Hospitalization outcomes among brain metastasis patients receiving radiation therapy with or without stereotactic radiosurgery from the 2005-2014 Nationwide Inpatient Sample.

The purpose of this study was to compare hospitalization outcomes among US inpatients with brain metastases who received stereotactic radiosurgery (SRS) and/or non-SRS radiation therapies without neurosurgical intervention. A cross-sectional study was conducted whereby existing data on 35,199 hospitalization records (non-SRS alone: 32,981; SRS alone: 1035; SRS + non-SRS: 1183) from 2005 to 2014 Nationwide Inpatient Sample were analyzed. Targeted maximum likelihood estimation and Super Learner algorithms were applied to estimate average treatment effects (ATE), marginal odds ratios (MOR) and causal risk ratio (CRR) for three distinct types of radiation therapy in relation to hospitalization outcomes, including length of stay (' ≥ 7 days' vs. ' < 7 days') and discharge destination ('non-routine' vs. 'routine'), controlling for patient and hospital characteristics. Recipients of SRS alone (ATE = - 0.071, CRR = 0.88, MOR = 0.75) or SRS + non-SRS (ATE = - 0.17, CRR = 0.70, MOR = 0.50) had shorter hospitalizations as compared to recipients of non-SRS alone. Recipients of SRS alone (ATE = - 0.13, CRR = 0.78, MOR = 0.59) or SRS + non-SRS (ATE = - 0.17, CRR = 0.72, MOR = 0.51) had reduced risks of non-routine discharge as compared to recipients of non-SRS alone. Similar analyses suggested recipients of SRS alone had shorter hospitalizations and similar risk of non-routine discharge when compared to recipients of SRS + non-SRS radiation therapies. SRS alone or in combination with non-SRS therapies may reduce the risks of prolonged hospitalization and non-routine discharge among hospitalized US patients with brain metastases who underwent radiation therapy without neurosurgical intervention.

Role of radiation in extensive stage small cell lung cancer: a National Cancer Database registry analysis.

The role of prophylactic cranial irradiation (PCI) and thoracic radiation therapy (TRT) in extensive-stage small cell lung cancer remains controversial. The authors examined the National Cancer Database and identified patients with extensive-stage small cell lung cancer with no brain metastasis. Patients were excluded if they died 30 days from diagnosis, did not receive polychemotherapy, had other palliative radiation or had missing information. A propensity score-matched analysis was also performed. A total of 21,019 patients were identified. The majority of patients did not receive radiation (69%), whereas 10% received PCI and 21% received TRT. The addition of PCI and TRT improved median survival and survival at 1 and 2 years (p ≤ 0.05). The propensity score-matched analysis confirmed the same overall survival benefit with both PCI and TRT. This registry-based analysis of >1500 accredited cancer programs shows that PCI and TRT are not commonly utilized for extensive-stage small cell lung cancer patients who are treated with multiagent chemotherapy. The addition of PCI and TRT significantly improves overall survival in this otherwise poor prognostic group. Further research is needed to confirm the role of PCI and TRT, especially in the era of improved systemic therapy.

Lay abstract The role of radiation therapy in patients with metastatic small cell lung cancer remains controversial. The authors examined the National Cancer Database and identified patients with metastatic small cell lung cancer without brain metastasis. Patients were excluded if they died 30 days from diagnosis, did not receive multiagent chemotherapy, had other palliative radiation or had missing information regarding treatment. A total of 21,019 patients were identified. The majority of patients did not receive radiation (69%), whereas 10% received radiation to the brain and 21% received radiation to their lungs. The addition of brain and lung radiation therapy improved median survival and survival at 1 and 2 years. The addition of prophylactic cranial irradiation and thoracic radiation therapy improves survival in extensive-stage small cell lung cancer. Future research is needed to evaluate the role of radiation in the era of chemoimmunotherapy.

Application of a multi-institutional nomogram predicting salvage whole brain radiation-free survival to patients treated with postoperative stereotactic radiotherapy for brain metastases.

PURPOSE: The ultimate goal of stereotactic radiotherapy (SRT) of brain metastases (BM) is to avoid or postpone whole brain radiotherapy (WBRT). A nomogram based on multi-institutional data was developed by Gorovets, et al. to estimate the 6 and 12-months WBRT-free survival (WFS). The aim of the current retrospective study was to validate the nomogram in a cohort of postoperative BM patients treated with adjuvant SRT. MATERIAL AND METHODS: We reviewed the data of 68 patients treated between 2008-2017 with postoperative SRT for BM. The primary endpoint was the WFS. The receiver operating characteristic curve and area under the curve (AUC) were calculated for both 6- and 12-months time points. RESULTS: After a median follow-up of 64 months, the 1-year cumulative incidence of local and distant brain relapse rates were 15% [95% CI=8-26%] and 34% [95% CI=24-48%], respectively. At recurrence, repeated SRT or salvage WBRT were applied in 33% and 57% cases, respectively. The WFS rates at 6 and 12 months were 88% [95% CI=81-97%] and 67% [95% CI=56-81%], respectively. Using the Gorovets nomogram, the 6 months rates were overestimated while they were accurate at 12 months. AUC values were 0.47 and 0.62 for the 6- and 12-months respectively. Overall, Harrell's concordance index was 0.54. CONCLUSION: This nomogram-predicted well the 12 months WFS but its discriminative power was quite low. This underlines the limits of this kind of predictive tool and leads us to consider the use of big data analysis in the future.

Childhood Neurotoxicity and Brain Resilience to Adverse Events during Adulthood.

OBJECTIVE: This study used childhood cancer survivors as a novel model to study whether children who experience central nervous system (CNS) injury are at higher risk for neurocognitive impairment associated with subsequent late onset chronic health conditions (CHCs). METHODS: Adult survivors of childhood cancer (n = 2,859, ≥10 years from diagnosis, ≥18 years old) completed a comprehensive neurocognitive battery and clinical examination. Neurocognitive impairment was defined as age-adjusted z score < 10th percentile. Participants impaired on ≥3 tests had global impairment. CHCs were graded using the Common Terminology Criteria for Adverse Events v4.3 (grade 1, mild; 2, moderate; 3, severe/disabling; 4, life-threatening) and were combined into a severity/burden score by frequency and grade (none/low, medium, high, and very high). A total of 1,598 survivors received CNS-directed therapy including cranial radiation, intrathecal methotrexate, or neurosurgery. Logistic regression estimated the odds of neurocognitive impairment associated with severity/burden score and grade 2 to 4 conditions, stratified by CNS treatment. RESULTS: CNS-treated survivors performed worse than non-CNS-treated survivors on all neurocognitive tests and were more likely to have global neurocognitive impairment (46.9% vs 35.3%, p < 0.001). After adjusting for demographic and treatment factors, there was a dose-response association between severity/burden score and global neurocognitive impairment, but only among CNS-treated survivors (high odds ratio [OR] = 2.24, 95% confidence interval [CI] = 1.42-3.53; very high OR = 4.07, 95% CI = 2.30-7.17). Cardiovascular and pulmonary conditions were associated with processing speed, executive function, and memory impairments in CNS-treated but not non-CNS-treated survivors who were impacted by neurologic conditions. INTERPRETATION: Reduced cognitive/brain reserve associated with CNS-directed therapy during childhood may make survivors vulnerable to adverse cognitive effects of cardiopulmonary conditions during adulthood. ANN NEUROL 2021;89:534-545.

Stereotactic Radiosurgery After Resection of Brain Metastases: Changing Patterns of Care in the United States.

OBJECTIVE: Management of symptomatic brain metastases often includes surgical resection with postoperative radiotherapy. Postoperative whole-brain radiotherapy (WBRT) improves intracranial control but detrimentally impacts quality of life and neurocognition. We sought to characterize the use in the United States of postoperative stereotactic radiosurgery (SRS), an evolving standard-of-care associated with reduced cognitive effects. METHODS: With the MarketScan Commercial Claims and Encounters Database from 2007 to 2015, we identified patients aged 18-65 years treated with resection of a brain metastasis followed by SRS or WBRT within 60 days of surgery. Logistic regression estimated associations between co-variables (treatment year, age, sex, geographic region, place of service, insurance type, disease histology, comorbidity score, and median area household income and educational attainment) and SRS receipt. RESULTS: Of 4007 patients included, 1506 (37.6%) received SRS and 2501 (62.4%) received WBRT. Postoperative SRS increased from 16.5% (2007-2008) to 56.8% (2014-2015). Patients residing in areas with a median household income or an educational attainment below 50th percentile were significantly less likely to receive SRS after controlling for treatment year and other demographic characteristics (P < 0.01). Factors associated with greater odds of receiving SRS included younger age, female sex, melanoma histology, Western region location, hospital-based facility, and high-deductible health plan enrollment (P < 0.05 for each). CONCLUSIONS: Postoperative SRS for brain metastases has increased from 2007 to 2015, with the majority of patients now receiving SRS over WBRT. Patients in areas of lower socioeconomic class were less likely to receive SRS, warranting further investigation of barriers to SRS adoption.

Surgical bed stereotactic radiotherapy of brain metastases: Clinical outcome and predictors of local and distant brain failure.

PURPOSE: To retrospectively analyze the outcomes of stereotactic radiotherapy (SRT) targeted at surgical bed of brain metastases (BM) and identify patterns of local/distant brain relapses (LR/DBR). PATIENTS/METHODS: Seventy patients were treated with SRT between 2008-2017. Marginal dose prescription on the 70% isodose line depended on the maximal diameter of the target volume and range between 15-18Gy for single fraction radiosurgery and 23.1-26Gy in 3-5 fractions for fractionated SRT. RESULTS: At 12 months, the overall survival (OS) was 69% [CI 95%=59%-81%]. At 6 and 12 months, the cumulative incidence functions (CIF) of local relapse were 4% [1%-13%] and 15% [8%-26%], respectively. According to univariate analysis, factors associated with LR were an initial volume larger than 7cc (hazard ratio: 4.6 [1.0-20.8], P=0.046) and a positive resection margin [hazard ratio: 3.6 [1.1-12.0], P=0.037. DBR occurred in 54.3% of patients with a median time of 8 months. None of the variables tested (histology, location or number of lesions) were found correlated with the DBR. Leptomeningeal disease occurred in 12.9% of cases. Salvage whole brain radiotherapy (WBRT) was required in 45.7% of patients and delayed by a median time of 9.6 months. Symptomatic radionecrosis (RN) occurred in 7.1%. CONCLUSIONS: Adjuvant SRT was an effective and well-tolerated treatment to control the postoperative risk of recurrence of BM without compromising OS. Positive resection margins and large volumes were predictors factor of local relapse.

Management and outcome of primary CNS lymphoma in the modern era: An LOC network study.

OBJECTIVE: Real-life studies on patients with primary CNS lymphoma (PCNSL) are scarce. Our objective was to analyze, in a nationwide population-based study, the current medical practice in the management of PCNSL. METHODS: The French oculo-cerebral lymphoma network (LOC) database prospectively records all newly diagnosed PCNSL cases from 32 French centers. Data of patients diagnosed between 2011 and 2016 were retrospectively analyzed. RESULTS: We identified 1,002 immunocompetent patients (43% aged >70 years, median Karnofsky Performance Status [KPS] 60). First-line treatment was high-dose methotrexate-based chemotherapy in 92% of cases, with an increasing use of rituximab over time (66%). Patients <60 years of age received consolidation treatment in 77% of cases, consisting of whole-brain radiotherapy (WBRT) (54%) or high-dose chemotherapy with autologous stem cell transplantation (HCT-ASCT) (23%). Among patients >60 years of age, WBRT and HCT-ASCT consolidation were administered in only 9% and 2%, respectively. The complete response rate to initial chemotherapy was 50%. Median progression-free survival was 10.5 months. For relapse, second-line chemotherapy, HCT-ASCT, WBRT, and palliative care were offered to 55%, 17%, 10%, and 18% of patients, respectively. The median, 2-year, and 5-year overall survival was 25.3 months, 51%, and 38%, respectively (<60 years: not reached [NR], 70%, and 61%; >60 years: 15.4 months, 44%, and 28%). Age, KPS, sex, and response to induction CT were independent prognostic factors in multivariate analysis. CONCLUSIONS: Our study confirms the increasing proportion of elderly within the PCNSL population and shows comparable outcome in this population-based study with those reported by clinical trials, reflecting a notable application of recent PCNSL advances in treatment.

Hypothalamic-Pituitary Disorders in Childhood Cancer Survivors: Prevalence, Risk Factors and Long-Term Health Outcomes.

CONTEXT: Data on hypothalamic-pituitary (HP) disorders in systematically evaluated childhood cancer survivors are limited. OBJECTIVE: To describe prevalence, risk factors, and associated adverse health outcomes of deficiencies in GH deficiency (GHD), TSH deficiency (TSHD), LH/FSH deficiency (LH/FSHD), and ACTH deficiency (ACTHD), and central precocious puberty (CPP). DESIGN: Retrospective with cross-sectional health outcomes analysis. SETTING: Established cohort; tertiary care center. PATIENTS: Participants (N = 3141; median age, 31.7 years) were followed for a median 24.1 years. MAIN OUTCOME MEASURE: Multivariable logistic regression was used to calculate ORs and 95% CIs for associations among HP disorders, tumor- and treatment-related risk factors, and health outcomes. RESULTS: The estimated prevalence was 40.2% for GHD, 11.1% for TSHD, 10.6% for LH/FSHD, 3.2% for ACTHD, and 0.9% for CPP among participants treated with HP radiotherapy (n = 1089), and 6.2% for GHD, and <1% for other HP disorders without HP radiotherapy. Clinical factors independently associated with HP disorders included HP radiotherapy (at any dose for GHD, TSHD, LH/FSHD, >30 Gy for ACTHD), alkylating agents (GHD, LH/FSHD), intrathecal chemotherapy (GHD), hydrocephalus with shunt placement (GHD, LH/FSHD), seizures (TSHD, ACTHD), and stroke (GHD, TSHD, LH/FSHD, ACTHD). Adverse health outcomes independently associated with HP disorders included short stature (GHD, TSHD), severe bone mineral density deficit (GHD, LH/FSHD), obesity (LH/FSHD), frailty (GHD), impaired physical health-related quality of life (TSHD), sexual dysfunction (LH/FSHD), impaired memory, and processing speed (GHD, TSHD). CONCLUSION: HP radiotherapy, central nervous system injury, and, to a lesser extent, chemotherapy are associated with HP disorders, which are associated with adverse health outcomes.

A pooled analysis of individual patient data from National Clinical Trials Network clinical trials of concurrent chemoradiotherapy for limited-stage small cell lung cancer in elderly patients versus younger patients.

BACKGROUND: Platinum and etoposide with thoracic radiation followed by prophylactic cranial irradiation constitute the standard treatment for limited-stage small cell lung cancer (LS-SCLC). Many patients with LS-SCLC are elderly with comorbidities. METHODS: Individual patient data were collected from 11 phase 2 or 3 trials for LS-SCLC conducted by the National Clinical Trials Network and activated from 1990 to 2010. The primary endpoint was overall survival (OS); the secondary endpoints were progression-free survival (PFS), the rate of severe adverse events, and off-treatment reasons. The outcomes were compared for patients 70 years old or older (elderly patients) and patients younger than 70 years (younger patients). RESULTS: Individual patient data from 1049 younger patients (81%) and 254 elderly patients (19%) were analyzed. In the multivariate model, elderly patients, in comparison with younger patients, had worse OS (hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.18-1.63; median OS for elderly patients, 17.8 months; OS for younger patients, 23.5 months) and worse PFS (HR, 1.19; 95% CI, 1.03-1.39; median PFS for elderly patients, 10.6 months; median PFS for younger patients, 12.3 months). Elderly patients, in comparison with younger patients, experienced more grade 5 adverse events (8% vs 3%; P < .01) and more grade 3 or higher dyspnea (11% vs 7%; P = .03) but less grade 3 or higher esophagitis/dysphagia (14% vs 19%; P = .04) and less grade 3 or higher vomiting (11% vs 17%; P = .01). Elderly patients completed treatment less often, discontinued treatment because of adverse events and patient refusal more frequently, and died during treatment more frequently. CONCLUSIONS: Elderly patients with LS-SCLC have worse PFS and OS and more difficulty in tolerating therapy. Future trials should incorporate assessments of elderly patients, novel monitoring of adverse events, and more tolerable radiation and systemic therapies.

Social adjustment in adolescent survivors of pediatric central nervous system tumors: A report from the Childhood Cancer Survivor Study.

BACKGROUND: The purpose of this study was to examine the prevalence and predictors of social difficulties in adolescent survivors of central nervous system (CNS) tumors. METHODS: Six hundred sixty-five survivors of CNS tumors (53.8% male and 51.7% treated with cranial radiation therapy [CRT]), who had a current median age of 15.0 years (range, 2.0-17.0 years) and were a median of 12.1 years (range, 8.0-17.7 years) from their diagnosis, were compared with 1376 survivors of solid tumors (50.4% male), who had a median age of 15.0 years (range, 12.0-17.0 years) and were a median of 13.2 years (range, 8.3-17.9 years) from their diagnosis, and 726 siblings (52.2% male), who had a median age of 15.0 years (range, 12.0-17.0 years). Social adjustment was measured with parent-proxy responses to the Behavior Problems Index. Latent profile analysis defined social classes. Multinomial logistic regression, adjusted for age, sex, and age at diagnosis, identified predictors of class membership. Path analyses tested mediating effects of physical limitations, sensory loss, and cognitive impairment on social outcomes. RESULTS: Caregivers reported that survivors of CNS tumors were more likely to have 0 friends (15.3%) and to interact with friends less than once per week (41.0%) in comparison with survivors of solid tumors (2.9% and 13.6%, respectively) and siblings (2.3% and 8.7%, respectively). Latent profile analysis identified 3 social classes for survivors of CNS tumors: well-adjusted (53.4%), social deficits (16.2%), and poor peer relationships (30.4%). However, 2 classes were identified for survivors of solid tumors and siblings: well-adjusted (86.2% and 91.1%, respectively) and social deficits (13.8% and 8.9%, respectively). CRT predicted class membership for CNS survivors (odds ratio [OR] for poor peer relationships, 1.16/10 Gy; 95% confidence interval [CI], 1.08-1.25; OR for social deficits 1.14/10 Gy; 95% CI, 1.04-1.25; reference, well-adjusted). Cognitive impairment mediated the association between all social outcomes and CRT (P values < .001). CONCLUSION: Almost 50% of survivors of CNS tumors experience social difficulties; the pattern is unique in comparison with solid tumor and sibling groups. Cognitive impairment is associated with increased risk, and this highlights the need for multitargeted interventions.

Evolution in the role of stereotactic radiosurgery in patients with multiple brain metastases: An international survey.

OBJECTIVE: Currently no firm consensus exists regarding utilization of stereotactic radiosurgery (SRS) alone versus whole brain radiation (WBRT) ±â€¯SRS in patients with multiple brain metastases. The International Gamma Knife Research Foundation conducted a survey to review international practice patterns. METHODS: Through 2 international radiosurgery societies, clinicians who are involved in the radiosurgical management of patients with brain metastases were invited to complete a questionnaire. Respondents selected therapeutic options based on brief case vignettes and could select (1) SRS alone, (2) SRS with adjuvant WBRT, (3) WBRT alone, or (4) omission of upfront local radiation. RESULTS: A total of 71 respondents replied to the survey, including 41 radiation oncologists (57%), 24 neurosurgeons (34%), and 6 (8%) other clinicians. For a patient with 7 brain metastases (NSCLC), all under 1 cm, and stable extracranial disease, 77% would perform SRS alone and 17% would recommend WBRT alone. For a patient with 7 or more brain metastases, the majority selected SRS alone, irrespective of tumor histology (p > 0.5). However, neurosurgeons would more often utilize SRS alone or SRS combined with WBRT compared to radiation oncologists (p = 0.002). Key clinical factors in selection were KPS (82% of respondents), total tumor volume (81%), number (80%), and less-so histology (42%). CONCLUSION: Regardless of number of metastases, patients with small total volume of brain disease, high KPS, or who are receiving novel therapies are often recommended to undergo SRS. Neurosurgeons more often recommend SRS, emphasizing the importance of additional studies to clarify the role of SRS in these patients.

Effect of Targeted Therapies on Prognostic Factors, Patterns of Care, and Survival in Patients With Renal Cell Carcinoma and Brain Metastases.

PURPOSE: To identify prognostic factors, define evolving patterns of care, and the effect of targeted therapies in a larger contemporary cohort of renal cell carcinoma (RCC) patients with new brain metastases (BM). METHODS AND MATERIALS: A multi-institutional retrospective institutional review board-approved database of 711 RCC patients with new BM diagnosed from January 1, 2006, to December 31, 2015, was created. Clinical parameters and treatment were correlated with median survival and time from primary diagnosis to BM. Multivariable analyses were performed. RESULTS: The median survival for the prior/present cohorts was 9.6/12 months, respectively (P < .01). Four prognostic factors (Karnofsky performance status, extracranial metastases, number of BM, and hemoglobin b) were significant for survival after the diagnosis of BM. Of the 6 drug types studied, only cytokine use after BM was associated with improved survival. The use of whole-brain radiation therapy declined from 50% to 22%, and the use of stereotactic radiosurgery alone increased from 46% to 58%. Nonneurologic causes of death were twice as common as neurologic causes. CONCLUSIONS: Additional prognostic factors refine prognostication in this larger contemporary cohort. Patterns of care have changed, and survival of RCC patients with BM has improved over time. The reasons for this improvement in survival remain unknown but may relate to more aggressive use of local brain metastasis therapy and a wider array of systemic treatment options for those patients with progressive extracranial tumor.

Twice weekly pulse and daily continuous-dose erlotinib as initial treatment for patients with epidermal growth factor receptor-mutant lung cancers and brain metastases.

BACKGROUND: In a phase 1 study of pulse/continuous-dose erlotinib, no patient had disease progression in the central nervous system (CNS). This expansion cohort of the phase 1 study tested the same regimen in a cohort of individuals with epidermal growth factor receptor (EGFR)-mutant lung cancers with untreated brain metastases. METHODS: Patients had not received EGFR tyrosine kinase inhibitors or radiation for brain metastases. All received 1200 mg of erlotinib on days 1 and 2 and 50 mg on days 3 to 7 weekly. The primary endpoints were the overall and CNS response rates (according to version 1.1 of the Response Evaluation Criteria in Solid Tumors). RESULTS: Between May 2015 and August 2016, 19 patients were enrolled. Forty-two percent of the patients had target brain lesions, and the median size of the target brain lesions was 13 mm. Overall, 14 patients (74%; 95% confidence interval [CI], 51%-89%) had partial responses. The response rate in brain metastases was 75%. The overall median progression-free survival was 10 months (95% CI, 7 months to not reached). Only 3 patients (16%) had CNS progression. To date, 4 patients required CNS radiation at some time during their course. The adverse events (any grade) seen in 10% or more of the patients were rash, diarrhea, nausea, an increase in alanine aminotransferase, and fatigue. CONCLUSIONS: Pulse/continuous-dose erlotinib produced a 74% overall response rate and a 75% response rate in brain metastases in patients with EGFR-mutant lung cancers and untreated brain metastases. CNS control persisted even after progression elsewhere. Although this regimen did not improve progression-free survival or delay the emergence of EGFR T790M, it prevented progression in the brain and could be useful in situations in which CNS control is critical. Cancer 2018;124:105-9. © 2017 American Cancer Society.

Usage of Prophylactic Cranial Irradiation in Elderly Patients With Small-cell Lung Cancer.

BACKGROUND: Prophylactic cranial irradiation (PCI) reduces the risk of overt brain metastases in patients with small-cell lung cancer (SCLC) and is currently recommended in guidelines for both limited and extensive disease. Given the concerns about the greater frequency of neurologic side effects in elderly patients, we studied the association among age, PCI usage, and survival for SCLC patients in the Netherlands. PATIENTS AND METHODS: Data from the Netherlands Cancer Registry for patients diagnosed with SCLC from 2009 to 2013 were queried. Separate analyses were performed for patients with stage I to III, treated with chemoradiotherapy (n = 1684) and patients with stage IV, treated with chemotherapy or chemoradiotherapy (n = 3481). Patients with brain metastasis at diagnosis were excluded. RESULTS: For patients with stage I to III, the overall PCI usage rate was 74%, and the rate decreased with age, from 78% for patients aged 18 to 59 years to 66% for patients aged ≥ 80 years. For patients with stage IV, the overall PCI usage rate was 41% and decreased with age, from 46% for patients aged 18 to 59 years to 23% for patients aged ≥ 80 years. Gender and socioeconomic status did not affect the PCI rates. For patients aged < 70 years and treated with PCI, the median survival was 45, 24, and 12 months for stage I and II, III, and IV, respectively. For patients aged ≥ 70 years treated with PCI, the corresponding survival duration was 33, 17, and 10 months. CONCLUSION: In the Dutch population, PCI usage rates were fairly high but were significantly lower for elderly patients.

Phase 1 Study of Ipilimumab Combined With Whole Brain Radiation Therapy or Radiosurgery for Melanoma Patients With Brain Metastases.

PURPOSE: We performed a phase 1 study to determine the maximum tolerable dose and safety of ipilimumab with stereotactic radiosurgery (SRS) or whole brain radiation therapy (WBRT) in patients with brain metastases from melanoma. METHODS AND MATERIALS: Based on the intracranial disease burden, patients underwent WBRT (arm A) or SRS (arm B). The ipilimumab starting dose was 3 mg/kg every 3 weeks, starting on day 3 of WBRT or 2 days after SRS. The ipilimumab dose was escalated to 10 mg/kg using a 2-stage, 3+3 design. The primary endpoint was to determine the maximum tolerable dose of ipilimumab combined with radiation therapy. The secondary endpoints were overall survival, intracranial and extracranial control, progression-free survival, and toxicity. The ClinicalTrials.gov registration number is NCT01703507. RESULTS: The characteristics of the 16 patients enrolled between 2011 and 2014 were mean age, 60 years; median number of brain metastases, 2 (range 1->10); and number with EC disease, 13 (81%). Treatment included WBRT (n=5), SRS (n=11), and ipilimumab 3 mg/kg (n=7) or 10 mg/kg (n=9). The median follow-up was 8 months (arm A) and 10.5 months (arm B). A total of 21 grade 1 to 2 neurotoxic effects occurred, with no dose-limiting toxicities. One patient experienced grade 3 neurotoxicity before ipilimumab administration. Ten additional grade 3 toxicities were reported, with gastrointestinal toxicities (n=5; 31%) the most common. No patient developed grade 4 or 5 toxicity. The median progression-free survival and overall survival in arm A was 2.5 months and 8 months and in arm B was 2.1 months and not reached, respectively. CONCLUSIONS: Concurrent ipilimumab 10 mg/kg with SRS is safe. The WBRT arm was closed early because of slow accrual but demonstrated safety with ipilimumab 3 mg/kg. No patient experienced dose-limiting toxicity. Larger studies, including those with combination checkpoint inhibitor therapy and SRS, are warranted.

A Bayesian network meta-analysis of whole brain radiotherapy and stereotactic radiotherapy for brain metastasis.

This study was conducted to compare the effects of whole brain radiotherapy (WBRT) and stereotactic radiotherapy (SRS) in treatment of brain metastasis.A systematical retrieval in PubMed and Embase databases was performed for relative literatures on the effects of WBRT and SRS in treatment of brain metastasis. A Bayesian network meta-analysis was performed by using the ADDIS software. The effect sizes included odds ratio (OR) and 95% confidence interval (CI). A random effects model was used for the pooled analysis for all the outcome measures, including 1-year distant control rate, 1-year local control rate, 1-year survival rate, and complication. The consistency was tested by using node-splitting analysis and inconsistency standard deviation. The convergence was estimated according to the Brooks-Gelman-Rubin method.A total of 12 literatures were included in this meta-analysis. WBRT + SRS showed higher 1-year distant control rate than SRS. WBRT + SRS was better for the 1-year local control rate than WBRT. SRS and WBRT + SRS had higher 1-year survival rate than the WBRT. In addition, there was no difference in complication among the three therapies.Comprehensively, WBRT + SRS might be the choice of treatment for brain metastasis.

Brain Metastasis Velocity: A Novel Prognostic Metric Predictive of Overall Survival and Freedom From Whole-Brain Radiation Therapy After Distant Brain Failure Following Upfront Radiosurgery Alone.

PURPOSE: Prior statistical models attempted to identify risk factors for time to distant brain failure (DBF) or time to salvage whole-brain radiation therapy (WBRT) to predict the benefit of early WBRT versus stereotactic radiosurgery (SRS) alone. We introduce a novel clinical metric, brain metastasis velocity (BMV), for predicting clinical outcomes after initial DBF following upfront SRS alone. METHODS AND MATERIALS: BMV was defined as the cumulative number of new brain metastases that developed over time since first SRS in years. Patients were classified by BMV into low-, intermediate-, and high-risk groups, consisting of <4, 4 to 13, and >13 new metastases per year, respectively. Histology, number of metastases at the time of first SRS, and systemic disease status were assessed for effect on BMV. RESULTS: Of 737 patients treated at our institution with upfront SRS without WBRT, 286 had ≥1 DBF event. A lower BMV predicted for improved overall survival (OS) following initial DBF (log-rank P<.0001). Median OS for the low, intermediate, and high BMV groups was 12.4 months (95% confidence interval [CI], 10.4-16.9 months), 8.2 months (95% CI, 5.0-9.7 months), and 4.3 months (95% CI, 2.6-6.7 months), respectively. Multivariate analysis showed that BMV remained the dominant predictor of OS, with a hazard ratio of 2.75 for the high BMV group (95% CI, 1.94-3.89; P<.0001) and a hazard ratio of 1.65 for the intermediate BMV group (95% CI, 1.18-2.30; P<.004). A lower BMV was associated with decreased rates of salvage WBRT (P=.02) and neurologic death (P=.008). Factors predictive for a higher BMV included ≥2 initial brain metastases (P=.004) and melanoma histology (P=.008). CONCLUSIONS: BMV is a novel metric associated with OS, neurologic death, and need for salvage WBRT after initial DBF following upfront SRS alone.

The Prognostic Role of Tumor Volume in the Outcome of Patients with Single Brain Metastasis After Stereotactic Radiosurgery.

BACKGROUND: Patients with single brain metastasis (SBM) have better outcomes after stereotactic radiosurgery (SRS). We analyzed our SRS database to evaluate possible prognostic factors in patients with SBM. METHODS: A total of 584 patients with SBM were treated with SRS at our institution (2000-2012). Study end points were overall survival (OS), and distant and local intracranial progression-free survival (DPFS and LPFS, respectively). Multivariable analysis was performed to develop prognostic models. RESULTS: Median OS was 10.8 months. A total of 196 patients (36.7%) had distant progression and 102 patients (19.2%) had local progression. New SBM prognostic indices (SPIs) were devised for OS, DPFS, and LPFS. Graded prognostic assessment, neurologic symptoms (P = 0.01), and tumor volume (P = 0.02) were independently associated with OS. The SPI for OS was defined: unfavorable (OS, 7.3 months), intermediate (OS, 10.6 months), and favorable (OS, 19.8 months). For DPFS, age (P = 0.0029), tumor volume (P = 0.0002), and previous whole-brain radiotherapy (P = 0.027) were prognostic and were used to define SPI for DPFS: favorable (6-month cumulative incidence failure [CIF], 10.9%), intermediate (6-month CIF, 16.7%), and unfavorable (6-month CIF, 26.0%) (P < 0.001). For LPFS, graded prognostic assessment (P = 0.0012) and tumor volume (P = 0.0004) were significant, and defined 2 groups in the LPFS SPI: unfavorable (6-month CIF, 12.3%) and favorable (6-month CIF, 6%) (P < 0.001). CONCLUSIONS: This is the largest series of patients with SBM treated with SRS analyzed for OS, LPFS, and DPFS. SPI was devised for end points. Tumor volume had a significant association with all 3 end points. Neurologic symptoms, age, and previous whole-brain radiotherapy were also found to be prognostic.