treated with stereotactic radiosurgery (SRS) alone are at increased risk of distant brain failure (DBF). A nomogram and recursive partitioning analysis (RPA) designed to predict for DBF at 1 year (yr) after SRS alone from a single institution Canadian tertiary care hospital was recently published (Rodrigues et al., Radio and Oncol 2014). We sought to evaluate the external validity of these tools using a multi-institutional independent validation cohort (VC). The records of consecutive pts with BM treated with SRS alone at 2 tertiary care cancer institutes between 2005-2013 were reviewed. Inclusion criteria were identical to the Canadian study and included pts treated with initial SRS alone, up to 3 BM, and no previous cranial irradiation. The nomogram variables included age, number of BM, largest lesion volume (cc), and WHO performance status (PS) to calculate probability of 1-yr DBF using the Kaplan-Meier method. The RPA defined 3 risk categories (low [LR], intermediate [IR], and high risk [HR]) based on PS, age, and number of BM. Discrimination was assessed using Harrell’s c-index and calibration was assessed using calibration plots and correlation between expected and observed DBF. After exclusions, a total of 282 pts with 390 BM and 303 pts with 416 BM were eligible for the nomogram and RPA VC, respectively. Median age was 60 years old, median tumor volume was 1.35 cc, and median number of BM was 1. Primary disease site was lung 44%, melanoma 20.2%, breast 17.4%, renal 7.8%, GI 2.8%, and other 11.6%. One-year actuarial DBF for the nomogram VC was 50.9% compared to 43.9% in the Canadian study. The Harrell’s c-index for the DBF nomogram using the VC was 0.56 compared to 0.69 in the Canadian study, indicating poor discrimination ability. Calibration plots for the nomogram demonstrated good correlation between predicted and observed DBF (r2=0.92), but with systematic underestimation of DBF risk by an average of 19.6% across all risk levels. RPA risk groups LR, IR, and HR had 1-yr DBF rates of 39%, 62%, and 51.8%, compared to Canadian rates of 25.1%, 45.9%, and 69.1%, respectively. RPA risk groups did demonstrate significantly different actuarial DBF rates (log-rank p=0.0008), but IR had a higher 1-yr DBF rate than HR and would have been categorized as high risk in the Canadian publication (> 40%). The accuracy of the RPA classification was 53% compared with 75% in the Canadian study. In an independent multi-institutional cohort, the Canadian nomogram and RPA classification were not found to be externally valid, had limited ability to accurately differentiate DBF at 1-yr, and generally underestimated risk of DBF. We currently recommend caution in using these tools to predict individualized risk of 1-yr DBF after SRS alone.

Local control after stereotactic radiosurgery for brain metastases in patients with melanoma with and without BRAF mutation and treatment

BRAF inhibitors improve progression-free and overall survival in patients with metastatic melanoma. Brain metastases are common, and stereotactic radiosurgery (SRS) has been used, resulting in excellent local control. Because BRAF inhibitors are associated with intracranial responses, the authors hypothesized that BRAF inhibitors would improve local control in patients with melanoma who are receiving SRS for brain metastases. The authors retrospectively identified patients with metastatic melanoma who had been tested for BRAF mutation and treated with SRS for brain metastases. Patients with previous resection, multiple brain metastases, or multiple courses of SRS were eligible. SRS was delivered in a single fraction to a median dose of 2000 cGy. Patients with a BRAF mutation were treated with a BRAF inhibitor on the basis of physician preference. The authors identified 52 patients who were treated in 82 treatment sessions for 185 brain metastases and 13 tumor beds. At a median follow-up of 10.5 months, the 1-year local control rate was 69.2%. At 1 year, the local control rate for brain metastases in patients with BRAF mutation with BRAF treatment was 85.0%, and the local control rate for brain metastases in those without BRAF treatment was 51.5% (p = 0.0077). The rates of distant brain failure, freedom from whole-brain radiation, and overall survival were not different on the basis of BRAF mutation status or inhibitor therapy. The number of new intratumoral hemorrhages after SRS was increased significantly in patients with BRAF treatment. Treatment with BRAF inhibitors was associated with improved local control after SRS in patients with melanoma and brain metastases. An increased number of intratumoral hemorrhages was associated with BRAF inhibitor therapy.

Prognostic Impact of Histologic Subtype in Non-Small Cell Lung Cancer Patients Treated with Gamma Knife Radiosurgery: Retrospective Analysis of 104 Patients.

In this study, factors affecting survival, local failure, distant brain failure, whole brain failure and whole-brain radiation therapy (WBRT) free survival according to histological subtypes were investigated in patients with brain metastases from non-small cell lung cancer (NSCLC). Patients with positive pathology reports for adenocarcinoma (ACA) and squamous cell carcinoma (SCC) were included in the study. Seventy-eight ACA and 26 SCC patients were included in the study. Patients with previous history of cerebral metastasis surgery and WBRT were excluded from the study. The median survival was calculated as 12.6 months for patients with ACA and 5.9 months for patients with SCC. One-year distant brain failure was calculated as 65.1% in ACA patients and 39.6% in SCC patients. One-year whole brain failure was calculated as 58.1% in ACA patients and 39.6% in SCC patients. The one-year freedom from WBRT rate was calculated as 72.8% in ACA patients and 56.3% in SCC patients. SCC histology was considered as a significant factor in deterioration of overall survival in multivariate analysis. SCC histology, the increase in the number of metastases and RPA class were factors that caused an increase in distant brain failure. Also, SCC histology, the increase in the number of metastases and RPA class were factors that caused an increase in whole brain failure. SCC histology may be an important prognostic factor for overall survival. Also, due to high distant brain failure rate in SCC histology, WBRT can be added to treatment early.

Treatment outcomes using CyberKnife for brain metastases from lung cancer.

We investigated the clinical outcomes following treatment using stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (SRT) for brain metastases from lung cancer. A total of 67 patients with 109 brain metastases from lung cancer treated using CyberKnife between 1998 and 2011 were retrospectively analyzed. SRS (median dose, 24 Gy) was used to treat 79 lesions, and 3-fraction SRT (median dose, 30 Gy) was used to treat 30 lesions. The median follow-up time was 9.4 months (range, 0.4–125 months). The 1-year local control rate was 83.3%, and the 1-year distant brain failure rate was 30.1%. The median survival time was 13.1 months, and the 1- and 3-year overall survival (OS) rates were 54.8% and 25.9%, respectively. On multivariate analysis, three factors were found to be statistically significant predictors of OS: (i) presence of uncontrolled primary disease [hazard ratio (HR) = 3.04; P = 0.002]; (ii) Brinkman index (BI) ≥ 1000 (HR = 2.75; P = 0.007); and (iii) pulmonary metastases (HR = 3.54; P = 0.009). Radionecrosis and worsening of neurocognitive function after radiosurgery were observed in 5 (7%) and 3 (4%) patients, respectively. Our results indicated that SRS/SRT for brain metastases from lung cancer was effective. Uncontrolled primary disease, high BI, and pulmonary metastases at treatment were significant risk factors for OS.

Whole brain radiotherapy plus simultaneous in-field boost with image guided intensity-modulated radiotherapy for brain metastases of non-small cell lung cancer.

BackgroundWhole brain radiotherapy (WBRT) plus sequential focal radiation boost is a commonly used therapeutic strategy for patients with brain metastases. However, recent reports on WBRT plus simultaneous in-field boost (SIB) also showed promising outcomes. The objective of present study is to retrospectively evaluate the efficacy and toxicities of WBRT plus SIB with image guided intensity-modulated radiotherapy (IG-IMRT) for inoperable brain metastases of NSCLC.MethodsTwenty-nine NSCLC patients with 87 inoperable brain metastases were included in this retrospective study. All patients received WBRT at a dose of 40 Gy/20 f, and SIB boost with IG-IMRT at a dose of 20 Gy/5 f concurrent with WBRT in the fourth week. Prior to each fraction of IG-IMRT boost, on-line positioning verification and correction were used to ensure that the set-up errors were within 2 mm by cone beam computed tomography in all patients.ResultsThe one-year intracranial control rate, local brain failure rate, and distant brain failure rate were 62.9%, 13.8%, and 19.2%, respectively. The two-year intracranial control rate, local brain failure rate, and distant brain failure rate were 42.5%, 30.9%, and 36.4%, respectively. Both median intracranial progression-free survival and median survival were 10 months. Six-month, one-year, and two-year survival rates were 65.5%, 41.4%, and 13.8%, corresponding to 62.1%, 41.4%, and 10.3% of intracranial progression-free survival rates. Patients with Score Index for Radiosurgery in Brain Metastases (SIR) >5, number of intracranial lesions <3, and history of EGFR-TKI treatment had better survival. Three lesions (3.45%) demonstrated radiation necrosis after radiotherapy. Grades 2 and 3 cognitive impairment with grade 2 radiation leukoencephalopathy were observed in 4 (13.8%) and 4 (13.8%) patients. No dosimetric parameters were found to be associated with these late toxicities. Patients received EGFR-TKI treatment had higher incidence of grades 2–3 cognitive impairment with grade 2 leukoencephalopathy.ConclusionsWBRT plus SIB with IG-IMRT is a tolerable and effective treatment for NSCLC patients with inoperable brain metastases. However, the results of present study need to be examined by the prospective investigations.

Resection Cavity Dynamics Following Implantation of Cesium-131 (Cs-131) Brachytherapy for Resection Brain Metastases Based on CT-Planning

months). When analyzing the time to recurrence in 2 month intervals, the highest rates of local brain failure occurred between 6-12 months after SRS. The highest rates of distant brain failure occurred between 4-12 months after SRS. Salvage options include SRS and WBRT; 12 patients (16%) were eventually salvaged by WBRT. Median overall survival was 18 months. Conclusions: For patients with a resected single brain metastasis treated with post-op SRS, local and distant brain failures were highest 4-12 months after radiosurgery. Therefore, surveillance imaging should be most frequent, possibly every 2 months, during the first year post-treatment and the frequency could be decreased thereafter. Author Disclosure: K. Kalakota: None. S.S. Rakhra: None. O. Hideki: None. I. Helenowski: None. M.H. Marymont: None. J.A. Kalapurakal: None. J.P. Chandler: None. M.P. Mehta: G. Consultant; Abbott, BristolMeyers-Squibb, Elekta, Genentech, Merck, Novartis, Novocure, Viewray. L. Stock Options; Accuray, Pharmacyclics. Q. Leadership; Pharmacyclics.

Factors Influencing Local Control and Survival in Patients Treated With Radiosurgery Following Surgical Resection of CNS Metastases

months). When analyzing the time to recurrence in 2 month intervals, the highest rates of local brain failure occurred between 6-12 months after SRS. The highest rates of distant brain failure occurred between 4-12 months after SRS. Salvage options include SRS and WBRT; 12 patients (16%) were eventually salvaged by WBRT. Median overall survival was 18 months. Conclusions: For patients with a resected single brain metastasis treated with post-op SRS, local and distant brain failures were highest 4-12 months after radiosurgery. Therefore, surveillance imaging should be most frequent, possibly every 2 months, during the first year post-treatment and the frequency could be decreased thereafter. Author Disclosure: K. Kalakota: None. S.S. Rakhra: None. O. Hideki: None. I. Helenowski: None. M.H. Marymont: None. J.A. Kalapurakal: None. J.P. Chandler: None. M.P. Mehta: G. Consultant; Abbott, BristolMeyers-Squibb, Elekta, Genentech, Merck, Novartis, Novocure, Viewray. L. Stock Options; Accuray, Pharmacyclics. Q. Leadership; Pharmacyclics.

Breast cancer subtype affects patterns of failure of brain metastases after treatment with stereotactic radiosurgery

We investigate the variance in patterns of failure after Gamma Knife™ radiosurgery (GKRS) for patients with brain metastases based on the subtype of the primary breast cancer. Between 2000 and 2010, 154 breast cancer patients were treated with GKRS for brain metastases. Tumor subtypes were approximated based on hormone receptor (HR) and HER2 status of the primary cancer: Luminal A/B (HR+/HER2(-)); HER2 (HER2+/HR(-)); Luminal HER2 (HR+/HER2+), Basal (HR(-)/HER2(-)), and then based on HER2 status alone. The median follow-up period was 54 months. Kaplan-Meier method was used to estimate survival times. Multivariable analysis was performed using Cox regression models. Median number of lesions treated was two (range 1-15) with a median dose of 20 Gy (range 9-24 Gy). Median overall survival (OS) was 7, 9, 11 and 22 months for Basal, Luminal A/B, HER2, and Luminal HER2, respectively (p = 0.001), and was 17 and 8 months for HER2+ and HER(-) patients, respectively (p < 0.001). Breast cancer subtype did not predict time to local failure (p = 0.554), but did predict distant brain failure rate (76, 47, 47, 36 % at 1 year for Basal, Luminal A/B, HER2, and Luminal HER2 respectively, p < 0.001). An increased proportion of HER2+ patients experienced neurologic death (46 vs 31 %, p = 0.066). Multivariate analysis revealed that HER2+ patients (p = 0.007) independently predicted for improved survival. Women with basal subtype have high rates of distant brain failure and worsened survival. Our data suggest that differences in biologic behavior of brain metastasis occur across breast cancer subtypes.

Stereotactic Radiosurgery of the Postoperative Resection Cavity for Brain Metastases: Prospective Evaluation of Target Margin on Tumor Control

Given the neurocognitive toxicity associated with whole-brain irradiation (WBRT), approaches to defer or avoid WBRT after surgical resection of brain metastases are desirable. Our initial experience with stereotactic radiosurgery (SRS) targeting the resection cavity showed promising results. We examined the outcomes of postoperative resection cavity SRS to determine the effect of adding a 2-mm margin around the resection cavity on local failure (LF) and toxicity. We retrospectively evaluated 120 cavities in 112 patients treated from 1998-2009. Factors associated with LF and distant brain failure (DF) were analyzed using competing risks analysis, with death as a competing risk. The overall survival (OS) rate was calculated by the Kaplan-Meier product-limit method; variables associated with OS were evaluated using the Cox proportional hazards and log rank tests. The 12-month cumulative incidence rates of LF and DF, with death as a competing risk, were 9.5% and 54%, respectively. On univariate analysis, expansion of the cavity with a 2-mm margin was associated with decreased LF; the 12-month cumulative incidence rates of LF with and without margin were 3% and 16%, respectively (P=.042). The 12-month toxicity rates with and without margin were 3% and 8%, respectively (P=.27). On multivariate analysis, melanoma histology (P=.038) and number of brain metastases (P=.0097) were associated with higher DF. The median OS time was 17 months (range, 2-114 months), with a 12-month OS rate of 62%. Overall, WBRT was avoided in 72% of the patients. Adjuvant SRS targeting the resection cavity of brain metastases results in excellent local control and allows WBRT to be avoided in a majority of patients. A 2-mm margin around the resection cavity improved local control without increasing toxicity compared with our prior technique with no margin.

Patterns of Failure in Patients Receiving Gamma Knife Radiosurgery for Breast Carcinoma to the Brain

Patterns of Failure in Patients Receiving Gamma Knife Radiosurgery for Breast Carcinoma to the Brain