Risk Of Distant Brain Failure Research Articles

P2.03-04 Predicting Risk of Distant Brain Failure with Radiosurgery and Systemic Therapy in a Diverse NSCLC Brain Metastasis Population

P2.03-04 Predicting Risk of Distant Brain Failure with Radiosurgery and Systemic Therapy in a Diverse NSCLC Brain Metastasis Population

Safety and efficacy of silibinin in patients with brain metastases after stereotactc radiosurgery: SUSTAIN trial.

e14012 Background: Brain metastases (BMs) account for more than one-half of all intracranial tumors. Over the past years, stereotactic radiosurgery (SRS) has become the mainstay of BMs treatment, providing high rates of local tumor control. Nevertheless, SRS alone is associated with a 30-50% risk of distant brain failure (DBF), consequently requiring careful follow-up and possible rescue treatments. Silibinin or silybin, a natural polyphenolic flavonoid, has shown promising antitumor activity, leading to improvement of BMs in patients (pts) with progressive non-small cell lung cancer. Therefore, our exploratory study aims to evaluate whether the use of a silibinin-based nutraceutical can significantly reduce DBF rate at 6 months in pts with first-diagnosed BMs treated with SRS with or without surgery. Methods: SUSTAIN is an interventional, prospective, single arm, phase II study. A total of 80 pts treated in our center are planned to be enrolled. Pts receive 2 capsules (cps) of silibinin-based nutraceutical per day for the first month after SRS and 1 cp per day thereafter. Primary endpoints are 6-month distant brain failure (DBF) rate and safety; secondary endpoint is 6-month overall survival (OS) rate. Contrast-enhanced magnetic resonance (MRI) of the brain is performed at baseline and every 12 weeks after SRS treatment; radiological response is assessed according to RANO criteria for brain metastases (RANO-BM). Results: Thirty pts has been enrolled at the time of this primary analysis (Tab1). NSCLC and breast cancer were the prevalent histologies (14 and 10 cases respectively). Twelve pts were chemotherapy naive at the time of BMs diagnosis; 10 pts has received 1 systemic therapy line and 8 pts has received 2 lines or more. Overall, the number of treated lesions was 73, with a median of 1 lesion (range 1-9). All pts underwent SRS (Fig.1), with a median prescription dose (PD) and a median prescription isodose line (IDL) of 24 Gy and 80% respectively. After a 14-month enrollment period, with a median follow-up of 9 months, 6 pts reported distant intracranial failure according to RANO-BM criteria, with a 6-month DBF rate of 20%. Only 1 treated lesion met the criteria for progression, accounting for a 6-month local control (LC) rate of 98%. Six pts died, with a 6-month OS rate of 80%. Radiological radionecrosis was detected in 3 pts (10%), who developed G1 neurological symptoms managed with low-dose dexamethasone. Two pts discontinued silibinin-based nutraceutical assumption due to G1 nausea. No other adverse events were reported. Conclusions: At about half of our enrollment target, the results show a favorable trend towards 6-month DBF rate reduction. Toxicity proved manageable, consistent with the literature and limited to gastrointestinal effects. A larger sample and longer follow-up is needed to confirm our hypothesis.

Stereotactic radiosurgery versus whole-brain radiotherapy after resection of solitary brain metastasis: A systematic review and meta-analysis

ObjectiveThe standard of care in patients with solitary brain metastasis involves surgical resection and postoperative whole-brain radiotherapy (WBRT). However, WBRT is associated with adverse effects, mainly neurocognitive deterioration. Stereotactic radiosurgery (SRS) is a more targeted form of radiation therapy that could be as effective as WBRT without the detrimental neurocognitive decline. MethodsWe performed the first systematic review and meta-analysis comparing postoperative SRS versus postoperative WBRT in patients with one resected brain metastasis. PubMed, Scopus, and Cochrane library were systematically searched for studies comparing the efficacy of the two radiation modalities in terms of local and distant brain control, leptomeningeal disease control, and overall survival. Additionally, we extracted patients’ neurocognitive function and quality of life after each postoperative radiation form. ResultsFour studies with 248 patients (128: WBRT, 120: SRS) were included in our analysis. There was no difference between SRS and WBRT in the risk of local recurrence (RR = 0.92, CI = 0.51–1.66, p = 0.78, I2 = 0%) and leptomeningeal disease (RR = 1.21, CI = 0.49–2.98, p = 0.67, I2 = 18%), neither in the patients’ overall survival (HR = 1.06, CI = 0.61–1.85, p = 0.83, I2 = 63%). Nevertheless, SRS appeared to increase the risk of distant brain failure (RR = 2.03, CI = 0.94–4.40, p = 0.07, I2 = 61%). Neurocognitive function and quality of life in the SRS group were equal or superior to the WBRT group. ConclusionsAlthough SRS may increase the risk of distant brain failure, it appears to be as effective as WBRT in terms of local control, risk of leptomeningeal disease, and overall survival while sparing the patients of the detrimental, WBRT-associated cognitive deterioration.

Abstract PS15-10: Survival outcomes and prognosis for patients with triple negative breast cancer who received stereotactic radiosurgery for brain metastases

Abstract Background: Triple-negative breast cancer (TNBC) has a high propensity for brain metastasis (BM) with poor prognosis. Stereotactic radiosurgery (SRS) has emerged as an effective treatment option for BM. However, clinical outcomes after SRS for BM from TNBC have not been well defined. We evaluated survival outcomes and prognostic factors among TNBC patients who received SRS for BMs.Methods: We retrospectively reviewed 99 patients with TNBC and BM who had received SRS at a single large-volume cancer center from May 2008 through April 2018. For the initial treatment of BM, 73 patients received SRS, 25 received whole-brain radiotherapy (WBRT), and 1 patient received surgery. Endpoints were overall survival (OS) from BM diagnosis, BM progression-free survival (BMPFS) from start of BM treatment, and times to intracranial local and distant failure from start of BM treatment. Both intracranial local and distant failure were considered BM progression. Local failure was defined as an increase in size of any treated lesions on imaging or assessment of treating physicians; enlargement attributable to radiation necrosis or post-radiation change was not counted as local failure. Kaplan-Meier analysis and Cox proportional hazard regression models were used to estimate survival curves and identify prognostic factors.Results: The median follow-up time from BM diagnosis was 12.7 months (95% confidence interval [CI] 1.3–52.1). The median age at BM diagnosis was 52 (range 24-82). The median interval between the diagnosis of primary breast cancer and BM was 25.8 months (95% CI 8.7–120.3). Of the 99 patients, 81 (81.8%) had 1-3 BMs and 18 (18.2%) had >3 BMs at diagnosis. The median OS time for all patients was 13.3 months (95% CI 10.3–16.4), and the cumulative survival rates were 55.1% at 1 year and 29.2% at 2 years. Factors independently associated with increased risk of death in multivariate analysis were Karnofsky performance score (KPS) ≤70 (p=0.01) and uncontrolled extracranial metastasis at BM diagnosis (p=0.05). No difference was found in OS according to type of initial treatment for BMs. Of the initial 99 patients, 12 were excluded from the evaluation of BMPFS, local and distant failure for missing follow-up imaging after initial treatment. The median BMPFS time was 7.2 months (95% CI 5.1–9.3). Of the 87 evaluable patients, 23 (26.4%) developed local recurrence after initial treatment, and among these 10 of 61 patients (16.4%) had received SRS and 13 of 25 patients (52%) had received WBRT. Patients initially treated with SRS had longer time to local failure than WBRT (50th percentile not reached vs. median 14.0 months, p=0.001). Multivariate analysis showed higher risk of local failure for patients who initially received WBRT versus SRS (hazard ratio [HR] 3.4, p=0.005). Forty-nine of 87 patients (56.3%) developed distant brain recurrence after initial treatment, and among these 35 of 61 patients (57.4%) had received SRS and 14 of 25 patients (56%) had received WBRT. No difference in risk of distant brain failure was found for patients initially treated with SRS versus WBRT (p=0.24). No difference was found in time to develop distant failure after initial treatment with SRS (median 18.4 months) versus WBRT (median 12.8 months, p=0.24).Conclusion: Patients with BM from TNBC had a median OS time of 13.3 months and a BMPFS time of 7.2 months. KPS≤70 and uncontrolled extracranial disease at the time of BM diagnosis were independent prognostic factors that increase risk of death. Patients initially treated with SRS had a longer time to develop intracranial local failure than those initially given WBRT, and this may be related to patient selection. Further prospective studies of larger numbers of patients with BM from TNBC are needed for a more accurate comparison of treatment modalities. Citation Format: Ran An, Yan Wang, Fuchenchu Wang, Chao Gao, Akshara Singareeka Raghavendra, Diana Amaya, Nuhad K Ibrahim, Jing Li. Survival outcomes and prognosis for patients with triple negative breast cancer who received stereotactic radiosurgery for brain metastases [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS15-10.

Preserving Neurocognition Without Compromising Tumor Control During Whole-Brain Radiotherapy Therapy In Patients With Numerous Brain Metastases Via A Novel Superoxide Dismutase Mimetic: Initial Safety Lead-In And Design Of A Clinical Trial

Patients with a large number of brain metastases (BM) present a clinical challenge. While stereotactic radiosurgery (SRS) has extended the number of BM that can be effectively treated, SRS does not treat occult disease and distant brain failure (DBF) post-SRS remains high. In contrast, whole-brain radiotherapy (WBRT) provides high rates of local control and, compared to SRS, reduces the risk of distant brain failure. Unfortunately, WBRT is also associated with substantial neurocognitive deficits, even with hippocampal avoidance, altered fractionation and neuroprotectants. BMX-001, a novel Mn-porphyrin superoxide dismutase mimetic, has been shown to protect normal tissues from ionizing radiation in preclinical trials, reducing neurocognitive adverse effects, as well as enhancing tumor response. We hypothesized that this agent would reduce neurocognitive decline while possibly improving tumor control in patients with numerous brain metastases undergoing WBRT. This protocol is composed of a lead-in safety study of 5 patients followed by a randomized Phase 2 clinical trial of BMX-001, in 64 patients with multiple brain metastases (MBM) undergoing WBRT. Eligible patients are adults with more than 10 brain metastases, a KPS of >60 and a life expectancy >3 months. All patients will undergo WBRT to a total dose of 30 Gy in 3 Gy daily fractions. Patients in the safety lead-in study and the BMX-001 cohort of the randomized trial will receive a loading dose of this agent immediately prior to starting WBRT, then a maintenance dose twice weekly during WBRT and once within 4 days of completing WBRT. Primary endpoint is change in neurocognition, as measured by Trailmaking, Hopkins Verbal Learning and Controlled Oral Word Association tests pre and post WBRT. Secondary endpoints include overall survival, quality of life, toxicity, local recurrence, distant brain failure, neurologic death and radionecrosis. The safety lead-in portion of this trial was completed in August 2019. All 5 patients completed WBRT and BMX-001 per protocol. The majority of subjects experienced Grade 1 non-hematologic AEs, primarily injection site reactions (including erythema, itching, welts, bruising around injection sites); 1 patient experienced a Grade 2 QT prolongation. No severe toxicities (Grade 3), life-threatening toxicities (Grade 4), or treatment related deaths (Grade 5) were reported. Initial post-WBRT brain MR imaging showed at least a partial tumor response. The randomized clinical trial is now open at multiple institutions. It appears reasonable to proceed with the randomized clinical trial of WBRT +/- BMX-001 in patients with numerous brain metastases. Enrollment on this trial is essential to test the hypothesis that this agent is an effective neuroprotectant.

TRLS-10. MITIGATING NEUROCOGNITIVE DEFICITS FROM WHOLE-BRAIN RADIOTHERAPY IN PATIENTS WITH NUMEROUS BRAIN METASTASES VIA A NOVEL SUPEROXIDE DISMUTASE MIMETIC: RATIONALE & DESIGN OF A CLINICAL TRIAL

BACKGROUND: Patients with a large number of brain metastases (BM) and/or micrometastatic disease in the brain present a clinical challenge. While technical innovations in stereotactic radiosurgery (SRS) have extended the number of BM that can be effectively treated, SRS does not treat occult disease and distant brain failure (DBF) post-SRS remains high. Immuno- and targeted therapies show promise in treating metastatic disease to the brain, though response rates are variable. In contrast, whole-brain radiotherapy (WBRT) provides high rates of local control and, compared to SRS, reduces the risk of distant brain failure. Unfortunately, WBRT is also associated with substantial neurocognitive deficits and neither altered fractionation nor the use of available neuroprotectants has adequately addressed this issue. An agent that safely minimizes the adverse effects of WBRT while preserving or enhancing tumor control would provide meaningful clinical benefit. TRIAL DESIGN: BMX-001, a novel Mn-porphyrin superoxide dismutase mimetic, has been shown to protect normal tissues from ionizing radiation in preclinical trials, reducing neurocognitive adverse effects as well as enhancing tumor response. Based on the first-in-human trial of this agent in patients with high-grade gliomas, we have instituted a clinical trial of WBRT +/- BMX-001 in adult patients with more than 10 BM from melanoma, non-small-cell lung, breast and renal cancer. Following a safety lead-in of 5 patients, all of whom will receive WBRT and BMX-001, 69 patients will be randomized to WBRT (3Gy/fraction x 10 fractions) with or without BMX-001 administered subcutaneously before, twice weekly during and once after WBRT (6 injections total.) The primary endpoint is cognition, as measured by the Hopkins Verbal Learning, Trailmaking A/B and Controlled Oral Word Association tests. Secondary endpoints include health-related quality-of-life, overall and progression-free survival, rates of radiation necrosis, DBF and neurologic death. Enrollment began January 2019. (ClinicalTrials.gov Identifier: NCT03608020.)

Improved Survival Following Immunotherapy in Patients with Lung and Melanoma Primaries Metastatic to the Brain Treated with Upfront Stereotactic Radiosurgery

For patients with lung or melanoma primaries metastatic to the brain, immunotherapy has improved extracranial disease control but results on intracranial disease outcomes after stereotactic radiosurgery (SRS) are not well understood. We sought to evaluate survival, risk of neurologic death and risk of distant brain failure (DBF) and to determine the brain metastasis velocity (BMV) in this patient population comparing those treated with and without immunotherapy. We performed a single institution retrospective analysis of 257 consecutive patients with lung or melanoma primaries metastatic to the brain treated with upfront SRS. 170 of these patients did not receive immunotherapy as part of their treatment and 87 of these patients did. Of the patients that received immunotherapy, 42 (48%) received nivolumab, 24 (28%) received pembrolizumab and 15 (17%) received ipilimumab. 1 (1%) used a combination of nivolumab/ipilimumab and 5 (6%) received other or unknown immunotherapy treatments. BMV was calculated as previously described and compared using the Mann-Whitney U test. The cumulative incidences (CI) of DBF were estimated with death as a competing risk. Overall survival was estimated using the Kaplan Meier method. From 2013-2016, 257 patients with lung or melanoma primaries metastatic to the brain and treated with upfront SRS were identified for review. The median age at diagnosis was 66 (IQR: 57-72). Median OS in patients treated with and without immunotherapy was 22.4 and 6.1 months (log-rank p<0.01), respectively. Median freedom from neurologic death in patients treated with and without immunotherapy was 24.8 and 10.2 months (log-rank p=0.04). The one-year CI of DBF in patients with and without immunotherapy was 57% and 36% (p < 0.01). When stratified by primary histology, 1-year DBF rates with and without immunotherapy were 53% vs. 30% for lung (p<0.01) and 65% vs 95% for melanoma (p<0.01). Of the 115 patients with distant brain failure, median BMV at first failure (BMV1) in patients with and without immunotherapy was 9.0 and 11.4 (p=0.85). Median BMV1 was 14.0 and 6.4 in patients who received immunotherapy before and after SRS (p=0.37). This difference was most pronounced in lung cancer patients (42.6 v. 6.2, p=0.14). Median total BMV over the course of follow-up in patients with and without immunotherapy was 6.8 and 7.3 and 8.0 versus 5.9 in patients who received immunotherapy before and after SRS. Univariate linear regression analysis revealed an association between total number of cycles of immunotherapy and total BMV (β=-1.67, SE=0.77, p=0.04). These findings suggest that while immunotherapy improves overall survival and decreases neurologic death in lung cancer and melanoma brain metastasis patients, continued progression in the brain remains an issue.

External validity of two nomograms for predicting distant brain failure after radiosurgery for brain metastases in a bi-institutional independent patient cohort.

Patients treated with stereotactic radiosurgery (SRS) for brain metastases (BM) are at increased risk of distant brain failure (DBF). Two nomograms have been recently published to predict individualized risk of DBF after SRS. The goal of this study was to assess the external validity of these nomograms in an independent patient cohort. The records of consecutive patients with BM treated with SRS at Levine Cancer Institute and Emory University between 2005 and 2013 were reviewed. Three validation cohorts were generated based on the specific nomogram or recursive partitioning analysis (RPA) entry criteria: Wake Forest nomogram (n = 281), Canadian nomogram (n = 282), and Canadian RPA (n = 303) validation cohorts. Freedom from DBF at 1-year in the Wake Forest study was 30% compared with 50% in the validation cohort. The validation c-index for both the 6-month and 9-month freedom from DBF Wake Forest nomograms was 0.55, indicating poor discrimination ability, and the goodness-of-fit test for both nomograms was highly significant (p < 0.001), indicating poor calibration. The 1-year actuarial DBF in the Canadian nomogram study was 43.9% compared with 50.9% in the validation cohort. The validation c-index for the Canadian 1-year DBF nomogram was 0.56, and the goodness-of-fit test was also highly significant (p < 0.001). The validation accuracy and c-index of the Canadian RPA classification was 53% and 0.61, respectively. The Wake Forest and Canadian nomograms for predicting risk of DBF after SRS were found to have limited predictive ability in an independent bi-institutional validation cohort. These results reinforce the importance of validating predictive models in independent patient cohorts.

External Validity of a Nomogram Predicting Risk of 6-Month and 9-Month Distant Brain Failure After Initial Stereotactic Radiosurgery Alone for Brain Metastases in an Independent Multi-institutional Patient Cohort

Patients (pts) treated with stereotactic radiosurgery (SRS) alone for brain metastases (BM) are at increased risk of distant brain failure (DBF). A nomogram for predicting individualized 6 and 9-month freedom from DBF after SRS was recently published based on a single institution database (Ayala-Peacock et al., Neuro Oncol 2014). This nomogram has not undergone external validation in an independent patient population. The goal of this study was to assess the external validity of this nomogram in a multi-institutional independent patient cohort. The records of consecutive pts with BM treated with SRS alone at 2 tertiary care cancer institutes between 2005-2013 were reviewed. Inclusion criteria was the same as the Ayala-Peacock study and included patients with BM treated with initial SRS alone, no previous cranial radiotherapy, up to 13 synchronous BM, and either non-small cell lung (NSCLC), breast, renal cell (RCC), or melanoma primary cancer. Additionally, our validation cohort excluded pts with less than 3 months MRI follow-up. The nomogram variables included age, sex, race, primary histology, systemic disease status, and number of BM to calculate 6 and 9-month freedom from DBF using the Kaplan-Meier method. Discrimination was assessed using the Harrell’s c-index and calibration was evaluated using calibration plots and correlation between expected and observed freedom from DBF. After exclusions, 281 patients with 416 BM were eligible and made up the validation cohort. The median patient age was 61 years old, 48% were male, and 78% were white. Primary site was NSCLC for 49%, melanoma - 25%, breast - 19%, RCC - 8%, and 63% had active systemic disease at the time of SRS. The median imaging follow-up period was 13.4 months (range 3 – 124.7 months). Freedom from DBF at 6-months and 1-year in the Ayala-Peacock study was 59% and 30% compared with 64% and 50% in the validation cohort. DBF occurred within 6 months from SRS in 99 pts (35%) and within 9 months in 119 pts (42%) in the validation cohort. The Harrell’s c-index for both the 6-month and 9-month DBF nomogram using the validation cohort was 0.55, indicating poor discrimination ability. Calibration plots for the 6-month DBF nomogram demonstrated underestimation of DBF risk at the lower end of predicted risk and overestimation at the upper end with moderate correlation (r2=0.72). Calibration plots of the 9-month nomogram demonstrated systematic overestimation of DBF risk with moderate correlation (r2=0.68). The Ayala-Peacock et al. nomogram for predicting 6 and 9-month freedom from DBF after SRS alone for BM was not found to be externally valid in an independent multi-institutional cohort and cannot be recommended for clinical use at this time. These results reinforce the importance of validating predictive models in independent cohorts.

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.

A phase 2 study of radiosurgery and temozolomide for patients with 1 to 4 brain metastases

PurposeTo determine if temozolomide reduces the risk of distant brain failure (DBF, metachronous brain metastases) in patients with 1 to 4 brain metastases treated with radiosurgery without whole-brain radiation therapy (WBRT). Methods and materialsTwenty-five patients with newly diagnosed brain metastases were enrolled in a single institution phase 2 trial of radiosurgery (15-24 Gy) and adjuvant temozolomide. Temozolomide was continued for a total of 12 cycles unless the patient developed DBF, unacceptable toxicity, or systemic progression requiring other therapy. ResultsTwenty-five patients were enrolled between 2002 and 2005; 3 were not evaluable for determining DBF. Of the remaining 22 patients, tumor types included non-small cell lung cancer (n = 8), melanoma (n = 7), and other (n = 7). Extracranial disease was present in 10 (45%) patients. The median number of tumors at the time of radiosurgery was 3 (range, 1-6). The median overall survival was 31 weeks. The median radiographic follow-up for patients who did not develop DBF was 33 weeks. Six patients developed DBF. The 1-year actuarial risk of DBF was 37%. ConclusionsIn this study, there was a relatively low risk of distant brain failure observed in the nonmelanoma subgroup receiving temozolamide. However, patient selection factors rather than chemotherapy treatment efficacy are more likely the reason for the relatively low risk of distant brain failure observed in this study. Future trial design should account for these risk factors.

Novel risk scores for survival and intracranial failure in patients treated with radiosurgery alone to melanoma brain metastases.

PurposeStereotactic radiosurgery (SRS) alone is an increasingly common treatment strategy for brain metastases. However, existing prognostic tools for overall survival (OS) were developed using cohorts of patients treated predominantly with approaches other than SRS alone. Therefore, we devised novel risk scores for OS and distant brain failure (DF) for melanoma brain metastases (MBM) treated with SRS alone.Methods and materialsWe retrospectively reviewed 86 patients treated with SRS alone for MBM from 2009-2014. OS and DF were estimated using the Kaplan-Meier method. Cox proportional hazards modeling identified clinical risk factors. Risk scores were created based on weighted regression coefficients. OS scores range from 0-10 (0 representing best OS), and DF risk scores range from 0-5 (0 representing lowest risk of DF). Predictive power was evaluated using c-index statistics. Bootstrapping with 200 resamples tested model stability.ResultsThe median OS was 8.1 months from SRS, and 54 (70.1 %) patients had DF at a median of 3.3 months. Risk scores for OS were predicated on performance status, extracranial disease (ED) status, number of lesions, and gender. Median OS for the low-risk group (0-3 points) was not reached. For the moderate-risk (4-6 points) and high-risk (6.5-10) groups, median OS was 7.6 months and 2.4 months, respectively (p < .0001). Scores for DF were predicated on performance status, ED status, and number of lesions. Median time to DF for the low-risk group (0 points) was not reached. For the moderate-risk (1-2 points) and high-risk (3-5 points) groups, time to DF was 4.8 and 2.0 months, respectively (p < .0001). The novel scores were more predictive (c-index = 0.72) than melanoma-specific graded prognostic assessment or RTOG recursive partitioning analysis tools (c-index = 0.66 and 0.57, respectively).ConclusionsWe devised novel risk scores for MBM treated with SRS alone. These scores have implications for prognosis and treatment strategy selection (SRS versus whole-brain radiotherapy).

Phase 3 Trials of Stereotactic Radiosurgery With or Without Whole-Brain Radiation Therapy for 1 to 4 Brain Metastases: Individual Patient Data Meta-Analysis

To perform an individual patient data (IPD) meta-analysis of randomized controlled trials evaluating stereotactic radiosurgery (SRS) with or without whole-brain radiation therapy (WBRT) for patients presenting with 1 to 4 brain metastases. Three trials were identified through a literature search, and IPD were obtained. Outcomes of interest were survival, local failure, and distant brain failure. The treatment effect was estimated after adjustments for age, recursive partitioning analysis (RPA) score, number of brain metastases, and treatment arm. A total of 364 of the pooled 389 patients met eligibility criteria, of whom 51% were treated with SRS alone and 49% were treated with SRS plus WBRT. For survival, age was a significant effect modifier (P=.04) favoring SRS alone in patients ≤50 years of age, and no significant differences were observed in older patients. Hazard ratios (HRs) for patients 35, 40, 45, and 50 years of age were 0.46 (95% confidence interval [CI] = 0.24-0.90), 0.52 (95% CI = 0.29-0.92), 0.58 (95% CI = 0.35-0.95), and 0.64 (95% CI = 0.42-0.99), respectively. Patients with a single metastasis had significantly better survival than those who had 2 to 4 metastases. For distant brain failure, age was a significant effect modifier (P=.043), with similar rates in the 2 arms for patients ≤50 of age; otherwise, the risk was reduced with WBRT for patients >50 years of age. Patients with a single metastasis also had a significantly lower risk of distant brain failure than patients who had 2 to 4 metastases. Local control significantly favored additional WBRT in all age groups. For patients ≤50 years of age, SRS alone favored survival, in addition, the initial omission of WBRT did not impact distant brain relapse rates. SRS alone may be the preferred treatment for this age group.

Clinical outcomes of reirradiation of brain metastases from small cell lung cancer with Cyberknife stereotactic radiosurgery

To analyze outcomes of reirradiation with stereotactic radiosurgery (SRS) for patients with brain metastases from small cell lung cancer (SCLC). We reviewed the clinical outcomes of 27 patients with brain metastases from SCLC treated with CyberKnife® robotic radiosurgery (Accuray Inc., Sunnyvale, CA). Kaplan-Meier analyses were used to estimate local control (LC), intracranial control (IC), and overall survival (OS). The Graded Prognostic Assessment (GPA) prognostic index was determined with a Cox Regression analysis to model predictors of outcome. The median follow-up from SRS was 12 months (2-24 months). Nine patients (32.1%) had Graded Prognostic Assessment (GPA) scores 0-1 and 19 patients (67.9%) had GPA scores 1.5-2.5. 19 patients (70%) received whole brain radiation therapy (WBRT) and 8 patients (30%) received prophylactic cranial irradiation (PCI). The median SRS dose was 20.5 Gy (15-24 Gy) in 1 fraction. Actuarial LC at 6 months and 12 months was 76.5% and 76.5%, respectively. New metastases outside the treated area developed in 60% of assessable patients at a median 3.5 months; 78% received previous WBRT. The median OS was 3 months from SRS with actuarial 6-month and 12-month rates of 25% and 3.6%, respectively. On multivariate analysis no factors were associated with LC, IC, or OS. SRS for reirradiation of brain metastases from SCLC is safe and achieves local tumor control in the majority of patients. Despite SRS, these patients are at high risk of distant brain failure.

Risk factors of distant brain failure for patients with newly diagnosed brain metastases treated with stereotactic radiotherapy alone

ObjectiveTo explore the risk factors of distant brain failure (DBF) for patients with brain metastasis (BM) who were treated with stereotactic radiotherapy alone and to group the patients on the basis of their risk levels.Methods and MaterialsWe retrospectively analyzed 132 newly diagnosed BM patients who were treated with stereotactic radiotherapy alone from May 2000 to April 2010. Kaplan-Meier and Cox proportional hazards regression analyses were performed for univariate and multivariate analyses.ResultsThe 1-year incidence rate of DBF was 44.7%, and the median DBF time (MDBFT) was 18 months. In multivariate analysis, the risk factors of DBF were the number of BMs greater than 1 (p = 0.041), uncontrolled extracranial disease (p = 0.005), interval time (IT) of less than 60 months between the diagnosis of primary tumor and BM (p = 0.024), and total volume of BM was greater than 6 cc (p = 0.049). Each risk factor was assigned 1 score. The median survival times for the patients with scores of 0-1, 2-3, and 4 were 31, 12, and 10 months, respectively, and the corresponding MDBFTs were not reached, 13, and 3 months, respectively, (p < 0.001). The crude DBF incidence rates in patients with scores of 0-1, 2-3, and 4 were 14.8%, 50.0%, and 76.9%, respectively, (p < 0.001).ConclusionsThe patients with scores of 0-1 had a lower risk of DBF than the patients with higher scores did, and it may be reasonable to treat these patients with SRS alone and resort to whole-brain radiation therapy only for salvage. The patients with a score of 4 had the highest risk of developing DBF after stereotactic radiotherapy alone, these patients may be candidates for initial whole-brain radiation therapy or clinical trials. The patients with a score of 2-3 had a moderate risk of developing DBF, SRT alone combined with close clinical monitoring would be the optimal treatment regimen for such patients, and for those patients with difficulties in receiving close clinical mornitoring, SRT combined with WBRT will be more suitable.

Patterns of failure for glioblastoma multiforme following concurrent radiation and temozolomide

To analyse patterns of failure in patients with glioblastoma multiforme treated with concurrent radiation and temozolomide. A retrospective review of patients treated with concurrent radiation and temozolomide was performed. Twenty patients treated at the University of Alabama at Birmingham, with biopsy-proven disease, documented disease progression after treatment, and adequate radiation dosimetry and imaging records were included in the study. Patients generally received 46 Gy to the primary tumour and surrounding oedema plus 1 cm, and 60 Gy to the enhancing tumour plus 1 cm. MRIs documenting failure after therapy were fused to the original treatment plans. Contours of post-treatment tumour volumes were generated from MRIs showing tumour failure and were overlaid onto the original isodose curves. The recurrent tumours were classified as in-field, marginal or regional. Recurrences were also evaluated for distant failure. Of the 20 documented failures, all patients had some component of failure at the primary site. Eighteen patients (90%) failed in-field, 2 patients (10%) had marginal failures, and no regional failures occurred. Four patients (20%) had a component of distant failure in which an independent satellite lesion was located completely outside of the 95% isodose curve. Radiation concurrent with temozolomide appears to be associated with a moderate risk of distant brain failure in addition to the high rate of local failure. The risk of distant failure was consistent with that observed with radiation alone, suggesting that temozolomide does not act to reduce distant brain failure but to improve local control.

Stereotactic radiosurgery alone for patients with 1–4 radioresistant brain metastases

Brain metastases from radioresistant histologies are perceived to be less responsive to WBRT compared to other histologies, and stereotactic radiosurgery (SRS) may provide better local control. The aim of this study was to examine the outcomes of patients with 1-4 brain metastasis from radioresistant histologies (renal cell carcinoma and melanoma) treated with SRS alone. Thirty-eight patients with 1-4 radioresistant brain metastases (66 lesions) were treated with SRS alone. The median age was 55 years. Fourteen and 24 patients had renal cell carcinoma (RCC) and melanoma brain metastases, respectively. Distribution of number of lesions was as follows: one lesion, 22 patients; 2 lesions, 8 patients; 3 lesions, 5 patients; and 4 lesions, 3 patients. Distribution of RTOG recursive partitioning analysis (RPA) classes was as follows: II, 37 patients and III, 1 patient. The median marginal dose was 20 Gy. The median follow-up was 6.1 months. The 3-, 6-, 9-, 12-, and 18-month local control (LC) rates were 87.9, 81.4, 67.9, 67.9, and 60.3%, respectively. The corresponding free-from-distant-brain failure (FFDBF) rates were 71.3, 58.1, 49.8, 40.2, and 27.6%. The corresponding progression-free survival (PFS) rates were 55.3, 41.9, 33, 23.3, and 13.3%. RCC histology was associated with better LC (P = 0.0055). Although SRS alone could yield reasonable LC in patients with 1-4 radioresistant brain metastases, the risk of distant brain failure was substantial. The approach of routine omission of WBRT outside of a trial setting should be used judiciously.

A phase II study of radiosurgery and temozolomide for patients with one to four brain metastases

2048 Background: To determine if temozolomide reduces the risk of distant brain failure (DBF, metachronous brain metastases) in patients with 1–4 brain metastases treated with radiosurgery without whole brain radiation therapy. Methods: Twenty-five patients with newly diagnosed brain metastases were enrolled in a single institution phase II trial of radiosurgery (15–24 Gy) and adjuvant temozolomide. Temozolomide was started within 14 days of radiosurgery and was administered 150–200 mg/m2 p.o. q day x 5 days in 28 day cycles. Temozolomide was continued for a total of 12 cycles unless the patient developed DBF, unacceptable toxicity, or systemic progression requiring other therapy. If more than 4 metastases were identified on the MRI performed on the day of radiosurgery, then the patient could still be treated on the clinical trial if all tumors could be treated with radiosurgery. In addition to clinical and radiographic follow-up, QOL was assessed utilizing the FACT-Br questionnaire. Results: Twenty-five patients were enrolled 2002–2005; three were not evaluable for determining DBF. Of the remaining twenty-two patients, tumor types included NSCLC (n=8), melanoma (n=7), other (n=7). Extracranial disease was present in ten (45%) patients. The median number of tumors was 3 (range 1–6). The median overall survival was 31 weeks. The median radiographic follow-up for patients that did not develop DBF was 33 weeks. Six patients developed DBF. The one year actuarial risk of DBF was 37%. Patients with melanoma had a higher risk of DBF than other patients (p&lt;0.001, log-rank). Only 1/15 patients without melanoma vs. 5/7 patients with melanoma developed DBF. 15 serious adverse events (SAEs) occurred in 10 of the patients, but none of the SAEs were judged to be likely related to temozolomide. Among patients that experienced DBF, no significant differences were seen in QOL when pretreatment FACT-Br and time of distant brain failure FACT-Br scores were compared. Conclusions: Adjuvant temolozomide after radiosurgery is associated with a low risk of distant brain failure in non-melanoma patients. Larger clinical trials should examine the relative efficacy and QOL of WBRT and temozolomide in non-melanoma brain metastases patients. No significant financial relationships to disclose.