Upfront Whole Brain Radiotherapy Research Articles

Whole-Brain Radiotherapy Alone vs Preceded by Bevacizumab, Etoposide, and Cisplatin for Untreated Brain Metastases From Breast Cancer

The incidence of brain metastasis is increasing in patients with metastatic breast cancer. Treatments to extend the control of brain metastasis are urgently required. To investigate whether the addition of an induction treatment of bevacizumab, etoposide, and cisplatin (BEEP) improves brain-specific progression-free survival (PFS) after whole-brain radiotherapy (WBRT). This open-label, randomized, multicenter clinical trial assessed patients with brain metastases from breast cancer (BMBC) in Taiwan from September 9, 2014, to December 24, 2018, with survival follow-up until December 31, 2021. Key inclusion criteria included metastatic brain tumors not suitable for focal treatment, WBRT naivety, age 20 to 75 years, and at least 1 measurable brain metastatic lesion. The primary end point was brain-specific PFS, with an expected hazard ratio of 0.60, a 2-sided α ≤ .20, and power of 0.8. Eligible patients were randomly assigned at a ratio of 2:1 to the experimental arm, which involved 3 cycles of BEEP followed by WBRT, or the control arm, which involved WBRT alone. The primary end point was the determination of brain-specific PFS by local investigators according to the Response Evaluation Criteria in Solid Tumors, version 1.1, the initiation of other brain-directed treatment after WBRT, or death. Other key end points included brain-specific objective response rate after 8 weeks of BEEP treatment or WBRT and 8-month brain-specific PFS rate, PFS, and overall survival. A total of 118 patients with BMBC were randomized, with the intention-to-treat cohort comprising 112 patients. The median age was 56 years (range, 34-71 years), and 61 patients (54.5%) had ERBB2 (formerly HER2 or HER2/neu)-positive disease. The median (range) brain-specific PFS was 8.1 (0.3-29.5) vs 6.5 (0.9-25.5) months in the experimental and control arms, respectively (hazard ratio, 0.71; 95% CI, 0.44-1.13; P = .15; significant at predefined α ≤ .20). The brain-specific objective response rate at 2 months was not significantly different (BEEP treatment vs WBRT, 41.9% vs 52.6%), but the 8-month brain-specific PFS rate was significantly higher in the experimental group (48.7% vs 26.3%; P = .03). Adverse events were generally manageable with prophylactic granulocyte colony-stimulating factor treatment. The findings show that induction BEEP before WBRT may improve the control of BMBC compared with using upfront WBRT, which could address an unmet need for an effective systemic treatment for intractable brain and extracranial metastases from metastatic breast cancer. ClinicalTrials.gov Identifier: NCT02185352.

Retinal Metastases as the Initial Presentation of Advanced Lung Adenocarcinoma.

Most lung cancers are diagnosed at an advanced stage. Common metastatic sites include the brain, bone, liver and adrenal glands. Ocular metastases, however, are extremely rare. We present a case of advanced lung adenocarcinoma presenting exclusively with photopsias attributable to retinal metastases. We describe a woman in her fifties, a lifetime non-smoker with an unremarkable medical and family history, who presented to the emergency department with photopsias for a week. Ophthalmology evaluation revealed decreased visual acuity bilaterally, and a fundus examination disclosed lesions suggestive of bilateral retinal metastases. A comprehensive evaluation diagnosed a stage IVb lung adenocarcinoma with exon 19 mutation on epidermal growth factor receptor gene. Subsequently, she developed complaints of headaches and dizziness. She received frontline osimertinib 80 mg daily, preceded by upfront whole-brain radiation therapy with partial orbital inclusion for symptomatic ocular and brain metastases. After ten radiation therapy sessions, her complaints were resolved and an ophthalmology revaluation revealed improvement in visual acuity and resolution of photopsia complaints. The patient is currently on osimertinib and preserves an ECOG score of 0. Retinal metastases usually indicate advanced disease, so presenting with isolated ocular symptoms is exceedingly rare. Especially in cases of uncommon metastases, a multidisciplinary approach is fundamental for a prompt diagnosis and timely treatment, impacting prognosis and quality of life. Ocular metastases in lung cancer are usually a sign of advanced disease.Advanced lung adenocarcinoma presenting solely with retinal metastases is extremely rare.A multidisciplinary team is essential for the diagnosis and treatment of lung cancer with uncommon metastases.

Selecting the Appropriate Radiation Therapy Technique for Extensive Brain Metastases from Tens to Hundreds: Should the Latest Technique Always Be the Best Option?

Brain metastases (BMs) are one of the most common metastatic lesions in adult cancer patients and the most common intracranial neoplasms in adult patients. Especially for multiple BMs, historically, whole-brain radiotherapy (WBRT) has been performed as the mainstay of therapy, which improves neurological symptoms and median survival. However, WBRT could negatively impact the patient's quality of life due to late complications. Owing to these complications, attempts have been made to use the latest radiotherapy (LRT) such as stereotactic radiosurgery (SRS) and intensity-modulated radiotherapy (IMRT) to treat BMs. However, for the extensive BMs (ranging from tens to hundreds), there are currently no prospective studies comparing WBRT with LRT such as IMRT or SRS. For extensive brain metastases, LRT cannot be the best option. Instead, upfront WBRT should be considered given its advantages and disadvantages, rather than LRT. We hope that faster and more reliable LRT for extensive BMs will be applicable for clinical practice without any clinical concerns in the near future.

FOCAL MANAGEMENT OF BRAIN METASTASES IN SMALL CELL LUNG CANCER: A SYSTEMATIC REVIEW

Abstract AIMS Small cell lung cancer (SCLC) brain metastases (BM) are common at both presentation and relapse. Historically, BM are managed with whole brain radiotherapy (WBRT) +/- chemotherapy. However, WBRT is associated with significant cognitive impairment, and so interest in the focal management of BM (encompassing stereotactic radiosurgery (SRS) and surgery) is increasing. We systematically reviewed the current literature regarding focal BM management. METHOD A systematic literature search of PubMed, Embase, and CENTRAL databases and clinicaltrials.gov was conducted to obtain published articles, abstracts, and ongoing studies regarding focal management of SCLC BM. Exclusion criteria included publication before 2005 and publication in a non-English language. Additional papers were added by reviewing citations of relevant papers. RESULTS Following initial review of 15,420 records, we identified 67 articles eligible for inclusion. 24 were published before 2015 and 44 published 2015-2023. 8 related to surgical BM treatment: case studies (n=6), retrospective cohort studies (n=2). 60 articles were identified regarding SRS: abstracts (n=13), case studies (n=5), retrospective cohort studies (n=14), retrospective case series (n=20), prospective trials (n=8). These papers have been further divided by topic: upfront SRS (n=23), salvage SRS (n=19) and WBRT with SRS boost (n=3). There are several ongoing trials (n=8) investigating outcomes in SRS for SCLC BM, both alone and when compared with WBRT. CONCLUSIONS Focal treatments for SCLC BM are being used more frequently. However, randomised trial evidence for their safety and effectiveness are still pending.

Reduced Mortality and Radiation Necrosis After Surgery With Postoperative Stereotactic Radiation in Patients With Multiple Brain Metastases.

Although stereotactic radiation has frequently supplanted whole-brain radiation therapy (WBRT) in treating patients with multiple brain metastases, the role of surgery for these patients remains unresolved. No randomized trials have compared surgical resection with postoperative stereotactic radiosurgery (SRS) or stereotactic radiotherapy (SRT) to SRS/SRT alone. Previous studies addressing surgery for patients with multiple brain metastases are often limited by small sample sizes, a lack of appropriate comparison groups, or a focus on patients treated before recent advances in targeted therapy and immunotherapy. We compared outcomes in patients with multiple brain metastases treated with surgical resection and postoperative SRS/SRT to those treated with SRS/SRT alone. We studied 734 patients with multiple newly diagnosed brain metastases (surgery with SRS/SRT, n = 228; SRS/SRT alone, n = 506) from 2011 to 2022 in a retrospective, single-institution cohort. Patients who received upfront whole-brain radiotherapy were excluded. Cox proportional hazards models were constructed for overall survival and additional intracranial outcomes. After adjustment for potential confounders, surgery with postoperative SRS/SRT was associated with decreased all-cause mortality compared with SRS/SRT alone (hazard ratio [HR]: 0.67, 95% CI [0.50-0.89], P = 5.56 × 10-3). The association between surgical resection and overall survival was replicated in a subset of the cohort after cardinality matching (HR: 0.64, 95% CI [0.46-0.88], P = 6.68 × 10-3). Patients with melanoma benefited significantly less from surgical resection compared with patients with other tumor types, most notably non-small-cell lung cancer. Compared with definitive SRS/SRT, cavity SRS/SRT was associated with a significantly reduced risk of both symptomatic radiation necrosis (HR: 0.22, 95% CI [0.08-0.59], P = 2.70 × 10-3) and radiographic radiation necrosis (HR: 0.23, 95% CI [0.09-0.57], P = 1.43 × 10-3) in multivariable models. In patients with multiple brain metastases, surgical resection before SRS/SRT is associated with reduced mortality and radiation necrosis. Prospective studies may further delineate patient populations that benefit from aggressive local, brain-directed treatment even with significant intracranial disease burden.

CNS Downstaging: An Emerging Treatment Paradigm for Extensive Brain Metastases in Oncogene-Addicted Lung Cancer

IntroductionFor extensive brain metastases (BrM) presentations arising from oncogene-addicted lung cancer, tyrosine kinase inhibitors (TKIs) with high response rates in the central nervous system (CNS) could potentially downstage the CNS disease burden, allowing for the avoidance of upfront whole-brain radiotherapy (WBRT) and the conversion of some patients into candidates for focal stereotactic radiosurgery (SRS). MethodsWe describe the outcomes of patients with ALK, EGFR, and ROS1-driven NSCLC with extensive BrM presentations (defined as > 10 BrMs or leptomeningeal disease) treated with upfront newer generation CNS-active TKIs alone, including osimertinib, alectinib, brigatinib, lorlatinib, and entrectinib, from 2012 to 2021 at our institution. All BrMs were contoured at study entry, best CNS response (nadir), and first CNS progression. ResultsTwelve patients met criteria including 6 with ALK, 3 with EGFR, and 3 with ROS1-driven NSCLC. The median number and volume of BrMs at presentation were 49 and 19.6 cm3, respectively. Eleven patients (91.7 %) achieved a CNS response by modified-RECIST criteria to upfront TKI (10 partial responses, 1 complete response, 1 stable disease) with nadir observed at a median of 5.1 months. At nadir, the median number and volume of BrMs were 5 (median 91.7 % reduction per-patient) and 0.3 cm3(median 96.5 % reduction per-patient), respectively. Eleven patients (91.6 %) developed subsequent CNS progression (7 local failures, 3 local + distant, 1 distant) at a median of 17.9 months. At CNS progression, the median number and volume of BrMs were 7 and 0.7 cm3, respectively. Seven patients (58.3 %) received salvage SRS and no patients received salvage WBRT. The median overall survival from initiation of TKI for the extensive BrM presentation was 43.2 months. ConclusionIn this initial case series, we describe CNS downstaging as a promising multidisciplinary treatment paradigm involving the upfront administration CNS-active systemic therapy and close MRI surveillance for extensive BrMs as a strategy to avoid upfront WBRT and to convert some patients into SRS candidates.

Abstract P1-21-01: Multicenter study for brain metastasis from breast cancer in Korea: The significance of molecular subtype (KROG 1612)

Abstract Background: We analyzed the treatment outcome of breast cancer patients with brain metastases (BM) in Korea to identify the prognostic factors and the role of whole brain radiation therapy (WBRT). Methods: Seven hundred thirty patients of breast cancer with BM treated at 17 institutions in Korea from 2000 to 2014 were analyzed. The median follow-up duration was 12 months. The analysis consisted of three cohorts: in cohort A, a total of 730 patients were included; in cohort B, 538 patients with available follow-up imaging after initial brain-directed treatment; and in cohort C, 54 patients receiving salvage WBRT due to recurrent BM after initial Stereotactic radiosurgery or WBRT. Overall survival (OS) was calculated from BM diagnosis in cohort A or from the last day of salvage WBRT in cohort C. Results: Median OS of cohort A was 15 months. In multivariate analysis, histologic grade 3, extracranial metastasis, number of BM >4, hormone receptor (HR) or HER2 negativity, and shorter time interval to diagnosis of BM were associated with inferior OS. Among 538 patients in cohort B, 201 showed subsequent development of new BM at a median of 11 months after stereotactic radiosurgery or WBRT for the management of initial BM (at 1 year, HR+/HER2- 51.9%, HER2+ 44.0%, and TNBC 69.6%, respectively; p=0.008). Upfront WBRT reduced subsequent development of new BM, which showed the significant difference among molecular subtypes (HR+/HER2-, 42% reduction at 1 year, p<0.001; HER2+, 18.5%, p=0.004; TNBC, 16.9%, p=0.071). Multivariate analysis of cohort B showed that shorter time interval to BM, TNBC subtype, extracranial systemic disease, number of BM >4, and involvement of both tentoria increased subsequent development of new BM. Anti-HER2 therapy for HER2+ patients and upfront WBRT significantly reduced risk of new BM. In cohort C, upfront WBRT prolonged the salvage WBRT-free duration (median 6.9 vs. 8.7 months, p=0.058). Median OS was 6.8 months after salvage WBRT. Longer interval to salvage WBRT, controlled primary tumor, high dose of salvage WBRT (BED10 >37.5 Gy), and systemic treatment after salvage WBRT showed better OS. Uncontrolled extracranial systemic disease and salvage WBRT due to local progression without distant intracranial failure showed worse OS. Conclusions: The rates of new BM showed the significant differences among molecular subtypes. Upfront WBRT decreased subsequent development of new BM and this effect was dependent on the molecular subtype as well. Anti-HER2 therapy for HER2+ patients significantly decreased the subsequent development of new BM. On salvage WBRT setting, the patients having high dose of salvage WBRT, stable extracranial systemic disease and subsequent systemic therapy showed better OS. Citation Format: Jae Sik Kim, Kyubo Kim, Wonguen Jung, Kyung Hwan Shin, Seock-Ah Im, Hee-Jun Kim, Yong Bae Kim, Jee Suk Chang, Jee Hyun Kim, Doo Ho Choi, Yeon Hee Park, Dae Yong Kim, Tae Hyun Kim, Byung Ock Choi, Sea-Won Lee, Suzy Kim, Jeanny Kwon, Ki Mun Kang, Woong-Ki Chung, Kyung Su Kim, Won Sup Yoon, Jin Hee Kim, Jihye Cha, Yoon Kyeong Oh, In Ah Kim. Multicenter study for brain metastasis from breast cancer in Korea: The significance of molecular subtype (KROG 1612) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-21-01.

Role of 23.4Gy upfront whole-brain radiation therapy following high-dose methotrexate for primary central nervous system lymphoma: a comparative analysis of whole-brain radiation therapy versus no radiation therapy.

We aimed to investigate the role of upfront whole-brain radiation therapy (RT), with a reduced dose of 23.4Gy, following high-dose methotrexate (HD-MTX) in patients with primary central nervous system lymphoma (PCNSL). We retrospectively reviewed 185 patients with PCNSL treated with HD-MTX between January 2013 and January 2020; 145 patients underwent no RT and 40 patients underwent upfront RT. Using propensity score matching (PSM) to adjust for clinical factors, 40 patients were selected from each treatment group. Event-free survival (EFS) and overall survival (OS) were compared between treatment groups. At baseline, patients in the upfront RT group were younger, had higher LDH levels, received less frequent rituximab and stem cell transplantation than those in the no-RT group. Patients in the upfront RT group also showed a lower response rate after initial HD-MTX than those in the no-RT group (73% vs. 88%, p = 0.038). The median follow-up was 25.1 (interquartile range 13.7-43.0) months. Comparable 2-year EFS and OS rates were observed between the upfront RT and no-RT groups (56.6% vs. 53.8%, p = 0.170; and 81.7% vs. 75.3%, p = 0.097, respectively). Upfront RT was related to improved EFS and OS in patients with stable disease or progressive disease after HD-MTX, but not in patients with complete or partial response after HD-MTX. Upfront RT was also an independent predictor of EFS and OS in the PSM cohort. The cumulative incidences of treatment-related neurotoxicity at 3years were 20.2% and 21.2% in the upfront RT and no-RT groups, respectively (p = 0.630). Upfront RT with a reduced dose of 23.4Gy, showed favorable outcomes in patients with stable disease or progressive disease after initial HD-MTX. In addition, upfront RT appears to be an effective treatment for PCNSL when rituximab or stem cell transplantation is not feasible.

Care Patterns for Stereotactic Radiosurgery in Small Cell Lung Cancer Brain Metastases

IntroductionThe historical standard of care for brain metastases (BMs) from small cell lung cancer (SCLC) has been whole-brain radiotherapy (WBRT). However, there is growing interest in upfront stereotactic radiosurgery (SRS) for select SCLC patients. Materials and MethodsWe invited United State-based Radiation Oncologists (ROs) via email to answer an anonymous survey using a branching logic system addressing their use of SRS and WBRT for SCLC BMs. Wilcoxon rank-sum test and Fisher's exact test were used to compare differences in continuous and categorical variables, respectively. Multivariable logistic regression analyses were fitted for outcome variables including covariates with P < .10 obtained on univariable analysis. ResultsIn total, 309 ROs completed the survey and 290 (95.7%) reported that they would consider SRS for SCLC BMs under certain clinical circumstances. Across patient characteristics, the number of BMs was the most heavily weighted factor (mean 4.3/5 in importance), followed by performance status, cognitive function, and response to prior therapy. Fewer BMs were correlated with increased SRS use (55.8% offered SRS “very frequently” [>75% of cases] or “often” [51%-75% of cases] for 1 BM vs. 1.1% for >10 BM, P < .001). In situations where WBRT was preferred, concern for rapid intracranial progression (45.3%) and lack of high-level data (36.9%) were the most important factors. The majority (60.6%) were aware of a large recent international retrospective analysis (the FIRE-SCLC study) reporting similar OS between upfront SRS and WBRT; awareness of this study was the only respondent variable predictive of SRS use for limited BMs (19.2% of those aware of the study preferring SRS for limited [≤4] BMs before vs. 61% preferring SRS after the publication, P < .001). The majority of respondents (88.2%) expressed a willingness to enroll patients on a recently opened recently opened randomized trial, NRG-CC009, comparing SRS versus hippocampal-avoidance WBRT. ConclusionsIn the first survey of SRS for SCLC BMs, we observed a high level of physician openness to upfront SRS in SCLC, particularly for patients with limited numbers of BMs, as well as significant interest in generating prospective randomized data to clarify the role of SRS in this population.

Multicenter study for brain metastasis from breast cancer in Korea: The significance of molecular subtype (Korean Radiation Oncology Group 1612).

e14008 Background: We analyzed the treatment outcome of breast cancer patients with brain metastases (BM) in Korea to identify the prognostic factors and the role of whole brain radiation therapy (WBRT). Methods: Seven hundred thirty patients of breast cancer with BM treated at 17 institutions in Korea from 2000 to 2014 were analyzed. The median follow-up duration was 12 months. The analysis consisted of three cohorts: in cohort A, a total of 730 patients were included; in cohort B, 538 patients with available follow-up imaging after initial brain-directed treatment; and in cohort C, 54 patients receiving salvage WBRT due to recurrent BM after initial Stereotactic radiosurgery or WBRT. Overall survival (OS) was calculated from BM diagnosis in cohort A or from the last day of salvage WBRT in cohort C. Results: Median OS of cohort A was 15 months. In multivariate analysis, histologic grade 3, extracranial metastasis, number of BM &gt; 4, hormone receptor (HR) or HER2 negativity, and shorter time interval to diagnosis of BM were associated with inferior OS. Among 538 patients in cohort B, 201 showed subsequent development of new BM at a median of 11 months after stereotactic radiosurgery or WBRT for the management of initial BM (at 1 year, HR+/HER2- 51.9%, HER2+ 44.0%, and TNBC 69.6%, respectively; p = 0.008). Upfront WBRT reduced subsequent development of new BM, which showed the significant difference among molecular subtypes (HR+/HER2-, 42% reduction at 1 year, p &lt; 0.001; HER2+, 18.5%, p = 0.004; TNBC, 16.9%, p = 0.071). Multivariate analysis showed that shorter time interval to BM, TNBC subtype, extracranial systemic disease, number of BM &gt; 4, and involvement of both tentoria increased subsequent development of new BM. Anti-HER2 therapy for HER2+ patients and upfront WBRT significantly reduced risk of new BM. In cohort C, upfront WBRT prolonged the salvage WBRT-free duration (median 6.9 vs. 8.7 months, p = 0.058). Median OS was 6.8 months after salvage WBRT. Longer interval to salvage WBRT, controlled primary tumor, high dose of salvage WBRT (BED10 &gt; 37.5 Gy), and systemic treatment after salvage WBRT showed better OS. Uncontrolled extracranial systemic disease and salvage WBRT due to local progression without distant intracranial failure showed worse OS. Conclusions: The rates of new BM showed the significant differences among molecular subtypes. Upfront WBRT decreased subsequent development of new BM and this effect was dependent on the molecular subtype as well. Anti-HER2 therapy for HER2+ patients significantly decreased the subsequent development of new BM. On salvage WBRT setting, the patients having high dose of salvage WBRT, stable extracranial systemic disease and subsequent systemic therapy showed better OS.

Quality-of-life trajectories after stereotactic radiosurgery for brain metastases.

Quality of life (QOL) is an important endpoint measure of cancer treatment. The authors' goal was to evaluate QOL trajectories and prognostic value in cancer patients treated with stereotactic radiosurgery (SRS) for brain metastases. Patients who underwent Gamma Knife radiosurgery (GKRS) between January 2016 and November 2019 were prospectively evaluated for QOL using the EQ-5D-3L questionnaire before SRS and at follow-up visits. Only patients who had pre-SRS and at least 1 post-SRS QOL assessment were considered. Fifty-four cancer patients underwent 109 GKRS procedures. The first post-SRS visit was at a median of 2.59 months (range 0.13-21.08 months), and the last post-SRS visit was at 14.72 months (range 2.52-45.21 months) after SRS. There was no statistically significant change in the EQ-5D index score (p = 0.539) at the first compared with last post-SRS visit. The proportion of patients reporting some problems on the EQ-5D dimension of self-care increased during the course of follow-up from 9% (pre-SRS visit) to 18% (last post-SRS visit; p = 0.03). The proportion of patients reporting problems on the EQ-5D dimensions of mobility, usual activities, pain/discomfort, and anxiety/depression remained stable during the course of follow-up (p ≥ 0.106). After adjusting for clinical variables, a higher recursive partitioning analysis (RPA) class (i.e., worse prognostic category) was independently associated with greater odds for EQ-5D index score deterioration (p = 0.050). Upfront whole-brain radiation therapy predicted deterioration of the EQ-5D self-care (p = 0.03) and usual activities (p = 0.024) dimensions, while a greater number of lesions predicted deterioration of the EQ-5D anxiety/depression dimension (p = 0.008). A lower pre-SRS EQ-5D index was associated with shorter survival independently from clinical and demographic variables (OR 18.956, 95% CI 2.793-128.64; p = 0.003). QOL is largely preserved in brain metastasis patients treated with SRS. Higher RPA class, upfront whole-brain radiation therapy, and greater intracranial disease burden are independent predictors of post-SRS QOL deterioration. Worse pre-SRS QOL predicts shorter survival. Assessment of QOL is recommended in brain metastasis patients managed with SRS.

Induction bevacizumab, etoposide and cisplatin followed by whole brain radiotherapy (WBRT) versus WBRT alone in breast cancer with untreated brain metastases: Results of a randomized phase II A-PLUS trial.

1082 Background: Our previous study ( Clin Cancer Res. 2015;21(8):1851) demonstrated that bevacizumab preconditioning followed by etoposide and cisplatin (BEEP) is a highly effective treatment for breast cancer (BC) patients (pts) with brain metastases (BM) progressing from WBRT. We conducted a randomized phase II study A-PLUS (NCT02185352) to test whether using BEEP as an induction therapy could enhance the efficacy of WBRT and provide systemic control. Methods: BC pts with measurable BM not suitable for surgery/radiosurgery and had not received WBRT were randomized (2:1) to experimental arm: induction BEEP for 3 cycles (~2 months [ms]) followed by WBRT or control arm: upfront WBRT. The BEEP regimen consists of bevacizumab 15 mg/kg on day 1, and etoposide 70 mg/m2/day on days 2-4, cisplatin 70 mg/m2 on day 2, followed by prophylaxis GCSF, every 21 days. After WBRT in both arms, pts received treatment of physician’s choice except BEEP until BM progression. Stratification was based on the Graded Prognostic Assessment score. Primary endpoint was brain-specific progression free survival (BS-PFS) based on RECIST 1.1, with a total of 108 pts, power of 0.8 at the 2-sided α level of 0.2. Results: Of 112 enrolled pts, 74 were in experimental arm and 38 in control arm. Baseline patient characteristics were generally balanced between arms. With median follow up of 28.7 ms, median BS-PFS was 8.1 vs. 6.5 ms ( p= 0.146; HR 0.71 [95% CI 0.44-1.13]), which met the primary endpoint (pre-defined α level of 0.2). Results of preplanned analysis included: 2-month brain-specific objective response rate of BEEP alone vs. WBRT was 41.9% vs. 52.6% ( p= 0.613); 8-month BS-PFS rate was 48.7% vs. 26.3% ( p= 0.027); median PFS was 6.4 vs. 4.7 ms ( p= 0.071; HR 0.67 [95% CI 0.43-1.04]), and extra-BM PFS was 7.9 vs. 5.0 ms ( p= 0.141; HR 0.71 [95% CI 0.46-1.12]). Median overall survival was 15.6 vs. 13.6 ms ( p= 0.855; HR 0.96 [95% CI 0.59-1.55]), with 31.6% of pts in control arm received BEEP regimen treatment after BM progression. The most common all-grade adverse events (AEs) in experimental arm were neutropenia (30.2%), nausea (27.9%), anemia (27.4%), and leukopenia (24.2%). Most AEs were mild to moderate in severity. Two pts discontinued BEEP treatment due to grade 4 nephrotoxicity and grade 3 infection, respectively. Conclusions: BEEP as induction treatment followed by WBRT for BC pts with BM may improve control of both BM and systemic disease. Further validation by a phase III study is necessary. Clinical trial information: NCT02185352 .

Outcomes according to initial and subsequent therapies following intracranial progression in patients with EGFR-mutant lung cancer and brain metastasis.

In patients with epidermal growth factor receptor (EGFR)-mutant non–small-cell lung cancer (NSCLC) with brain metastases, it remains controversial whether the use of EGFR-tyrosine kinase inhibitor (TKI) alone without radiotherapy (RT) is an optimal approach. Here, we investigated the clinical outcomes according to the use of upfront RT as well as the subsequent therapy following intracranial progression. This single-centre retrospective study included a total of 173 patients who were treated with EGFR-TKI alone (TKI alone group) or with upfront whole-brain RT (WBRT) or stereotactic radiosurgery (SRS) followed by EGFR-TKI (RT plus TKI group). Clinical outcomes according to initial and subsequent therapies following intracranial progression were analysed. There was no significant difference in OS according to the use of upfront RT (TKI alone group, 24.5 months vs. WBRT group, 20.0 months vs. SRS group, 17.8 months; P = 0.186). Intracranial progression was found in 35 (32.7%) of 107 patients in the TKI alone group. Among them, 19 patients who received salvage RT had the better prognosis than others [median overall survival (OS); 28.6 vs. 11.2 months; P = 0.041]. In the RT plus TKI group, 12 (18.1%) of the 66 patients experienced intracranial progression and 3 of them received salvage RT (median OS; 37.4 vs. 20.0 months; P = 0.044). In multivariate analysis, upfront WBRT was associated with trends towards a lower probability of intracranial progression, whereas upfront SRS was found to be an independent risk factor for poor OS. In conclusion, using EGFR-TKI alone for brain metastasis in EGFR-mutant lung cancer patients showed outcomes comparable to those using upfront RT followed by EGFR-TKI. Patients who could not receive salvage RT following intracranial progression had the worst survival regardless of the type of initial treatment.

131P - Upfront whole brain radiotherapy for multiple brain metastases in patients with EGFR-mutant lung adenocarcinoma

Purpose: This study aimed to evaluate the efficacy of upfront whole-brain radiotherapy (WBRT) in EGFR-mutant lung adenocarcinoma patients with multiple brain metastases (BM). Methods: In this study, 195 patients with EGFR mutations who had multiple BM at preliminary diagnosis were included and retrospectively reviewed. Patients were admitted to receive the following treatments in a multi-disciplinary setting: upfront WBRT followed by EGFR-TKI, concurrent EGFR-TKI and WBRT and upfront EGFR-TKI followed by WBRT. A disease-specific graded prognostic assessment (DS-GPA) was performed for all the patients. The treatment response and overall survival (OS) were assessed as well. Results: The median OS of these patients was 27 months. Objective response rate (ORR) was significantly better in upfront WBRT group than other two groups (P=0.004). Moreover, patients who received upfront WBRT (n=67) had longer OS than the concomitant group (36 vs 25 months; P=0.006) and the upfront EGFR-TKI group (36 vs 25 months; P<0.0001). The prognosis of patients with different DS-GPA scores significantly differed (P<0.0001). In concomitant group and upfront EGFR-TKIs group, patients with higher DS-GPA scores of 2-3 had more favorable prognosis compared with those with lower DS-GPA scores of 0-1.5 (27 vs 25 months; P=0.023). Patients who received EGFR-TKIs concurrently with WBRT had longer OS than those received upfront EGFR-TKIs with high DS-GPA scores. (37 vs 17 months; P=0.023). Conclusion: The use of upfront WBRT for EGFR-mutated lung adenocarcinoma patients with multiple BM can improve ORR and OS. More importantly, patients with high DS-GPA scores are recommended to receive WBRT immediately after EGFR-TKIs therapy.

Upfront whole brain radiotherapy for multiple brain metastases in patients with EGFR-mutant lung adenocarcinoma.

Purpose: This study aimed to evaluate the efficacy of upfront whole-brain radiotherapy (WBRT) in EGFR-mutant lung adenocarcinoma patients with multiple brain metastases (BM).Methods: In this study, 195 patients with EGFR mutations who had multiple BM at preliminary diagnosis were included and retrospectively reviewed. Patients were admitted to receive the following treatments in a multi-disciplinary setting: upfront WBRT followed by EGFR-TKI, concurrent EGFR-TKI and WBRT and upfront EGFR-TKI followed by WBRT. A disease-specific graded prognostic assessment (DS-GPA) was performed for all the patients. The treatment response and overall survival (OS) were assessed as well.Results: The median OS of these patients was 27 months. Objective response rate (ORR) was significantly better in upfront WBRT group than other two groups (P=0.004). Moreover, patients who received upfront WBRT (n=67) had longer OS than the concomitant group (36 vs 25 months; P=0.006) and the upfront EGFR-TKI group (36 vs 25 months; P<0.0001). The prognosis of patients with different DS-GPA scores significantly differed (P<0.0001). In concomitant group and upfront EGFR-TKIs group, patients with higher DS-GPA scores of 2–3 had more favorable prognosis compared with those with lower DS-GPA scores of 0–1.5 (27 vs 25 months; P=0.023). Patients who received EGFR-TKIs concurrently with WBRT had longer OS than those received upfront EGFR-TKIs with high DS-GPA scores. (37 vs 17 months; P=0.023).Conclusion: The use of upfront WBRT for EGFR-mutated lung adenocarcinoma patients with multiple BM can improve ORR and OS. More importantly, patients with high DS-GPA scores are recommended to receive WBRT immediately after EGFR-TKIs therapy.

Stereotactic radiosurgery for brain metastases from newly diagnosed small cell lung cancer: practice patterns and outcomes

Background: Up-front stereotactic radiosurgery (SRS) has been historically thought of as inadequate for brain metastases (BM) from newly diagnosed small cell lung cancer (SCLC). This study evaluates national practice patterns and clinical outcomes for BM from SCLC.Material and methods: The National Cancer Database was queried (2004–2013) for patients with newly diagnosed metastatic SCLC receiving intracranial radiotherapy. Patients were grouped into three categories: upfront SRS, whole-brain radiotherapy (WBRT) alone, or WBRT with boost (SRS or fractionated radiotherapy). Statistics included temporal trend assessment by annual percent change (APC), logistic regression, exploratory Kaplan–Meier overall survival (OS) analysis without and with propensity matching, and Cox proportional hazards modeling.Results: A total of 14,722 patients met selection criteria, of whom 487 (3.3%), 13,657 (92.8%), and 578 (3.9%) received upfront SRS, WBRT and WBRT with boost, respectively. Utilization of SRS showed a slight increasing trend from 2004 to 2013 (2.7–4.3%). In addition to socioeconomic factors, other variables associated with SRS use included diagnosis after 2010, treatment at academic centers, and residing in higher-educated regions. SRS was less often delivered to patients with node-positive disease (p < .05). On exploratory analysis, SRS cohort was observed to have a higher overall survival (OS) than WBRT-based groups (p < .001), namely in patients without extracranial metastases.Conclusions: Utilization of up-front SRS for SCLC BM has been increasing over time but is driven by socioeconomic disparities. Although there are likely numerous biases associated with the OS findings herein, further research is needed to validate this finding as well as the role of SRS on patients with brain metastases due to SCLC.

Upfront Cranial Radiotherapy vs. EGFR Tyrosine Kinase Inhibitors Alone for the Treatment of Brain Metastases From Non-small-cell Lung Cancer: A Meta-Analysis of 1465 Patients.

Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is revolutionizing the management of brain metastases (BMs). This study was to explore the value of upfront cranial radiotherapy (RT) in EGFR-mutated non-small cell lung cancer (NSCLC) with BMs compared with EGFR-TKIs alone.Methods: We searched all topic-related comparative articles in public databases (MEDLINE, EMBASE, Cochrane Library, and Web of Science) and conference proceedings. Outcomes of interest were intracranial objective response rate (ORR), overall survival (OS), and intracranial progression-free survival (PFS). Statistical analyses were calculated using Review Manager 5.3 software.Results: Thirteen comparative studies that included a total of 1,456 patients were eligible. Upfront brain RT had significantly higher OS (HR = 0.78, 95% CI = 0.65–0.93, P = 0.005) than EGFR-TKI alone. Upfront RT plus TKI had superior OS (HR = 0.71, 95% CI = 0.58–0.86, P = 0.0005) and intracranial PFS (HR = 0.69, 95% CI = 0.49–0.99, P = 0.04). The pooled data favored upfront whole brain RT (WBRT) plus TKI in terms of intracranial PFS (HR = 0.64, 95% CI = 0.48–0.85, P = 0.002) and OS (HR = 0.75, 95% CI = 0.57–1, P = 0.05). Upfront stereotactic radiosurgery (SRS) was associated with better OS (HR = 0.37, 95% CI = 0.26–0.54, P < 0.00001). Similar results were observed when analysis was restricted to the use of erlotinib or geftinib.Conclusions: The upfront use of brain RT seemed critical, especially for SRS. Upfront administration of upfront WBRT plus EGFR-TKI had better survival outcomes and seemed superior to EGFR-TKI alone.

Stereotactic Radiosurgery for Brain Metastases of Small Cell Lung Cancer at Diagnosis: Local Management Patterns

Retrospective reports have suggested up-front stereotactic radiosurgery (SRS) to be a potentially effective treatment option for brain metastases (BM) from small cell lung cancer (SCLC). However, due to the likelihood of multiple microscopic intracranial metastases and distant brain failure, SRS has not typically been deemed to be an appropriate stand-alone treatment for these patients, as it is in patients with BM due to non-small cell lung cancer. The purpose of the present study is to evaluate national practice patterns and clinical outcomes for SCLC patients with BM receiving up front SRS. The National Cancer Data Base was queried (2004-2013) for patients with metastatic SCLC receiving intracranial radiotherapy for management of BM. Patients were grouped into categories based on the radiation treatment selected for the brain: upfront SRS, whole-brain radiotherapy(WBRT) or WBRT with concomitant boost (SRS or fractionated radiotherapy). Univariable and multivariable logistic regression were performed to evaluate factors associated with SRS administration. Temporal trends were analyzed graphically. Survival was analyzed with the Kaplan-Meier method and Cox proportional hazards modeling was used to evaluate predictors of overall survival (OS). To account for indication bias, survival analysis was repeated following and propensity score matching. A total of 14,722 patients met the selection criteria, of whom 487 (3.3%), 13,657 (92.8%) and 578 (3.9%) received upfront SRS, WBRT and WBRT with boost, respectively. The utilization of upfront SRS showed a slight increase from 2004 to 2013 (2.7% to 4.3%). Diagnosis in more recent time periods (2011-2013) was predictive of SRS use (p=0.004). Other socioeconomic factors associated with upfront SRS use included receiving therapy at academic centers and residing in higher-educated regions. SRS was less likely to be used in patients with node positive disease (p<0.05). The upfront SRS cohort was found to have a higher overall survival (OS) than WBRT-based groups before and after propensity matching (p<0.001). Younger patients, female gender, Charlson Deyo Score of 0, treatment at an academic center, higher-income, private insurance, recent years at diagnosis, early T stage, node negative disease and receipt of chemotherapy independently predicted for higher OS. This NCDB analysis demonstrates that utilization of upfront SRS for SCLC BMs has been increasing over time. Socioeconomic disparities exist with regards to SRS utilization. Use of SRS was associated with improved OS, though this could partially be due to selection bias. Further research is required to further elucidate the role of SRS in BMs due to SCLC.

23 Long-term survivors of brain metastases

Purpose: We identified key clinicopathologic features of brain metastasis (BM) patients who are long-term survivors (LTS). Methods: We screened a prospective database of 1892 patients (treated 2006-2017), identified 92 (5%) who lived &gt; 3 years following BM diagnosis, and performed per patient analyses. Results: Median age at diagnosis of BM was 57 years (range 19-77), 77% were women. The most common tumors were lung (50%), breast (26%), thyroid (7%) and skin (5%). 42% had tumors with drug-targetable oncoproteins (e.g. EGFR mutant) and 15% expressed hormonal receptors. ECOG was &lt;2 in 70%. 47% had stage IV disease at diagnosis (75% with brain as the first site). 55% had controlled extracranial disease at the time of BM diagnosis. Median BM diameter was 1.5 cm (range 0.2-7) and 62% had a single lesion. Treatment was with surgery, radiosurgery, whole brain radiation (WBRT), or systemic therapy alone in 38%, 62%, 52%, and 4%, respectively. 53% received targeted- or immuno-therapy. Median follow up was 63 months (range 36-113). 61% failed intracranially at a median 24 months (range 1-99). 5 and 10- year survival (from BM diagnosis) was 82%, and 34%, respectively. Neither upfront WBRT nor other variables tested correlated with improved survival. In patients who died, an MRI was available within 3 months from death in 57%; of those 55% had no active intracranial disease, suggesting that the majority of deaths were non-neurologic. Conclusion: In general, LTS of BM had a limited number of BM, inactive extracranial disease, and drug targetable mutations.

Cost-effectiveness Analysis of Stereotactic Radiosurgery Alone Versus Stereotactic Radiosurgery with Upfront Whole Brain Radiation Therapy for Brain Metastases

AimsStereotactic radiosurgery (SRS) alone or upfront whole brain radiation therapy (WBRT) plus SRS are the most commonly used treatment options for one to three brain oligometastases. The most recent randomised clinical trial result comparing SRS alone with upfront WBRT plus SRS (NCCTG N0574) has favoured SRS alone for neurocognitive function, whereas treatment options remain controversial in terms of cognitive decline and local control. The aim of this study was to conduct a cost-effectiveness analysis of these two competing treatments. Materials and methodsA Markov model was constructed for patients treated with SRS alone or SRS plus upfront WBRT based on largely randomised clinical trials. Costs were based on 2016 Medicare reimbursement. Strategies were compared using the incremental cost-effectiveness ratio (ICER) and effectiveness was measured in quality-adjusted life years (QALYs). One-way and probabilistic sensitivity analyses were carried out. Strategies were evaluated from the healthcare payer's perspective with a willingness-to-pay threshold of $100 000 per QALY gained. ResultsIn the base case analysis, the median survival was 9 months for both arms. SRS alone resulted in an ICER of $9917 per QALY gained. In one-way sensitivity analyses, results were most sensitive to variation in cognitive decline rates for both groups and median survival rates, but the SRS alone remained cost-effective for most parameter ranges. ConclusionsBased on the current available evidence, SRS alone was found to be cost-effective for patients with one to three brain metastases compared with upfront WBRT plus SRS.